Potential of guggulsterone, a farnesoid X receptor antagonist, in the prevention and treatment of cancer.

Introduction

Cancer is one of the most life-threatening diseases of the present century, which consists of over 277 different types [ 1 ]. According to GLOBOCAN 2018, cancer has a very high rate of occurrence with a mortality of around 9.6 million per year globally [ 2 – 6 ]. It is now well-established that the alterations of various vital genes and proteins drive the transformation of normal cells to cancer phenotypes, which ultimately lead to cancer [ 1 , 7 – 16 ]. Besides, many factors contribute to the pathogenesis of cancer, including elevated metabolic requirements that lead to the upregulation of enzymes required for the synthesis of fatty acids and modulation of several signaling pathways [ 17 , 18 ]. These molecular alterations are caused by various factors such as an imbalanced diet, physical inactivity, pollution, and consumption of addictive substances such as tobacco and alcohol [ 4 , 19 ]. The past couple of decades have evidenced substantial improvements in conventional methods for the treatment of cancer, such as surgery, radiation, and chemotherapy [ 20 – 23 ]. In addition, novel therapeutic modalities have emerged for the treatment of this disease such as immunotherapy, gene therapy, targeted therapy, personalized medicine, and nano vaccines [ 24 – 29 ].

Regardless of the advancement, the treatment approaches have not shown significant improvement in terms of survival and quality of life (QOL) of cancer patients due to several factors such as chemoresistance, radioresistance, adverse side effects of drugs, and cancer recurrence [ 30 – 34 ]. Further, the majority of the drugs used in conventional methods target a single protein or pathway, which induce several survival signals that restrict their efficacy. Therefore, the development of alternative therapy is required for improving the survival and QOL of cancer patients. This drives the urge to develop safe, efficacious, affordable, and multi-targeted agents for the management of this disease [ 4 , 9 , 35 – 38 ].

Accumulating pieces of evidence, since the rise of human civilization, suggest that medicinal plants have gained colossal importance in different traditional medicinal systems such as Ayurveda, Siddha, Unani, and Traditional Chinese Medicine (TCM) owing to their limitless properties in disease prevention and treatment [ 5 , 39 – 42 ]. Studies have also advocated the immense biological properties of compounds isolated from these plants as potential candidates against various fatal diseases, including cancer [ 43 – 56 ]. Guggulsterone (GS) is one of those naturally derived multi–targeted compounds that have exhibited massive therapeutic potential against cancer. Therefore, the current review summarizes its prospects in the prevention and treatment of cancer.

GS is a sterol compound derived from the gum resins of the guggul plant Commiphora wightii ( C. wightii ) that belongs to the family of Burseraceae [ 57 , 58 ]. C. wightii is commonly found in Somalia, Northeast Africa, Southern Arab countries, and countries of Southeast Asia such as India, Bangladesh, and Pakistan [ 59 – 61 ]. In India, C. wightii is mostly distributed in the States of Maharashtra, Gujarat, Rajasthan, and Karnataka; however, the States of Rajasthan and Gujarat form the commercial centers of this gum [ 59 ]. Before being justified with its present name as C. wightii by Bhandari, it was named as C. mukul or Blasmodendron mukul and then as C. roxburghii [ 62 ]. The oleogum resin of this plant is commonly known as guggul (in Hindi), guggulu (in Sanskrit), gukkulu and maishakshi (in Tamil), and Indian bdellium (in English) [ 59 ]. The therapeutic benefits of C. wightii have been reported in the treatment of various diseases including tumors, malignant sores, ulcers, obesity, and liver and intestinal problems; hence, it has been widely used in Ayurveda for thousands of years [ 57 ]. Besides, GS has also gained importance due to its chemopreventive and therapeutic properties against various cancers and their hallmarks [ 63 , 64 ]. This plant metabolite was first recognized as an antagonist for the nuclear receptor, farnesoid X receptor (FXR) [ 57 ]. The later studies revealed that it could also target the receptors of mineralocorticoid, glucocorticoid, androgen and estrogen [ 60 ]. Subsequently, the underlying mechanism behind GS-mediated hypolipidemic effect was identified. GS was found to decrease FXR activity and increase bile salt export pump, a transporter that regulates bile efflux [ 60 ]. Further, this sterol was also found to modulate the expression of several proteins such as cyclin D1, c-Myc, matrix metalloproteinase (MMP)-9, cyclooxygenase 2 (COX-2), and vascular endothelial growth factor (VEGF); and anti-apoptotic proteins such as inhibitor of apoptosis protein 1 (IAP1), X-linked inhibitor of apoptosis protein (XIAP), B-cell lymphoma 2 (Bcl-2), Bcl-2-related protein A1 (Bfl-1/A1), cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (cFLIP), and survivin in various cancer models [ 64 ]. GS has also shown to suppress tumor necrosis factor (TNF)-α, IkappaB kinase (IKK), IkappaB alpha (IκBα), nuclear factor kappa B (NF-κB) activation, and NF-κB regulated gene expression [ 64 , 65 ]. This compound was also reported to modulate other pathways like phosphoinositide 3-kinase (PI3K)-Akt, steroid receptor coactivator (Src)/focal adhesion kinase (FAK), Janus kinase (JAK)/signal transducers and activators of transcription (STAT) and their downstream molecules [ 66 , 67 ].

As mentioned, GS acts as an antagonist for FXR. Studies have reported that FXR helps in stabilizing the metabolism of bile acids and cholesterol and it is involved in the development of different diseases such as cardiovascular diseases and cancer [ 57 , 68 , 69 ]. Numerous lines of evidence also suggest that interruption of cholesterol homeostasis is one of the major events in cancer development as the failure in the sustenance of cholesterol synthesis through feedback inhibition results in high recruitment of cholesterol and its precursors in cancer cells [ 70 , 71 ]. Thus, GS, being an FXR antagonist, could be used as an effective regimen for the treatment of cancer. Therefore, through inhibition of FXR and modulation of several other genes and proteins, GS has shown promising effects in the prevention and treatment of different cancers.

Sources of GS

GS is the main component of guggulipid, which consists of a mixture of diterpenes, steroids, sterols, esters, and higher alcohols, extracted from the gum resin of the medicinal plant C. wightii [ 72 – 75 ]. The Z- and E-stereoisomers of GS represent the main active compound of the plant [ 76 ]. The plant gum resin also contains 0.4% essential oils that mainly include myrcene, long-chain aliphatic tetrols that are esterified at the primary-OH group with the ferulic acid [ 77 ].

Traditional uses of C. wightii

The importance of C. wightii has been mentioned in its ancient medicinal writings of Ayurveda. The Sushruta Samhita explains the use of this plant and its gum resin against various diseases [ 58 ]. These medicinal writings mention the oral consumption of guggul can be used to heal conditions such as internal tumors and malignant sores, intestinal worms, liver dysfunction, edema, and to treat inflammatory diseases, gynaecological diseases, and obesity [ 78 , 79 ]. C. wightii is one of the common ancient medicinal plants, that is taken to improve heart condition, vascular health, wound healing, and to treat vitiligo in Ayurveda [ 80 , 81 ]. Further, the gum resin of C. wightii finds its use in TCM for the treatment of arthritis, trauma, and other blood-related diseases [ 78 ]. The guggul is also used in Yunani medicine for treating nervous diseases, scrofulous infections, urinary disorders, and skin diseases. It is also locally applied as a paste in hemorrhoids, incipient abscesses, and ulcers [ 82 ].

Biological properties of C. wightii

It is already well established that the gum resin of C. wightii has been used traditionally for centuries against various chronic diseases like arthritis, obesity, diabetes and cardiovascular diseases ( Figure 1 ) [ 83 ]. Recent studies have reported that the resin extracts from C. wightii lower the levels of low-density lipoprotein (LDL) and cholesterol in different experimental settings [ 58 , 84 , 85 ]. The C. wightii was shown to decrease LDL, very-low-density lipoprotein (VLDL), and cholesterol and increase high-density lipoprotein (HDL). It was also shown to reduce high fat-induced obesity in rat models [ 86 ]. Additionally, C. wightii was reported to improve oxidative stress, inflammation, edema, and necrosis in an ischemic rat model, thereby displaying its cardioprotective effects [ 80 ]. In another study, C. wightii was also shown to prevent lipid layer damage by inhibiting lipid peroxidation [ 87 ]. Further, this plant was shown to inhibit diabetes by decreasing the expression of aspartate aminotransferase, alanine aminotransferase, and oxidative markers, i.e. lipid peroxidation and protein oxidation; and inducing nuclear receptors such as peroxisome proliferator-activated receptor alpha (PPARα), peroxisome proliferator-activated receptor-gamma (PPARγ) and liver X receptor [ 88 , 89 ]. Besides, another constituent, dehydroabietic acid, from Commiphora sp. was found to enhance the diabetic wound healing via reversing TNF-α-induced activation of forkhead box protein O1 (FOXO1) and the transforming growth factor β (TGF-β)1/Smad3 signaling [ 90 ].

Further, guggulipid could act as an antinociceptive agent by reducing neural responses and hyperalgesic activities in an in vivo model of neuropathic pain [ 91 ]. Studies have also advocated the neuroprotective properties of C. wightii by modulating various markers of oxidative stress such as thiobarbituric acid reactive substances, nitric oxide (NO), TNF-α, glutathione (GSH), superoxide dismutase (SOD), and catalase levels [ 92 ], thus indicating its potential against neuroinflammation-related disorders [ 93 ]. The anticancer property of C. wightii has also been highlighted in several studies where it was found to inhibit cancer cell proliferation by inducing cell cycle arrest and apoptosis in prostate cancer (PC) cells [ 94 , 95 ]. Similar anticancer activities were also reported by different compounds isolated from C. wightii in various cancers such as breast cancer, lung cancer, colon cancer, and melanoma [ 96 ]. Furthermore, C. wightii was shown to induce anti-bacterial properties by inhibiting the growth of gram-positive and gram-negative bacteria [ 97 ]. Additional findings also suggest the use of this plant and its extracts against gastric ulcer, skin injury [ 98 ], dementia [ 99 ], arthritic inflammation [ 100 ], and blood clots [ 101 ].

Chemical nature of GS

GS, also known as 4, 17(20)-pregnadiene-3, 16-dione (C 21 H 28 O 2 ), is the key component of the guggulu resin from C. wightii , which exists in E- and Z-isomers ( Figure 2 ) and are represented as its cis - and trans -forms respectively [ 72 , 77 , 102 , 103 ]. These E- and Z-GS are steroidal isomers and are inter-convertible in 3D space. They differ in the arrangement of CH3 molecule at C20 position and a distorted rotation of C-C double bond present at C17 and C20 positions is observed [ 104 ].

Molecular targets of GS

The multi-targeted compound, GS, is basically identified as an FXR inhibitor. FXR is a nuclear hormone receptor that regulates bile acid production and transport [ 79 ]. This protein might also plausibly regulate apoptosis in the cancer cells [ 105 ]. The activation of FXR is known to promote TGF-β-induced epithelial-mesenchymal transition (EMT), which is a hallmark of cancer [ 106 ]. FXR has also been identified as a marker of breast cancer-associated bone metastasis, and Z-GS has been found to efficiently inhibit FXR and its target associated bone proteins such as osteopontin, osteocalcin, and bone sialoprotein [ 107 ]. Besides FXR, GS is also known to alter the expression of various proteins in the cell and thus regulate different cellular processes such as cell growth, cell metabolism, cell survival, invasion, EMT and metastasis. Numerous preclinical studies on different cancer models have reported the chemoprotective effect of GS via modulation of multiple factors that are involved in cell growth and proliferation: COX-2, receptor activator of nuclear factor-κB ligand (RANKL); cell cycle proteins: c-Myc, cyclin D, cdc2, p21, p27; VEGF, MMP-9; proteins contributing to EMT: N-cadherin, TGF-β; molecules involved in apoptosis: caspases, survivin, Bcl-2, IAP1, XIAP, Bfl-1/A1, Bcl-2-associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak); enzymes: IκBα kinase, Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1); markers involved in cell development: homeobox 2, caudal type homeobox 2 (CDX2) [ 65 , 94 , 106 , 108 – 122 ]. Most of these targets constitute the key components of the major pathways regulated by GS in cancer cells such as the NF-κB pathway [ 123 , 124 ]; the intrinsic mitochondrial apoptotic pathway [ 125 , 126 ]; the JAK/STAT pathway [ 67 ] and the STAT3 pathway [ 123 ]. GS also regulates other pathways like the Akt pathway [ 66 , 112 ]; the c-Jun N-terminal kinase (JNK) pathway [ 112 , 127 ]; the extracellular signal-regulated kinase (ERK) pathway [ 127 ]; steroid Src/FAK signaling [ 67 ]; β-catenin signaling [ 128 ]; and the mitogen-activated protein kinase (MAPK) pathway [ 124 ]. Further, the proteomic profiling of GS treated cancer cells have revealed that GS-induced downregulation of several factors such as proteins contributing to cell growth: methionine adenosyltransferase 2A (MAT2A) and U1 small nuclear ribonucleoprotein A (SNRPA); proteins involved in cell growth and migration: F-box only protein 2 (FBXO2), high mobility group box 3 (HMGB3), and Ras-related protein Rab-21; proteins contributing to tumorigenesis: caveolin-1, importin karyopherin subunit alpha 2 (KPNA2), and protein arginine N-methyltransferase 5 (PRMT5); proteins involved in purine metabolism: purine nucleoside phosphorylase (PNP); proteins involved in DNA replication: DNA replication licensing factor minichromosome maintenance complex component 3 (MCM3), and replication protein A 70 kDa DNA-binding subunit (RPA1); heat shock proteins (HSP): heme oxygenase-2 (HO-2), Hsp70 and Hsp27 [ 126 ]. GS also induced upregulation of annexin A7, which is involved in exocytosis/tumor suppression and the cytoskeletal protein, filamin B that regulates cell shape and migration [ 126 ]. In concordance with other studies, this study also demonstrated that GS-mediated suppression of colorectal cancer (CRC) involved modulation of the prime cellular pathway, the TNF-α/NF-κB signaling pathway [ 126 ]. GS is also known to induce reactive oxygen species (ROS)-dependent apoptosis in cancer cells via modulation of JNK [ 129 – 131 ]. Furthermore, 14-3-3 zeta, which is involved in cancer recurrence and therapeutic resistance, has also been identified as a molecular target of GS [ 132 , 133 ]. In addition, GS is also known to inhibit expression of P-glycoprotein (P-gp) in cancer cells, thereby chemosensitizing these cells to standard chemotherapeutic drugs [ 134 – 136 ]. For example, GS sensitized hepatocellular carcinoma (HCC) cells to doxorubicin (DOX) by modulation of COX-2/P-gp dependent pathway [ 137 ], MCF-7/DOX cells to DOX by reducing the levels of Bcl-2 and P-gp [ 138 ], gall bladder cancer cells to gemcitabine through suppression of NF-κB [ 139 ], and glioblastoma cells to sonic hedgehog inhibitor SANT-1 via inflection of Ras/NF-κB pathway [ 140 ]. Furthermore, the combination of GS with bexarotene decreased DOX resistance in breast cancer cells by stimulating the secretion of exosome-associated breast cancer resistance protein (BCRP) [ 141 ]. GS has also been reported to induce CCAAT/enhancer-binding protein homologous protein (CHOP)-dependent death receptor (DR)-5 expressions through modulation of ROS-dependent endoplasmic reticulum (ER)-stress, and thus sensitize liver cancer cells to TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis [ 142 ]. Thus, GS acts on a diverse range of molecular targets and prevent the development and progression of cancer ( Figure 3 ).

The tumor microenvironment (TME) comprises of cancer cells, cancer stem cells, immune cells, factors such as growth factors, cytokines, enzymes, chemotherapeutic drugs, the components of the extracellular matrix (ECM), fibroblasts, inflammatory cells, blood vessels, and signaling molecules [ 143 – 146 ]. These components regulate tumorigenesis and various associated processes, such as oxidative stress, EMT, metastasis and autophagy [ 147 – 153 ]. The TME is immunosuppressive; therefore, identification of new and effective compounds that would restore the immune response in tumor cells and inhibit the progression of tumors is critical for the prevention and treatment of cancer [ 154 , 155 ]. The natural compound, GS, plays a potential role in remodeling of TME by regulating oxidative stress, autophagy, and expression of ECM proteins. For instance, GS was reported to protect PC12 cells from hydrogen peroxide-induced oxidative stress by decreasing the levels of extracellular lactate dehydrogenase, NO and ROS, and preventing the loss of mitochondrial membrane potential (ΔΨm) [ 156 ]. The antioxidant activity of GS was further evinced through GS-induced reduction of plasma trimethylamine- N -oxide expression and stimulation of Nrf2/HO-1 signaling that protects the cells from ROS-induced oxidative stress [ 157 , 158 ]. GS, being an FXR antagonist, was also found to be involved in the regulation of autophagy [ 159 , 160 ]. This compound has also been reportedly associated with FXR-mediated differentiation of bone marrow stromal cells into osteoblasts or adipocytes [ 161 ]. A particular study also evinced GS-induced modulation of TME components like TGFβ-induced EMT markers and COX-2 in inflammatory cells [ 162 ]. Furthermore, GS was reported to regulate the survival and stimulation of hepatic stellate cells through the regulation of NF-κB and apoptosis [ 114 ]. Thus, GS shows efficacy in the regulation of TME remodeling and exerts a significant anticancer effect.

Biological activities of GS

Congregate evidence suggests that GS has enormous potential in the prevention and treatment of various chronic diseases in humans owing to its multi-targeted properties. These include Alzheimer’s disease, arthritis, asthma, cancer, dermatitis, diabetes, gingivitis, inflammatory bowel disease, infectious diseases, intestinal metaplasia, otitis media, respiratory diseases, pancreatitis and psoriasis [ 79 ]. However, in the current review, we focus on its anti-cancer properties.

Effect of GS in different cancers

Surfeit number of preclinical evidences unveiled the cancer chemopreventive and therapeutic properties of GS against a wide range of cancers, including cancers of the brain, breast, colon, head and neck, liver, pancreas and prostate, and hematological malignancies like leukemia and lymphoma.

These studies proved that GS has enormous potential for both the prevention and treatment of different cancers ( Table 1 ) and are briefly summarized below.

Brain cancer

Brain cancer consists of more than 120 types that cover 2% of the entire global cancer incidence. It can be defined as a primary and secondary tumor depending on its tumor development status, type of tissue, and nature of its malignancy [ 163 , 164 ]. Few studies reported that GS exhibited significant anticancer properties against brain cancer cells in preclinical settings. For example, GS was shown to decrease the expression of P-gp and increase the activity of P-gp ATPase dose-dependently in rat brain microvessel endothelial cells (rBMECs), thus overcoming the low accumulation of the drug and resistance in brain cancer [ 134 ]. Furthermore, GS reduced expression of Ras and NF-κB in glioblastoma cells resulting in the sensitization of these cells to SANT-1 (which is a Gli1 protein inhibitor). It also increased the expression of caspases-3 and -9, Bax, and cytochrome c, which ultimately leads to the intrinsic pathway of apoptosis [ 140 ].

Breast cancer

Breast cancer is the most commonly diagnosed cancer among females, and triple-negative breast cancer is the most aggressive form which is more frequently diagnosed in younger females with poor prognosis and a high recurrence rate [ 165 – 171 ]. Metastasis of breast cancer cells is common which is mostly seen in the bone, liver, lungs, and brain tissues [ 149 ] and contributes to an increased mortality rate due to this disease [ 146 ]. Several studies have well-documented the prospective of GS in inhibiting the growth of breast cancer. For example, a study showed that GS induced radiosensitization in breast cancer cells and reduced the growth of estrogen-positive tumors resistant to tamoxifen, through the suppression of NF-κB activation and IGF1-Rβ, and ERα [ 172 ]. Another study on the effect of GS isomers against breast cancer cells demonstrated that cis-GS repressed TPA-induced MMP expression by blocking IKK/NF-κB signaling, whereas trans-GS blocked the MAPK/AP-1 signaling. Moreover, the combination of these isomers exhibited an additive effect on the inhibition of invasion of MCF-7 cells [ 117 ]. Besides, the treatment of monocytes with GS reduced RANKL-activated NF-κB activation, which correlated with inhibition of IKK and phosphorylation and degradation of IκBα. In addition, GS also suppressed the differentiation of monocytes to osteoclasts that were induced by co-incubating breast cancer cells, MDA-MB-468, or human multiple myeloma cells, U266 with monocytes [ 116 ]. A study conducted by Silva et al. [ 173 ], revealed that the release of deoxycholate from osteoblast-like cells, MG63 and bone tissues trigger the survival and migration of metastatic breast cancer cells, MDA-MB231, which was inhibited upon treatment with GS through the induction of apoptosis and modulation of the expression of urokinase-type plasminogen activator (uPA).

Further, the guggulipid that contains GS has shown immense potential in the reduction of breast cancer cell growth and stimulation of apoptosis through the induction of cytoplasmic histone-associated DNA fragmentation, activation of caspase-3, and suppression of T-cell factor 4 and Wnt/β-Catenin pathway via suppression of its targets proteins such as cyclin D1, c-Myc, and survivin [ 128 ]. Additionally, the combined treatment of GS and DOX increased the sensitivity of the MCF-7/DOX cells to DOX by increasing the population of the apoptotic cells compared to DOX. This effect was plausibly mediated via the suppression of multi-drug resistance (MDR) protein, MRP1 [ 174 ]. Further, the combination of GS and DOX also inhibited tumor growth in BALB/c mice model by suppressing the expression of Bcl-2 and P-gp [ 138 ]. Similarly, the combination of GS and bexarotene increased DOX retention in breast cancer cells and enhanced cell death through increased secretion of exosome-associated BCRP/ABCG2 and reduced MDR levels [ 141 ].

CRC

CRC is the third most common cancer occurring globally [ 175 , 176 ]. Copious investigations have found the enormous potential of GS in combating this disease. For example, An et al. [ 72 ], found that treatment of HT29 colon cancer cells with GS elevated apoptosis by activating caspases-3 and -8. It has also been reported that GS increased the expression of truncated BH3 interacting domain death agonist (Bid), Fas, p-JNK, and p-c-Jun levels in vitro and decreased the expression of cIAP-1, cIAP-2, and Bcl-2, and suppressed tumor growth in an in vivo mouse model. Further, GS induced apoptosome and apoptosis in HCT 116 colon cancer cells via activation of caspase-3/7, through modulating the expression of Bcl-2, and releasing cytochrome c from mitochondria. The same study also showed that GS increased the levels of p53, and suppressed the expression of NF-κB and its regulated molecules, survivin, Bcl-2, and cIAP-1 [ 126 ]. Moreover, GS suppressed viability, angiogenesis, and metastasis of colon cancer cells by inhibiting the expression of VEGF, aryl hydrocarbon receptor nuclear translocator (ARNT), STAT3 proteins, and the activity of MMP-2 and -9 [ 110 ]. Besides, GS also increased the radiation sensitivity of colon cancer cells through the suppression of IGF1-Rβ and NF-κB [ 172 ]. Contrasting to other studies, Peng et al. [ 177 ], reported that over-expression of FXR suppressed the proliferation of H508, SNU-C4, and HT-29 colon cancer cells, whereas the inhibition of FXR by GS resulted in increased proliferation of the colon cancer cells through the upregulation of Src, EGFR, and ERK-1/2.

Esophageal cancer (EC)

EC ranks eighth among all cancers globally and it is the sixth most common cause of cancer-related mortality with a 5-year survival rate of 15–25%. It originates in the GE junction and cardia and represents two major histological subtypes, i.e. esophageal squamous cell carcinoma and esophageal adenocarcinoma (EAC) [ 178 ]. Many studies have proven the efficacy of GS against EC. It was reported that overexpression of FXR in EAC is linked with increased tumor grade, tumor size, and high lymph node metastasis and inverse expression of retinoic acid receptor-β2 (RAR-β 2 ), therefore knockdown of FXR yielded in decreased cell growth in vitro and decreased tumor size in the mouse model. This study suggests that GS holds enormous potential in the treatment of EC through the reduction of cell viability and induction of apoptosis via FXR suppression [ 179 ]. Similarly, the treatment of FXR overexpressed Barrett’s esophagus (BE)-derived cells with GS induced caspase-3 activity and resulted in apoptosis [ 105 ]. Further, GS treatment blocked IκBα phosphorylation induced by deoxycholic acid and decreased CDX2, COX-2, and prostaglandin E2 (PGE2) expressions in EAC cells, and also caused increased sub-G1 phase apoptosis in BE and EAC cells [ 115 ]. Besides, GS in combination with amiloride suppressed the viability of EC cells, induced apoptosis, and inhibited tumor growth in a mouse model [ 180 ].

Head and neck cancer (HNC)

HNC includes a range of cancers among which more than 90% is represented by head and neck squamous cell carcinoma (HNSCC) [ 181 – 187 ]. HNSCC has a widespread global incidence rate with poor prognosis and a 50% occurrence in the oropharynx region mostly observed in the palatine tonsil and bottom of the tongue [ 188 ]. Several studies have demonstrated the potential of GS in inhibiting HNC. For instance, the SCC4 cells treated with GS were found to exhibit apoptosis via decreased expression of cyclin D1, phosphorylated Bcl-2-associated death promoter (BAD), XIAP, myeloid cell leukemia 1 (Mcl-1), c-Myc, and survivin, and increased expression of p21 and p27, Bax/Bcl2 ratio, caspases-9, -3, -8 and Fas/CD95 proteins [ 133 ]. Further, the pre-treatment of HNC cells with GS resulted in inhibition of smokeless tobacco/nicotine-induced expression of PI3K, phosphoinositide-dependent kinase-1 (PDK1), Akt, Raf, Glycogen synthase kinase 3 beta (GSK3β), and pS6, thereby blocking the PI3K/Akt pathway. It also suppressed Akt-associated Bax and BAD phosphorylation in HNC cells [ 66 ]. Similarly, in another study, GS was shown to suppress NF-κB and pSTAT3 and their target proteins COX-2 and VEGF, and also reduced the expression of phosphorylated IκBα and IL-6, induced by smokeless tobacco/nicotine in HNC cells [ 123 ]. Further, GS inhibited the growth of HNC cells by decreasing the expression of STAT3 [ 109 ]. The inhibition of STAT3 by GS was enhanced when combined with erlotinib or cetuximab in vitro and in vivo . Besides, GS also reduced the invasion of HNC cells by suppressing the expression of HIF-1α [ 108 ]. Additionally, it was also shown that the proteasome inhibitor bortezomib causes an increase in total STAT3, pSTAT3, and cellular STAT3 levels in HNC cells and the combined treatment of GS (natural STAT3 inhibitor) with bortezomib could induce synergistic death of cancer cells [ 189 ].

HCC

HCC or liver cancer is one of the highest occurring malignancies in the world [ 2 , 53 , 190 – 197 ]. Despite the advancement in therapeutic strategies, there is a lack of efficacious and non-toxic drugs for the treatment of HCC. In pursuit of alternative medicine for the treatment of HCC, GS was investigated in several studies. For instance, treatment with GS significantly reduced the proliferation, induced G0/G1 phase arrest and apoptosis in HepG2 cells via regulating the expression of Bax, Bcl-2, TGF-β1, TNF-α, and VEGF [ 125 ]. Further, GS was also found to inhibit TGF-β-induced EMT in HCC cells [ 106 ]. In this study, GS was found to decrease the mRNA expression of CDH2 , which codes for N-cadherin, a marker of EMT, and nuclear receptor subfamily 0, group B, member 2 ( NR0B2 ), which is an FXR target gene [ 106 ]. Additionally, the treatment of GS sensitized DOX-resistant PLC/PRF/5R cells to DOX via suppression of the expression of COX-2, P-gp, and PGE2 [ 137 ]. In another study, the combination of GS with TRAIL was found to induce apoptosis in HCC cells through the reduction of mitochondrial transmembrane potential and caspase activation [ 142 ]. The receptor for TRAIL, DR5, was also found to be upregulated along with activation of proteins associated with ER stress and apoptosis such as eukaryotic initiation factor-2α (eIF2α) and CHOP in GS treated cells [ 142 ].

Hematological malignancies

Hematological malignancies such as leukemia, lymphoma, and multiple myeloma are serious health issues worldwide [ 2 , 198 – 201 ]. Most of the hematological malignancies are a result of genetic alterations, as an example, the mutation of FMS-like tyrosine kinase3-internal tandem duplication (FLT3-ITD), which is common in acute myeloid leukemia (AML) [ 27 , 29 ]. Therefore, the therapeutic potential of GS was explored for the treatment of hematological malignancies. GS was shown to potentiate the TNF-induced apoptosis of leukemia cells by inhibiting NF-κB and increasing caspase-mediated cleavage of PARP protein [ 65 ]. This plant sterol was also reported to reduce the proliferation of U937 leukemia cells by inhibiting DNA synthesis, inducing G1/S phase arrest, and decreasing the levels of cyclin D1 and cdc2 and upregulating CDK inhibitors such as p21 and p27. Further, GS was shown to induce apoptosis in these cells through activation of caspases-3, -8, and -9, the release of cytochrome c, Bid and PARP cleavage, and by decreasing anti-apoptotic proteins such as Bfl-1, XIAP, cFLIP, Bcl-xL, Bcl-2, survivin, COX-2, c-Myc, IL-6, IL-1β and TNF levels. In addition, GS also activated JNK and suppressed Akt activity in these cells [ 112 ]. Moreover, the cis - and trans- GS was reported to cause apoptosis in AML cells, HL60 and U937, through phosphatidylserine externalization and loss of ΔΨm. The trans-GS was also reported to play a remarkable role in the differentiation of these cells as evidenced through elevated levels of surface proteins such as CD11b and CD14, while cis -GS reduced intracellular GSH levels and promoted oxidation of cardiolipin, which is known to be involved in mitochondrial function and prevention of apoptosis [ 202 ]. Moreover, the combined treatment of GS and DOX reversed MDR by inhibiting P-gp and increasing cellular accumulation of DOX in K562/DOX cells [ 135 ]. Additionally, GS inhibited the proliferation of multiple myeloma cells by decreasing the expression of STAT3 via activation of SHP-1, which leads to the suppression of c-Src and p-JAK2 proteins. Further, GS was also shown to inhibit Bcl-2 , Bcl-xL , Mcl-1 , and cyclin D1 gene expressions in these cells [ 109 ].

Pancreatic cancer (PaCa)

PaCa is one of the most fatal malignancies in the world that ranks seventh in both males and females worldwide [ 2 ]. Studies have shown the efficacy of natural compounds like resveratrol, curcumin, γ-tocotrienol, food supplement like Zyflamend TM , and small molecules like protein kinase D (PKD) inhibitor, CRT0066101 against PaCa [ 203 – 208 ]. Similarly, GS has also been reported to exhibit antineoplastic and chemosensitizing potential in PaCa models. In a particular study, GS was found to suppress proliferation and survival and induce apoptosis in PaCa cells, Capan1 and CD18/HPAF, through enhanced activation of caspase-3, altered BAD phosphorylation, decreased cyclin D1, and reduced level of anti-apoptotic proteins, Bcl-2 and XIAP. This compound also suppressed invasion and metastasis in PaCa cells by dysregulating the cytoskeletal organization, inhibiting the activation of FAK and Src signaling, and reducing MMP-9 levels and JAK/STAT pathway-mediated mucin4 ( MUC4 ) expressions [ 67 ]. Similarly, GS-mediated FXR inhibition was found to remarkably suppress migration and invasion in PaCa cells [ 209 ]. Besides, the derivatives of GS, GSD-1, and GSD-7 were also reported to induce morphological changes and reduce cell survival in PANC-1 cells by inhibiting Akt protein [ 210 ]. Further, GS was also evinced to induce radiosensitization in PC-Sw cells through reduced levels of NF-κB and IGF1-Rβ [ 172 ]. In addition, GS administration enhanced gemcitabine-mediated growth suppression and apoptosis in PaCa cells via suppression of NF-κB activity, levels of Akt and Bcl-2, and activation of c-JNK and Bax [ 211 ].

PC

In terms of incidence, PC is the second most common malignancy in males worldwide [ 2 , 212 – 215 ]. The factors like unhealthy diet and lifestyles were reported to be associated with the development of PC [ 216 , 217 ]. Multiple lines of evidence indicate that GS has immense potential in the prevention and treatment of PC. For example, GS induced apoptosis in PC-3 and LNCaP cells by triggering ROI-dependent JNK activation [ 131 ]. In LNCaP cells, GS was also found to reduce the expression and promoter activity of the androgen receptor [ 131 ]. Besides, GS treatment was also reported to induce apoptosis in PC-3 cells by inducing DNA fragmentation and upregulating the expression of Bax, Bak, and caspases -3, -8, and -9 [ 94 ]. Further, the administration of Z-GS was reported to inhibit tube formation of HUVEC cells and migration of DU145 and HUVEC cells via suppression of VEGF, granulocyte colony-stimulating factor (G-CSF), VEGF receptor (VEGF-R2), and Akt. The anti-angiogenic effect of GS was also evident in the nude mice model, where the oral administration of GS was found to suppress tumor growth and decrease levels of angiogenic markers, factor VIII, CD31, and VEGF-R2 [ 218 ].

Other cancers

Apart from the aforementioned cancers, the anticancer potential of GS was documented in other cancers such as cholangiocarcinoma (CCA), gallbladder cancer, melanoma, and lung cancer. For example, GS was shown to reduce the growth of CCA cells (Sk-ChA-1 and Mz-ChA-1) and induce apoptosis via enhancement of caspases -3, -8, and -9 expression and PARP cleavage, and suppression of survivin and Bcl-2 [ 111 ]. Further, GS treatment was reported to induce apoptosis in HuCC-T1 and RBE CCA cells through the regulation of the ROS/JNK pathway [ 130 ]. In addition, treatment with GS was shown to inhibit melanogenesis in B16 murine melanoma cells through the reduction of tyrosinase, microphthalmia-associated transcription factor (MITF), and tyrosinase-related protein (TRP-1 and TRP-2). This compound was also found to suppress melanogenesis induced by α-melanocyte-stimulating hormone and forskolin [ 219 ]. Another study revealed that GS lowered skin tumor incidence in SENCAR mice by inhibiting various inflammation and tumor-associated markers such as COX-2, iNOS, MAPKs, IKKα, IκBα, and NF-κB [ 124 ]. Furthermore, the activity of GS was also studied in H1299 lung cancer cells where it inhibited NF-κB activation induced by various agents such as TNF, IL-1β, and carcinogens; and also inhibited IκBα and IKK. Besides, GS suppressed the activities of other proteins such as COX2, MMP9, VEGF, cell cycle proteins, and anti-apoptotic proteins [ 65 ]. In another study, the potential of GS on gall bladder cancer (GBC) was investigated. This study showed that GS suppressed the proliferation and invasion of TGBC1 and TGBC2, GBC cells via inhibition of NF-κB p65, VEGF-C, and MMP-2. In addition, the combination of GS and gemcitabine significantly inhibited the growth of GBC, thereby exerting its chemosensitizing potential [ 139 ]. Thus, GS has immense potential as a drug candidate for cancer treatment as proved by preclinical studies. However, the pharmacokinetics (Pk) and pharmacodynamics of this compound should be studied for its safe and effective use as a clinical drug.

Pk and pharmacodynamics of GS

A limited number of studies have reported the Pk and pharmacodynamics of GS to date. In 1998, Verma et al. [ 220 ], performed HPLC of Z-GS, E-GS, drug-free rat serum, GS-spiked serum, serum from GS (50 mg/kg)-dosed rats (at 4 h), and serum from GS-dosed rats (at 24 h). The recovery percentage of Z-GS and E-GS from spiked serum samples was more than 90% at all concentrations of spiking (25, 50, 250, 2, 500 ng/mL) while the chromatogram analysis suggested that under in vivo conditions, GS is plausibly metabolized from Z- to E-form upon administration and is retained in the same form in the body. In another study, the effect of both oral and intravenous administration on various Pk parameters of Z-GS and E-GS were analysed; however, no statistically significant difference was observed. It was reported that the Pk parameters like terminal half-life, systemic clearance, area under the curve, and volume of distribution were 4.48 and 3.56 h, 1.76 and 2.24 L/h, 5.95 and 4.75 μgh/mL, and 11.36 and 10.76 L, respectively. These results demonstrated that the absorption of Z-GS was rapid from the gastrointestinal tract, leading to maximum concentration (C max ) in the serum 2 h after oral administration. Moreover, the bioavailability of orally administered Z-GS relative to the intravenous administration was found to be 42.9% [ 221 ]. In another study, Bhatta et al. [ 222 ], developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of both Z- and E-GS in rabbit plasma. However, this method faced a limitation of the long run time of 20 min. Subsequently, in 2015, Chhonker et al. [ 223 ], developed and validated an extremely specific and sensitive LC-MS/MS method for the estimation of E- and Z-GS in rat plasma within a run time of 6 min. Using this method, the ADME properties of GS such as metabolic stability, pH-dependent stability, plasma protein binding, solubility and Pk of GS isomers administered orally in rats were evaluated. Moreover, E- and Z-GS were reported to be soluble up to 50 μM (1, 561 ng/mL) under physiological conditions. The findings also suggested that E- and Z-GS were stable in the gastrointestinal fluid and were not subjected to enzymatic degradation; their plasma protein binding was high and independent of the concentration of GS. Further, both the stereoisomers exhibited low bioavailability of GS owing to wide first pass metabolism through high clearance and short half-life in rats [ 223 ].

The efficacy, toxicity, and pharmacodynamics of a drug depend hugely on its metabolic fate. In 2012, Yang et al. [ 224 ], reported a basic metabolic profile of Z-GS. However, to gain an in-depth understanding of the Pk and metabolism of GS, in 2018, Chhonker et al. [ 225 ], conducted another metabolic investigation where GS was found to metabolize to produce nineteen metabolites in human liver microsomes, and S9 fractions and hydroxylation was identified as the prime metabolic pathway. Also, the binding efficiency of GS with human serum albumin ranged from low to moderate. Further, CYP profiling and inhibition studies revealed that GS is a substrate for various CYPs, majorly CYP3A4, and it inhibited CYP2C19 [ 225 ]. Recently, another study was performed to detect electrophilic reactive metabolites of GS isomers. It was hypothesized that these metabolites are responsible for the toxic reactions of GS. The results showed that hydroxylated metabolites of GS isomers formed adducts with the trapping agents, GSH and N-acetylcysteine [ 226 ]. Overall, these studies form the background for further structural modification of GS, enhancement in the stability, and designing of its analogs.

Discussion and conclusion

The increasing rate of cancer cases and deaths pose a huge concern worldwide [ 227 – 231 ]. The currently available drugs are expensive, induce severe adverse side-effects, and are not very effective [ 6 , 38 , 232 ]. Thus, alternative drugs are sought for the efficient management of cancer, and natural compounds have shown promising results [ 233 – 245 ]. Among these compounds, GS, the FXR antagonist, has exhibited immense potential as an anticancer agent against various cancer types. This multi-targeted agent has shown to affect different cellular processes such as inflammation, cell proliferation, survival, angiogenesis, invasion, metastasis, EMT, and apoptosis in cancer cells in various preclinical models. In this process, GS has been reported to inflect multiple pathways like NF-κB, STAT-3, ERK/MAPK, JAK/STAT, ROS/JNK and PI3K/Akt, and several genes and proteins such as COX-2, MMP-9, p38, PGE2, HIF-1α, VEGF, interleukins, cyclin D1, survivin, p21, p27, p53, PARP, Bid and caspases. This active metabolite of guggulipid has also been known to regulate cellular stress and ΔΨm in several in vitro models. Further, GS also inhibited tumor growth remarkably in in vivo models of cancer. Not only this, but GS could also induce sensitization of cancer cells to standard chemotherapeutic drugs like DOX and gemcitabine in various cancer models. It has also been reported to sensitize the cancer cells to TRAIL and enhance the efficacy of radiation in cancer models, thereby leading to cancer cell death. These studies show that GS is a potential therapeutic agent for the prevention and treatment of various cancers. However, the preclinical findings need to be validated in clinical settings with a detailed investigation of its safety, toxicity, and bioavailability. Studies have identified two prime stereoisoforms of GS, Z-GS and E-GS, along with 19 metabolites. GS is characterized by physiological solubility upto 50 μM, high plasma protein binding, and limited bioavailability. Hence, studies have been carried out to design analogs of this pharmacophore with enhanced bioavailability. Thus, modulation of the pharmacodynamics and Pk properties of this compound may lead to the development of analogs and derivatives of GS for better management of cancer.

Abbreviations

acute myeloid leukemia

aryl hydrocarbon receptor nuclear translocator

Bcl-2-associated death promoter

Bcl-2 homologous antagonist/killer

Bcl-2-associated X protein

B-cell lymphoma 2

breast cancer resistance protein

Barrett’s esophagus

Bcl-2-related protein A1

BH3 interacting domain death agonist

Commiphora wightii

cholangiocarcinoma

caudal type homeobox 2

cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein

CCAAT/enhancer-binding protein homologous protein

cyclooxygenase 2

colorectal cancer

doxorubicin

death receptor

esophageal adenocarcinoma

esophageal cancer

extracellular matrix

eukaryotic initiation factor-2α

epithelial-mesenchymal transition

endoplasmic reticulum

extracellular signal-regulated kinase

focal adhesion kinase

farnesoid X receptor

gall bladder cancer

guggulsterone

glutathione

Glycogen synthase kinase 3 beta

hepatocellular carcinoma

head and neck cancer

head and neck squamous cell carcinoma

inhibitor of apoptosis protein 1

IkappaB kinase

IkappaB alpha

Janus kinase

Jun N-terminal kinase

liquid chromatography-tandem mass spectrometry

low-density lipoprotein

mitogen-activated protein kinase

myeloid cell leukemia 1

multi-drug resistance

microphthalmia-associated transcription factor

matrix metalloproteinase

mucin 4

nuclear factor kappa B

nitric oxide

nuclear receptor subfamily 0, group B, member 2

pancreatic cancer

prostate cancer

phosphoinositide-dependent kinase-1

prostaglandin E2

P-glycoprotein

phosphoinositide 3-kinase

pharmacokinetics

protein kinase D

peroxisome proliferator-activated receptor-gamma

quality of life

receptor activator of nuclear factor-κB ligand

rat brain microvessel endothelial cells

reactive oxygen species

Src homology 2 domain-containing protein tyrosine phosphatase 1

steroid receptor coactivator

signal transducers and activators of transcription

transforming growth factor β

tumor microenvironment

tumor necrosis factor

tumor necrosis factor receptor

TNF-related apoptosis-inducing ligand

tyrosinase-related protein

vascular endothelial growth factor

X-linked inhibitor of apoptosis protein

mitochondrial membrane potential

Declarations

Acknowledgments

The author Kishore Banik acknowledges UGC, New Delhi, India, for providing him the fellowship.

Author contributions

ABK contributed to the study design, conceptualisation, supervision and review editing. SG, CH, and KB performed bibliographic search. SG and CH contributed to original manuscript. DP contributed to table preparation and proofreading. KB and DP performed artwork. CH, KB and DP contributed to review editing. SG, CH and KB contributed to proofreading.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This project was supported by NCD/NER/4/2018-19 awarded to ABK by Indian Council of Medical Research (ICMR), Government of India. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

© The Author(s) 2020.

References

1. Hassanpour SH Dehghani M. Review of cancer from perspective of molecular . J Cancer Res Pract. 2017 ; 4 : 127 – 9 . 10.1016/j.jcrpr.2017.07.001

2. Bray F Ferlay J Soerjomataram I Siegel RL Torre LA Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries . CA Cancer J Clin. 2018 ; 68 : 394 – 424 . 10.3322/caac.21492 30207593

3. Ferlay J Colombet M Soerjomataram I Mathers C Parkin DM Piñeros M Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods . Int J Cancer. 2019 ; 144 : 1941 – 53 . 10.1002/ijc.31937 30350310

4. Girisa S Shabnam B Monisha J Fan L Halim CE Arfuso F Potential of zerumbone as an anti-cancer agent . Molecules. 2019 ; 24 : 734 . 10.3390/molecules24040734 PMC6413012 30781671

5. Henamayee S Banik K Sailo BL Shabnam B Harsha C Srilakshmi S Therapeutic emergence of rhein as a potential anticancer drug: a review of its molecular targets and anticancer properties . Molecules. 2020 ; 25 : 2278 . 10.3390/molecules25102278 PMC7288145 32408623

6. Khatoon E Banik K Harsha C Sailo BL Thakur KK Khwairakpam AD Phytochemicals in cancer cell chemosensitization: current knowledge and future perspectives . Semin Cancer Biol. 2020 ;[Epub ahead of print]. 10.1016/j.semcancer.2020.06.014 32610149

7. Anand P Kunnumakkara AB Sundaram C Harikumar KB Tharakan ST Lai OS Cancer is a preventable disease that requires major lifestyle changes . Pharm Res. 2008 ; 25 : 2097 – 116 . 10.1007/s11095-008-9661-9 18626751 PMC2515569

8. Kunnumakkara AB Anand P Aggarwal BB. Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins . Cancer Lett. 2008 ; 269 : 199 – 225 . 10.1016/j.canlet.2008.03.009 18479807

9. Kunnumakkara AB Bordoloi D Harsha C Banik K Gupta SC Aggarwal BB. Curcumin mediates anticancer effects by modulating multiple cell signaling pathways . Clin Sci (Lond). 2017 ; 131 : 1781 – 99 . 10.1042/CS20160935 28679846

10. Roy NK Bordoloi D Monisha J Padmavathi G Kotoky J Golla R Specific targeting of Akt kinase isoforms: taking the precise path for prevention and treatment of cancer . Curr Drug Targets. 2017 ; 18 : 421 – 35 . 10.2174/1389450117666160307145236 26953242

11. Shabnam B Padmavathi G Banik K Girisa S Monisha J Sethi G Sorcin a potential molecular target for cancer therapy . Transl Oncol. 2018 ; 11 : 1379 – 89 . 10.1016/j.tranon.2018.08.015 30216763 PMC6134165

12. Banik K Ranaware AM Deshpande V Nalawade SP Padmavathi G Bordoloi D Honokiol for cancer therapeutics: a traditional medicine that can modulate multiple oncogenic targets . Pharmacol Res. 2019 ; 144 : 192 – 209 . 10.1016/j.phrs.2019.04.004 31002949

13. Kunnumakkara AB Shabnam B Girisa S Harsha C Banik K Devi TB Inflammation, NF-κB, and chronic diseases: how are they linked? Crit Rev Immunol . 2020 ; 40 : 1 – 39 . 10.1615/CritRevImmunol.2020033210 32421977

14. Shanmugam MK Warrier S Kumar AP Sethi G Arfuso F. Potential role of natural compounds as anti-angiogenic agents in cancer . Curr Vasc Pharmacol. 2017 ; 15 : 503 – 19 . 10.2174/1570161115666170713094319 28707601

15. Hsieh YS Yang SF Sethi G Hu DN. Natural bioactives in cancer treatment and prevention . Biomed Res Int. 2015 ; 2015 : 182835 . 10.1155/2015/182835 25883943 PMC4391150

16. Dai X Zhang J Arfuso F Chinnathambi A Zayed ME Alharbi SA Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy . Exp Biol Med (Maywood). 2015 ; 240 : 760 – 73 . 10.1177/1535370215579167 25854879 PMC4935211

17. Khwairakpam AD Shyamananda MS Sailo BL Rathnakaram SR Padmavathi G Kotoky J ATP citrate lyase (ACLY): a promising target for cancer prevention and treatment . Curr Drug Targets. 2015 ; 16 : 156 – 63 . 10.2174/1389450115666141224125117 25537655

18. Sailo BL Banik K Girisa S Bordoloi D Fan L Halim CE FBXW7 in cancer: what has been unraveled thus far? Cancers (Basel) . 2019 ; 11 : 246 . 10.3390/cancers11020246 PMC6406609 30791487

19. Aggarwal BB Kunnumakkara AB Harikumar KB Tharakan ST Sung B Anand P. Potential of spice-derived phytochemicals for cancer prevention . Planta Med. 2008 ; 74 : 1560 – 9 . 10.1055/s-2008-1074578 18612945

20. Guruvayoorappan C Sakthivel KM Padmavathi G Bakliwal V Monisha J Kunnumakkara AB. Cancer preventive and therapeutic properties of fruits and vegetables: an overview . In: Kunnumakkara AB editors. Anticancer properties of fruits and vegetable: Scientific Review . Singapore : World Scientific ; 2015 . pp. 1 – 52 .

21. Roy PS Saikia BJ. Cancer and cure: a critical analysis . Indian J Cancer. 2016 ; 53 : 441 – 2 . 10.4103/0019-509X.200658 28244479

22. Chakraborty C Sharma AR Sharma G Sarkar BK Lee SS. The novel strategies for next-generation cancer treatment: miRNA combined with chemotherapeutic agents for the treatment of cancer . Oncotarget. 2018 ; 9 : 10164 – 74 . 10.18632/oncotarget.24309 29515800 PMC5839381

23. Ranaware AM Banik K Deshpande V Padmavathi G Roy NK Sethi G Magnolol: a neolignan from the magnolia family for the prevention and treatment of cancer . Int J Mol Sci. 2018 ; 19 : 2362 . 10.3390/ijms19082362 PMC6121321 30103472

24. Arruebo M Vilaboa N Sáez-Gutierrez B Lambea J Tres A Valladares M Assessment of the evolution of cancer treatment therapies . Cancers (Basel). 2011 ; 3 : 3279 – 330 . 10.3390/cancers3033279 24212956 PMC3759197

25. Kanojia D Garg M Martinez J M TA Luty SB Doan NB Kinase profiling of liposarcomas using RNAi and drug screening assays identified druggable targets . J Hematol Oncol. 2017 ; 10 : 173 . 10.1186/s13045-017-0540-x 29132397 PMC5683536

26. Warrier VU Makandar AI Garg M Sethi G Kant R Pal JK Engineering anti-cancer nanovaccine based on antigen cross-presentation . Biosci Rep. 2019 ; 39 : BSR20193220 . 10.1042/BSR20193220 31652460 PMC6822533

27. Garg M Nagata Y Kanojia D Mayakonda A Yoshida K Haridas Keloth S Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse . Blood. 2015 ; 126 : 2491 – 501 . 10.1182/blood-2015-05-646240 26438511 PMC4661172

28. Kirtonia A Gala K Fernandes SG Pandya G Pandey AK Sethi G Repurposing of drugs: an attractive pharmacological strategy for cancer therapeutics . Semin Cancer Biol. 2020 ;[Epub ahead of print]. 10.1016/j.semcancer.2020.04.006 32380233

29. Kirtonia A Pandya G Sethi G Pandey AK Das BC Garg M. A comprehensive review of genetic alterations and molecular targeted therapies for the implementation of personalized medicine in acute myeloid leukemia . J Mol Med (Berl). 2020 ; 98 : 1069 – 91 . 10.1007/s00109-020-01944-5 32620999

30. Monisha J Padmavathi G Roy NK Deka A Bordoloi D Anip A NF-κB blockers gifted by mother nature: prospectives in cancer cell chemosensitization . Curr Pharm Des. 2016 ; 22 : 4173 – 200 . 10.2174/1381612822666160609110231 27291284

31. Roy NK Deka A Bordoloi D Mishra S Kumar AP Sethi G The potential role of boswellic acids in cancer prevention and treatment . Cancer Lett. 2016 ; 377 : 74 – 86 . 10.1016/j.canlet.2016.04.017 27091399

32. Khwairakpam AD Bordoloi D Thakur KK Monisha J Arfuso F Sethi G Possible use of Punica granatum (Pomegranate) in cancer therapy . Pharmacol Res. 2018 ; 133 : 53 – 64 . 10.1016/j.phrs.2018.04.021 29729421

33. Monisha J Jaiswal A Banik K Choudhary H Singh AK Bordoloi D Cancer cell chemoresistance: a prime obstacle in cancer therapy . In: Kunnumakkara AB Bordoloi D Monisha J editors. Cancer cell chemoresistance and chemosensitization . Sinapore : World Scientific ; 2018 . pp. 15 – 49 .

34. Banik K Ranaware AM Harsha C Nitesh T Girisa S Deshpande V Piceatannol: a natural stilbene for the prevention and treatment of cancer . Pharmacol Res. 2020 ; 153 : 104635 . 10.1016/j.phrs.2020.104635 31926274

35. Kunnumakkara AB Nair AS Ahn KS Pandey MK Yi Z Liu M Gossypin, a pentahydroxy glucosyl flavone, inhibits the transforming growth factor beta-activated kinase-1-mediated NF-kappaB activation pathway, leading to potentiation of apoptosis, suppression of invasion, and abrogation of osteoclastogenesis . Blood. 2007 ; 109 : 5112 – 21 . 10.1182/blood-2007-01-067256 17332240 PMC1890830

36. Bordoloi D Roy NK Monisha J Padmavathi G Kunnumakkara AB. Multi-targeted agents in cancer cell chemosensitization: what we learnt from curcumin thus far . Recent Pat Anticancer Drug Discov. 2016 ; 11 : 67 – 97 . 10.2174/1574892810666151020101706 26537958

37. Sailo BL Banik K Padmavathi G Javadi M Bordoloi D Kunnumakkara AB. Tocotrienols: the promising analogues of vitamin E for cancer therapeutics . Pharmacol Res. 2018 ; 130 : 259 – 72 . 10.1016/j.phrs.2018.02.017 29496592

38. Kunnumakkara AB Bordoloi D Sailo BL Roy NK Thakur KK Banik K Cancer drug development: the missing links . Exp Biol Med (Maywood). 2019 ; 244 : 663 – 89 . 10.1177/1535370219839163 30961357 PMC6552400

39. Thomas D Govindhan S Baiju EC Padmavathi G Kunnumakkara AB Padikkala J. Cyperus rotundus L. prevents non-steroidal anti-inflammatory drug-induced gastric mucosal damage by inhibiting oxidative stress . J Basic Clin Physiol Pharmacol. 2015 ; 26 : 485 – 90 . 10.1515/jbcpp-2014-0093 25915081

40. Deng S Shanmugam MK Kumar AP Yap CT Sethi G Bishayee A. Targeting autophagy using natural compounds for cancer prevention and therapy . Cancer. 2019 ; 125 : 1228 – 46 . 10.1002/cncr.31978 30748003

41. Tewari D Nabavi SF Nabavi SM Sureda A Farooqi AA Atanasov AG Targeting activator protein 1 signaling pathway by bioactive natural agents: possible therapeutic strategy for cancer prevention and intervention . Pharmacol Res. 2018 ; 128 : 366 – 75 . 10.1016/j.phrs.2017.09.014 28951297

42. Mishra S Verma SS Rai V Awasthee N Chava S Hui KM Long non-coding RNAs are emerging targets of phytochemicals for cancer and other chronic diseases . Cell Mol Life Sci. 2019 ; 76 : 1947 – 66 . 10.1007/s00018-019-03053-0 30879091 PMC7775409

43. Pandey MK Sung B Ahn KS Kunnumakkara AB Chaturvedi MM Aggarwal BB. Gambogic acid, a novel ligand for transferrin receptor, potentiates TNF-induced apoptosis through modulation of the nuclear factor-kappaB signaling pathway . Blood. 2007 ; 110 : 3517 – 25 . 10.1182/blood-2007-03-079616 17673602 PMC2077305

44. Khwairakpam AD Monisha J Roy NK Bordoloi D Padmavathi G Banik K Vietnamese coriander inhibits cell proliferation, survival and migration via suppression of Akt/mTOR pathway in oral squamous cell carcinoma . J Basic Clin Physiol Pharmacol. 2019 ; 31 :/j/jbcpp.2020.31.issue-3/jbcpp-2019-0162/jbcpp-2019-0162.xml. 10.1515/jbcpp-2019-0162 31747377

45. Padmavathi G Rathnakaram SR Monisha J Bordoloi D Roy NK Kunnumakkara AB. Potential of butein, a tetrahydroxychalcone to obliterate cancer . Phytomedicine. 2015 ; 22 : 1163 – 71 . 10.1016/j.phymed.2015.08.015 26598915

46. Padmavathi G Roy NK Bordoloi D Arfuso F Mishra S Sethi G Butein in health and disease: a comprehensive review . Phytomedicine. 2017 ; 25 : 118 – 27 . 10.1016/j.phymed.2016.12.002 28190465

47. Banik K Harsha C Bordoloi D Lalduhsaki Sailo B Sethi G Leong HC Therapeutic potential of gambogic acid, a caged xanthone, to target cancer . Cancer Lett. 2018 ; 416 : 75 – 86 . 10.1016/j.canlet.2017.12.014 29246645

48. Khwairakpam AD Damayenti YD Deka A Monisha J Roy NK Padmavathi G Acorus calamus: a bio-reserve of medicinal values . J Basic Clin Physiol Pharmacol. 2018 ; 29 : 107 – 22 . 10.1515/jbcpp-2016-0132 29389665

49. Bordoloi D Monisha J Roy NK Padmavathi G Banik K Harsha C An investigation on the therapeutic potential of butein, a tretrahydroxychalcone against human oral squamous cell carcinoma . Asian Pac J Cancer Prev. 2019 ; 20 : 3437 – 46 . 10.31557/APJCP.2019.20.11.3437 31759370 PMC7063020

50. Roy NK Parama D Banik K Bordoloi D Devi AK Thakur KK An update on pharmacological potential of boswellic acids against chronic diseases . Int J Mol Sci. 2019 ; 20 : 4101 . 10.3390/ijms20174101 PMC6747466 31443458

51. Singh YP Girisa S Banik K Ghosh S Swathi P Deka M Potential application of zerumbone in the prevention and therapy of chronic human diseases . J Funct Foods. 2019 ; 53 : 248 – 58 . 10.1016/j.jff.2018.12.020

52. Prasannan R Kalesh KA Shanmugam MK Nachiyappan A Ramachandran L Nguyen AH Key cell signaling pathways modulated by zerumbone: role in the prevention and treatment of cancer . Biochem Pharmacol. 2012 ; 84 : 1268 – 76 . 10.1016/j.bcp.2012.07.015 22842489

53. Siveen KS Ahn KS Ong TH Shanmugam MK Li F Yap WN Y-tocotrienol inhibits angiogenesis-dependent growth of human hepatocellular carcinoma through abrogation of AKT/mTOR pathway in an orthotopic mouse model . Oncotarget. 2014 ; 5 : 1897 – 911 . 10.18632/oncotarget.1876 24722367 PMC4039111

54. Ramachandran L Manu KA Shanmugam MK Li F Siveen KS Vali S Isorhamnetin inhibits proliferation and invasion and induces apoptosis through the modulation of peroxisome proliferator-activated receptor γ activation pathway in gastric cancer . J Biol Chem. 2012 ; 287 : 38028 – 40 . 10.1074/jbc.M112.388702 22992727 PMC3488073

55. Manu KA Shanmugam MK Ramachandran L Li F Siveen KS Chinnathambi A Isorhamnetin augments the anti-tumor effect of capecitabine through the negative regulation of NF-κB signaling cascade in gastric cancer . Cancer Lett. 2015 ; 363 : 28 – 36 . 10.1016/j.canlet.2015.03.033 25827070

56. Lee JH Chiang SY Nam D Chung WS Lee J Na YS Capillarisin inhibits constitutive and inducible STAT3 activation through induction of SHP-1 and SHP-2 tyrosine phosphatases . Cancer Lett. 2014 ; 345 : 140 – 8 . 10.1016/j.canlet.2013.12.008 24333736

57. Yamada T Sugimoto K. Guggulsterone and its role in chronic diseases . Adv Exp Med Biol. 2016 ; 929 : 329 – 61 . 10.1007/978-3-319-41342-6_15 27771932

58. Urizar NL Moore DD. GUGULIPID: a natural cholesterol-lowering agent . Annu Rev Nutr. 2003 ; 23 : 303 – 13 . 10.1146/annurev.nutr.23.011702.073102 12626688

59. Soni V Swarnkar PL. Conservation strategies for Commiphora wightii . An important medicinal plant species . Medicinal Plant Conservation. 2006 ; 12 : 40 – 2 .

60. Deng R. Therapeutic effects of guggul and its constituent guggulsterone: cardiovascular benefits . Cardiovasc Drug Rev. 2007 ; 25 : 375 – 90 . 10.1111/j.1527-3466.2007.00023.x 18078436

61. Ghritlahare SK Satapathy T Panda PK Mishra G. Ethnopharmacological story of guggul sterones: an overview . Res J Pharmacognosy and Phytochem. 2017 ; 9 : 182 – 8 . 10.5958/0975-4385.2017.00034.6

62. Jain N Nadgauda R. Commiphora wightii (Arnott) Bhandari-a natural source of guggulsterone: facing a high risk of extinction in its natural habitat . Am J Plant Sci. 2013 ; 04 : 57 – 68 . 10.4236/ajps.2013.46A009

63. Almazari I Surh YJ. Cancer chemopreventive and therapeutic potential of guggulsterone . Top Curr Chem. 2013 ; 329 : 35 – 60 . 10.1007/128_2012_344 22851157

64. Shishodia S Azu N Rosenzweig JA Jackson DA. Guggulsterone for chemoprevention of cancer . Curr Pharm Des. 2016 ; 22 : 294 – 306 . 10.2174/1381612822666151112153117 26561056

65. Shishodia S Aggarwal BB. Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis . J Biol Chem. 2004 ; 279 : 47148 – 58 . 10.1074/jbc.M408093200 15322087

66. Macha MA Matta A Chauhan SS Siu KW Ralhan R. Guggulsterone targets smokeless tobacco induced PI3K/Akt pathway in head and neck cancer cells . PLoS One. 2011 ; 6 : e14728 . 10.1371/journal.pone.0014728 21383988 PMC3044714

67. Macha MA Rachagani S Gupta S Pai P Ponnusamy MP Batra SK Guggulsterone decreases proliferation and metastatic behavior of pancreatic cancer cells by modulating JAK/STAT and Src/FAK signaling . Cancer Lett. 2013 ; 341 : 166 – 77 . 10.1016/j.canlet.2013.07.037 23920124 PMC3825785

68. Liu X Guo GL Kong B Hilburn DB Hubchak SC Park S Farnesoid X receptor signaling activates the hepatic X-box binding protein 1 pathway in vitro and in mice . Hepatology. 2018 ; 68 : 304 – 16 . 10.1002/hep.29815 29377207 PMC6033648

69. Owsley E Chiang JY. Guggulsterone antagonizes farnesoid X receptor induction of bile salt export pump but activates pregnane X receptor to inhibit cholesterol 7alpha-hydroxylase gene . Biochem Biophys Res Commun. 2003 ; 304 : 191 – 5 . 10.1016/s0006-291x(03)00551-5 12705905

70. Kuzu OF Noory MA Robertson GP. The role of cholesterol in cancer . Cancer Res. 2016 ; 76 : 2063 – 70 . 10.1158/0008-5472.CAN-15-2613 27197250 PMC5813477

71. Buchwald H. Cholesterol inhibition, cancer, and chemotherapy . Lancet. 1992 ; 339 : 1154 – 6 . 10.1016/0140-6736(92)90744-n 1349377

72. An MJ Cheon JH Kim SW Kim ES Kim TI Kim WH. Guggulsterone induces apoptosis in colon cancer cells and inhibits tumor growth in murine colorectal cancer xenografts . Cancer Lett. 2009 ; 279 : 93 – 100 . 10.1016/j.canlet.2009.01.026 19232820

73. Witkamp R. Biologically active compounds in food products and their effects on obesity and diabetes . Comprehensive natural products II: Chemistry and biology . Oxford : Elsevier ; 2010 . pp. 509 – 45 .

74. Jasuja ND Choudhary J Sharama P Sharma N Joshi SC. A review on bioactive compounds and medicinal uses of Commiphora mukul . J Plant Sci. 2012 ; 7 : 113 – 37 . 10.3923/jps.2012.113.137

75. Shah R Gulati V Palombo EA. Pharmacological properties of guggulsterones, the major active components of gum guggul . Phytother Res. 2012 ; 26 : 1594 – 605 . 10.1002/ptr.4647 22388973

76. Shishodia S Harikumar KB Dass S Ramawat KG Aggarwal BB. The guggul for chronic diseases: ancient medicine, modern targets . Anticancer Res. 2008 ; 28 : 3647 – 64 . 19189646

77. Bajaj AG Dev S. Chemistry of ayurvedic crude drugs-V: Guggulu (resin from commiphora mukul)-5 some new steroidal components and, stereochemistry of guggulsterol-I at C-20 and C-22 . Tetrahedron. 1982 ; 38 : 2949 – 54 . 10.1016/0040-4020(82)85024-2

78. Shen T Li GH Wang XN Lou HX. The genus Commiphora: a review of its traditional uses, phytochemistry and pharmacology . J Ethnopharmacol. 2012 ; 142 : 319 – 30 . 10.1016/j.jep.2012.05.025 22626923

79. Kunnumakkara AB Banik K Bordoloi D Harsha C Sailo BL Padmavathi G Googling the Guggul (Commiphora and Boswellia) for prevention of chronic diseases . Front Pharmacol. 2018 ; 9 : 686 . 10.3389/fphar.2018.00686 30127736 PMC6087759

80. Ojha S Bhatia J Arora S Golechha M Kumari S Arya DS. Cardioprotective effects of Commiphora mukul against isoprenaline-induced cardiotoxicity: a biochemical and histopathological evaluation . J Environ Biol. 2011 ; 32 : 731 – 8 . 22471209

81. Rupani R Chavez A. Medicinal plants with traditional use: ethnobotany in the Indian subcontinent . Clin Dermatol. 2018 ; 36 : 306 – 9 . 10.1016/j.clindermatol.2018.03.005 29908572

82. Sharma A Kumar A. Traditional uses of herbal medicinal plants of Rajashthan: Guggal . Int J Life Sci Pharma Res. 2012 ; 2 : 77 – 82 .

83. Baliga MS Nandhini J Emma F Venkataranganna MV Venkatesh P Fayad R. Indian medicinal plants and spices in the prevention and treatment of ulcerative colitis . In: Watson R Preedy V editors. Bioactive food as dietary interventions for liver and gastrointestinal disease . San Diego : Academic Press ; 2013 . pp. 173 – 85 .

84. Urizar NL Liverman AB Dodds DT Silva FV Ordentlich P Yan Y A natural product that lowers cholesterol as an antagonist ligand for FXR . Science. 2002 ; 296 : 1703 – 6 . 10.1126/science.1072891 11988537

85. Agrawal P Vegda R Laddha K. Simultaneous estimation of Withaferin A and Z-Guggulsterone in marketed formulation by RP-HPLC . J Chromatogr Sci. 2015 ; 53 : 940 – 4 . 10.1093/chromsci/bmu153 25572656

86. Nadeem S. Synergistic effect of Commiphora mukul (gum resin) and Lagenaria siceraria (fruit) extracts in high fat diet induced obese rats . Asian Pac J Trop Dis. 2012 ; 2 : S883 – 6 . 10.1016/S2222-1808(12)60285-0 22805720

87. Rehman NU Al-Riyami SA Hussain H Ali A Khan AL Al-Harrasi A. Secondary metabolites from the resins of Aloe vera and Commiphora mukul mitigate lipid peroxidation . Acta Pharm. 2019 ; 69 : 433 – 41 . 10.2478/acph-2019-0027 31259740

88. Ramesh B Karuna R Sreenivasa RS Haritha K Sai MD Sasi BR Effect of Commiphora mukul gum resin on hepatic marker enzymes, lipid peroxidation and antioxidants status in pancreas and heart of streptozotocin induced diabetic rats . Asian Pac J Trop Biomed. 2012 ; 2 : 895 – 900 . 10.1016/S2221-1691(12)60249-4 23569867 PMC3609238

89. Cornick CL Strongitharm BH Sassano G Rawlins C Mayes AE Joseph AN Identification of a novel agonist of peroxisome proliferator-activated receptors alpha and gamma that may contribute to the anti-diabetic activity of guggulipid in Lep(ob)/Lep(ob) mice . J Nutr Biochem. 2009 ; 20 : 806 – 15 . 10.1016/j.jnutbio.2008.07.010 18926687

90. Wang XW Yu Y Gu L. Dehydroabietic acid reverses TNF-α-induced the activation of FOXO1 and suppression of TGF-β1/Smad signaling in human adult dermal fibroblasts . Int J Clin Exp Pathol. 2014 ; 7 : 8616 – 26 . 25674226 PMC4314026

91. Goyal S Khilnani G Singhvi I Singla S Khilnani AK. Guggulipid of Commiphora mukul, with antiallodynic and antihyperalgesic activities in both sciatic nerve and spinal nerve ligation models of neuropathic pain . Pharm Biol. 2013 ; 51 : 1487 – 98 . 10.3109/13880209.2013.796392 23862659

92. Ahmad MA Najmi AK Mujeeb M Akhtar M. Protective effect of guggulipid in high fat diet and middle cerebral artery occlusion (MCAO) induced ischemic cerebral injury in rats . Drug Res (Stuttg). 2016 ; 66 : 407 – 14 . 10.1055/s-0042-107787 27224907

93. Niranjan R Nath C Shukla R. Guggulipid and nimesulide differentially regulated inflammatory genes mRNA expressions via inhibition of NF-kB and CHOP activation in LPS-stimulated rat astrocytoma cells, C6 . Cell Mol Neurobiol. 2011 ; 31 : 755 – 64 . 10.1007/s10571-011-9684-3 21461920 PMC11498630

94. Singh SV Zeng Y Xiao D Vogel VG Nelson JB Dhir R Caspase-dependent apoptosis induction by guggulsterone, a constituent of Ayurvedic medicinal plant Commiphora mukul, in PC-3 human prostate cancer cells is mediated by Bax and Bak . Mol Cancer Ther. 2005 ; 4 : 1747 – 54 . 10.1158/1535-7163.MCT-05-0223 16275996

95. Shen T Zhang L Wang YY Fan PH Wang XN Lin ZM Steroids from Commiphora mukul display antiproliferative effect against human prostate cancer PC3 cells via induction of apoptosis . Bioorg Med Chem Lett. 2012 ; 22 : 4801 – 6 . 10.1016/j.bmcl.2012.05.052 22687747

96. Mallavadhani UV Chandrashekhar M Nayak VL Ramakrishna S. Synthesis and anticancer activity of novel fused pyrimidine hybrids of myrrhanone C, a bicyclic triterpene of Commiphora mukul gum resin . Mol Divers. 2015 ; 19 : 745 – 57 . 10.1007/s11030-015-9621-3 26232027

97. Saeed MA Sabir AW. Antibacterial activities of some constituents from oleo-gum-resin of Commiphora mukul . Fitoterapia. 2004 ; 75 : 204 – 8 . 10.1016/j.fitote.2003.12.003 15030926

98. Haffor AS. Effect of myrrh (Commiphora molmol) on leukocyte levels before and during healing from gastric ulcer or skin injury . J Immunotoxicol. 2010 ; 7 : 68 – 75 . 10.3109/15476910903409835 19995243

99. Saxena G Singh SP Pal R Singh S Pratap R Nath C. Gugulipid, an extract of Commiphora whighitii with lipid-lowering properties, has protective effects against streptozotocin-induced memory deficits in mice . Pharmacol Biochem Behav. 2007 ; 86 : 797 – 805 . 10.1016/j.pbb.2007.03.010 17477963

100. Gujral ML Sareen K Tangri KK Amma MK Roy AK. Antiarthritic and anti-inflammatory activity of gum guggul (Balsamodendron mukul Hook) . Indian J Physiol Pharmacol. 1960 ; 4 : 267 – 73 . 13709695

101. Dini I. Spices and herbs as therapeutic foods . In: Grumezescu A Holban AM editors. Food quality: balancing health and disease . San Diego : Academic Press ; 2018 . pp. 433 – 69 .

102. Chander R Rizvi F Khanna AK Pratap R. Cardioprotective activity of synthetic guggulsterone (E and Z-isomers) in isoproterenol induced myocardial ischemia in rats: a comparative study . Indian J Clin Biochem. 2003 ; 18 : 71 – 9 . 10.1007/BF02867370 PMC3453889 23105395

103. Kalshetti PB Thakurdesai P Alluri R. A review on bioactive phytoconstituents and pharmacological uses of Commiphora mukul . J Curr Pharma Res. 2014 ; 5 : 1392 – 405 .

104. Kulhari A Sheorayan A Chaudhury A Sarkar S Kalia RK. Quantitative determination of guggulsterone in existing natural populations of Commiphora wightii (Arn.) Bhandari for identification of germplasm having higher guggulsterone content . Physiol Mol Biol Plants. 2015 ; 21 : 71 – 81 . 10.1007/s12298-014-0271-1 25648764 PMC4312330

105. De Gottardi A Dumonceau JM Bruttin F Vonlaufen A Morard I Spahr L Expression of the bile acid receptor FXR in Barrett’s esophagus and enhancement of apoptosis by guggulsterone in vitro . Mol Cancer. 2006 ; 5 : 48 . 10.1186/1476-4598-5-48 17054793 PMC1624849

106. Kainuma M Takada I Makishima M Sano K. Farnesoid X receptor activation enhances transforming growth factor β-induced epithelial-mesenchymal transition in hepatocellular carcinoma cells . Int J Mol Sci. 2018 ; 19 : 1898 . 10.3390/ijms19071898 PMC6073264 29958417

107. Absil L Journé F Larsimont D Body JJ Tafforeau L Nonclercq D. Farnesoid X receptor as marker of osteotropism of breast cancers through its role in the osteomimetism of tumor cells . BMC Cancer. 2020 ; 20 : 640 . 10.1186/s12885-020-07106-7 32650752 PMC7350202

108. Leeman-Neill RJ Wheeler SE Singh SV Thomas SM Seethala RR Neill DB Guggulsterone enhances head and neck cancer therapies via inhibition of signal transducer and activator of transcription-3 . Carcinogenesis. 2009 ; 30 : 1848 – 56 . 10.1093/carcin/bgp211 19762335 PMC2783003

109. Ahn KS Sethi G Sung B Goel A Ralhan R Aggarwal BB. Guggulsterone, a farnesoid X receptor antagonist, inhibits constitutive and inducible STAT3 activation through induction of a protein tyrosine phosphatase SHP-1 . Cancer Res. 2008 ; 68 : 4406 – 15 . Erratum in: Cancer Res. 2018;78:5184. 10.1158/0008-5472.CAN-07-6696 18519703

110. Kim ES Hong SY Lee HK Kim SW An MJ Kim TI Guggulsterone inhibits angiogenesis by blocking STAT3 and VEGF expression in colon cancer cells . Oncol Rep. 2008 ; 20 : 1321 – 7 . 19020709

111. Zhong F Yang J Tong ZT Chen LL Fan LL Wang F Guggulsterone inhibits human cholangiocarcinoma Sk-ChA-1 and Mz-ChA-1 cell growth by inducing caspase-dependent apoptosis and downregulation of survivin and Bcl-2 expression . Oncol Lett. 2015 ; 10 : 1416 – 22 . 10.3892/ol.2015.3391 26622683 PMC4533301

112. Shishodia S Sethi G Ahn KS Aggarwal BB. Guggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products . Biochem Pharmacol. 2007 ; 74 : 118 – 30 . 10.1016/j.bcp.2007.03.026 17475222 PMC2744036

113. Yamada T Osawa S Hamaya Y Furuta T Hishida A Kajimura M Guggulsterone suppresses bile acid-induced and constitutive caudal-related homeobox 2 expression in gut-derived adenocarcinoma cells . Anticancer Res. 2010 ; 30 : 1953 – 60 . 20651339

114. Kim BH Yoon JH Yang JI Myung SJ Lee JH Jung EU Guggulsterone attenuates activation and survival of hepatic stellate cell by inhibiting nuclear factor kappa B activation and inducing apoptosis . J Gastroenterol Hepatol. 2013 ; 28 : 1859 – 68 . 10.1111/jgh.12314 23808824

115. Yamada T Osawa S Ikuma M Kajimura M Sugimoto M Furuta T Guggulsterone, a plant-derived inhibitor of NF-TB, suppresses CDX2 and COX-2 expression and reduces the viability of esophageal adenocarcinoma cells . Digestion. 2014 ; 90 : 208 – 17 . 10.1159/000365750 25427631

116. Ichikawa H Aggarwal BB. Guggulsterone inhibits osteoclastogenesis induced by receptor activator of nuclear factor-kappaB ligand and by tumor cells by suppressing nuclear factor-kappaB activation . Clin Cancer Res. 2006 ; 12 : 662 – 8 . Erratum in: Clin Cancer Res. 2018;24:4347. 10.1158/1078-0432.CCR-05-1749 16428513

117. Noh EM Chung EY Youn HJ Jung SH Hur H Lee YR Cis-guggulsterone inhibits the IKK/NF-κB pathway, whereas trans-guggulsterone inhibits MAPK/AP-1 in MCF-7 breast cancer cells: guggulsterone regulates MMP-9 expression in an isomer-specific manner . Int J Mol Med. 2013 ; 31 : 393 – 9 . 10.3892/ijmm.2012.1214 23242121

118. Puar YR Shanmugam MK Fan L Arfuso F Sethi G Tergaonkar V. Evidence for the involvement of the master transcription factor NF-κB in cancer initiation and progression . Biomedicines. 2018 ; 6 : 82 . 10.3390/biomedicines6030082 PMC6163404 30060453

119. Shin EM Hay HS Lee MH Goh JN Tan TZ Sen YP DEAD-box helicase DP103 defines metastatic potential of human breast cancers . J Clin Invest. 2014 ; 124 : 3807 – 24 . 10.1172/JCI73451 25083991 PMC4151228

120. Ahn KS Sethi G Chaturvedi MM Aggarwal BB. Simvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, suppresses osteoclastogenesis induced by receptor activator of nuclear factor-kappaB ligand through modulation of NF-kappaB pathway . Int J Cancer. 2008 ; 123 : 1733 – 40 . 10.1002/ijc.23745 18688862

121. Sethi G Ahn KS Sung B Aggarwal BB. Pinitol targets nuclear factor-kappaB activation pathway leading to inhibition of gene products associated with proliferation, apoptosis, invasion, and angiogenesis . Mol Cancer Ther. 2008 ; 7 : 1604 – 14 . 10.1158/1535-7163.MCT-07-2424 18566231

122. Ahn KS Sethi G Jain AK Jaiswal AK Aggarwal BB. Genetic deletion of NAD(P)H: quinone oxidoreductase 1 abrogates activation of nuclear factor-kappaB, IkappaBalpha kinase, c-Jun N-terminal kinase, Akt, p38, and p44/42 mitogen-activated protein kinases and potentiates apoptosis . J Biol Chem. 2006 ; 281 : 19798 – 808 . 10.1074/jbc.M601162200 16682409

123. Macha MA Matta A Chauhan SS Siu KW Ralhan R. Guggulsterone (GS) inhibits smokeless tobacco and nicotine-induced NF-κB and STAT3 pathways in head and neck cancer cells . Carcinogenesis. 2011 ; 32 : 368 – 80 . 10.1093/carcin/bgq278 21177768

124. Sarfaraz S Siddiqui IA Syed DN Afaq F Mukhtar H. Guggulsterone modulates MAPK and NF-kappaB pathways and inhibits skin tumorigenesis in SENCAR mice . Carcinogenesis. 2008 ; 29 : 2011 – 8 . 10.1093/carcin/bgn180 18684729 PMC2722858

125. Shi JJ Jia XL Li M Yang N Li YP Zhang X Guggulsterone induces apoptosis of human hepatocellular carcinoma cells through intrinsic mitochondrial pathway . World J Gastroenterol. 2015 ; 21 : 13277 – 87 . 10.3748/wjg.v21.i47.13277 26715810 PMC4679759

126. Leo R Therachiyil L Siveen SK Uddin S Kulinski M Buddenkotte J Protein expression profiling identifies key proteins and pathways involved in growth inhibitory effects exerted by guggulsterone in human colorectal cancer cells . Cancers (Basel). 2019 ; 11 : 1478 . 10.3390/cancers11101478 PMC6826505 31581454

127. Kim DG Bae GS Choi SB Jo IJ Shin JY Lee SK Guggulsterone attenuates cerulein-induced acute pancreatitis via inhibition of ERK and JNK activation . Int Immunopharmacol. 2015 ; 26 : 194 – 202 . 10.1016/j.intimp.2015.03.030 25843255

128. Jiang G Xiao X Zeng Y Nagabhushanam K Majeed M Xiao D. Targeting beta-catenin signaling to induce apoptosis in human breast cancer cells by z-guggulsterone and Gugulipid extract of Ayurvedic medicine plant Commiphora mukul . BMC Complement Altern Med. 2013 ; 13 : 203 . 10.1186/1472-6882-13-203 23914993 PMC3735424

129. Xiao D Zeng Y Prakash L Badmaev V Majeed M Singh SV. Reactive oxygen species-dependent apoptosis by gugulipid extract of Ayurvedic medicine plant Commiphora mukul in human prostate cancer cells is regulated by c-Jun N-terminal kinase . Mol Pharmacol. 2011 ; 79 : 499 – 507 . 10.1124/mol.110.068551 21115635 PMC3061364

130. Zhong F Tong ZT Fan LL Zha LX Wang F Yao MQ Guggulsterone-induced apoptosis in cholangiocarcinoma cells through ROS/JNK signaling pathway . Am J Cancer Res. 2016 ; 6 : 226 – 37 . 27186398 PMC4859655

131. Singh SV Choi S Zeng Y Hahm ER Xiao D. Guggulsterone-induced apoptosis in human prostate cancer cells is caused by reactive oxygen intermediate dependent activation of c-Jun NH2-terminal kinase . Cancer Res. 2007 ; 67 : 7439 – 49 . 10.1158/0008-5472.CAN-07-0120 17671214

132. Neal CL Yu D. 14-3-3 ζ as a prognostic marker and therapeutic target for cancer . Expert Opin Ther Targets. 2010 ; 14 : 1343 – 54 . 10.1517/14728222.2010.531011 21058923 PMC3017465

133. Macha MA Matta A Chauhan S Siu KM Ralhan R. 14-3-3 zeta is a molecular target in guggulsterone induced apoptosis in head and neck cancer cells . BMC Cancer. 2010 ; 10 : 655 . 10.1186/1471-2407-10-655 21118500 PMC3002356

134. Chen XZ Xu HB Xu LZ Mao XP Li L. Guggulsterone regulates the function and expression of P-glycoprotein in rat brain microvessel endothelial cells . Eur J Pharmacol. 2013 ; 718 : 24 – 9 . 10.1016/j.ejphar.2013.09.010 24041929

135. Xu HB Li L Liu GQ. Reversal of P-glycoprotein-mediated multidrug resistance by guggulsterone in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells . Pharmazie. 2009 ; 64 : 660 – 5 . 19947169

136. Xu HB Xu LZ Li L Fu J Mao XP. Reversion of P-glycoprotein-mediated multidrug resistance by guggulsterone in multidrug-resistant human cancer cell lines . Eur J Pharmacol. 2012 ; 694 : 39 – 44 . 10.1016/j.ejphar.2012.06.046 22960326

137. Xu HB Fu J Huang F Yu J. Guggulsterone sensitized drug-resistant human hepatocarcinoma cells to doxorubicin through a Cox-2/P-gp dependent pathway . Eur J Pharmacol. 2017 ; 803 : 57 – 64 . 10.1016/j.ejphar.2017.03.045 28342979

138. Xu HB Shen ZL Fu J Xu LZ. Reversal of doxorubicin resistance by guggulsterone of Commiphora mukul in vivo . Phytomedicine. 2014 ; 21 : 1221 – 9 . 10.1016/j.phymed.2014.06.003 25172783

139. Yang MH Lee KT Yang S Lee JK Lee KH Moon IH Guggulsterone enhances antitumor activity of gemcitabine in gallbladder cancer cells through suppression of NF-κB . J Cancer Res Clin Oncol. 2012 ; 138 : 1743 – 51 . 10.1007/s00432-012-1254-7 22699931 PMC11824197

140. Dixit D Ghildiyal R Anto NP Ghosh S Sharma V Sen E. Guggulsterone sensitizes glioblastoma cells to Sonic hedgehog inhibitor SANT-1 induced apoptosis in a Ras/NFκB dependent manner . Cancer Lett. 2013 ; 336 : 347 – 58 . 10.1016/j.canlet.2013.03.025 23548480

141. Kong JN He Q Wang G Dasgupta S Dinkins MB Zhu G Guggulsterone and bexarotene induce secretion of exosome-associated breast cancer resistance protein and reduce doxorubicin resistance in MDA-MB-231 cells . Int J Cancer. 2015 ; 137 : 1610 – 20 . 10.1002/ijc.29542 25833198 PMC4503537

142. Moon DO Park SY Choi YH Ahn JS Kim GY. Guggulsterone sensitizes hepatoma cells to TRAIL-induced apoptosis through the induction of CHOP-dependent DR5: involvement of ROS-dependent ER-stress . Biochem Pharmacol. 2011 ; 82 : 1641 – 50 . 10.1016/j.bcp.2011.08.019 21903093

143. Wang M Zhao J Zhang L Wei F Lian Y Wu Y Role of tumor microenvironment in tumorigenesis . J Cancer. 2017 ; 8 : 761 – 73 . 10.7150/jca.17648 28382138 PMC5381164

144. Denton AE Roberts EW Fearon DT. Stromal cells in the tumor microenvironment . Adv Exp Med Biol. 2018 ; 1060 : 99 – 114 . 10.1007/978-3-319-78127-3_6 30155624

145. Arneth B. Tumor microenvironment . Medicina (Kaunas). 2019 ; 56 : 15 . 10.3390/medicina56010015 PMC7023392 31906017

146. Libring S Shinde A Chanda MK Nuru M George H Saleh AM The dynamic relationship of breast cancer cells and fibroblasts in fibronectin accumulation at primary and metastatic tumor sites . Cancers (Basel). 2020 ; 12 : 1270 . 10.3390/cancers12051270 PMC7281295 32429591

147. Hardy SD Shinde A Wang WH Wendt MK Geahlen RL. Regulation of epithelial-mesenchymal transition and metastasis by TGF-β, P-bodies, and autophagy . Oncotarget. 2017 ; 8 : 103302 – 14 . 10.18632/oncotarget.21871 29262563 PMC5732729

148. Shinde A Libring S Alpsoy A Abdullah A Schaber JA Solorio L Autocrine fibronectin inhibits breast cancer metastasis . Mol Cancer Res. 2018 ; 16 : 1579 – 89 . 10.1158/1541-7786.MCR-18-0151 29934326 PMC6511995

149. Shinde A Wilmanski T Chen H Teegarden D Wendt MK. Pyruvate carboxylase supports the pulmonary tropism of metastatic breast cancer . Breast Cancer Res. 2018 ; 20 : 76 . 10.1186/s13058-018-1008-9 30005601 PMC6045837

150. Shinde A Hardy SD Kim D Akhand SS Jolly MK Wang WH Spleen tyrosine kinase-mediated autophagy is required for epithelial-mesenchymal plasticity and metastasis in breast cancer . Cancer Res. 2019 ; 79 : 1831 – 43 . 10.1158/0008-5472.CAN-18-2636 30733195 PMC6467765

151. Shinde A Paez JS Libring S Hopkins K Solorio L Wendt MK. Transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche . Oncogenesis. 2020 ; 9 : 16 . 10.1038/s41389-020-0204-5 32054828 PMC7018754

152. Uzunalli G Dieterly AM Kemet CM Weng HY Soepriatna AH Goergen CJ Dynamic transition of the blood-brain barrier in the development of non-small cell lung cancer brain metastases . Oncotarget. 2019 ; 10 : 6334 – 48 . 10.18632/oncotarget.27274 31695842 PMC6824867

153. Wilmanski T Zhou X Zheng W Shinde A Donkin SS Wendt M Inhibition of pyruvate carboxylase by 1α,25-dihydroxyvitamin D promotes oxidative stress in early breast cancer progression . Cancer Lett. 2017 ; 411 : 171 – 81 . 10.1016/j.canlet.2017.09.045 29024812 PMC5763507

154. Wu AA Drake V Huang HS Chiu S Zheng L. Reprogramming the tumor microenvironment: tumor-induced immunosuppressive factors paralyze T cells . Oncoimmunology. 2015 ; 4 : e1016700 . 10.1080/2162402X.2015.1016700 26140242 PMC4485788

155. Tormoen GW Crittenden MR Gough MJ. Role of the immunosuppressive microenvironment in immunotherapy . Adv Radiat Oncol. 2018 ; 3 : 520 – 6 . 10.1016/j.adro.2018.08.018 30370351 PMC6200899

156. Xu HB Li L Liu GQ. Protection against hydrogen peroxide-induced cytotoxicity in PC12 cells by guggulsterone . Yao Xue Xue Bao. 2008 ; 43 : 1190 – 7 . 19244748

157. Gautam A Paudel YN Abidin S Bhandari U. Guggulsterone, a farnesoid X receptor antagonist lowers plasma trimethylamine- N -oxide levels: an evidence from in vitro and in vivo studies . Hum Exp Toxicol. 2019 ; 38 : 356 – 70 . 10.1177/0960327118817862 30526076

158. Xu Y Guan J Xu J Chen S Sun G. Z-Guggulsterone attenuates glucocorticoid-induced osteoporosis through activation of Nrf2/HO-1 signaling . Life Sci. 2019 ; 224 : 58 – 66 . 10.1016/j.lfs.2019.03.051 30905781

159. Wu K Zhao T Hogstrand C Xu YC Ling SC Chen GH FXR-mediated inhibition of autophagy contributes to FA-induced TG accumulation and accordingly reduces FA-induced lipotoxicity . Cell Commun Signal. 2020 ; 18 : 47 . 10.1186/s12964-020-0525-1 32192487 PMC7082988

160. Yang R Hu Z Zhang P Wu S Song Z Shen X Probucol ameliorates hepatic stellate cell activation and autophagy is associated with farnesoid X receptor . J Pharmacol Sci. 2019 ; 139 : 120 – 8 . 10.1016/j.jphs.2018.12.005 30638990

161. Id Boufker H Lagneaux L Fayyad-Kazan H Badran B Najar M Wiedig M Role of farnesoid X receptor (FXR) in the process of differentiation of bone marrow stromal cells into osteoblasts . Bone. 2011 ; 49 : 1219 – 31 . 10.1016/j.bone.2011.08.013 21893226

162. Chen B You WJ Xue S Qin H Zhao XJ Zhang M Overexpression of farnesoid X receptor in small airways contributes to epithelial to mesenchymal transition and COX-2 expression in chronic obstructive pulmonary disease . J Thorac Dis. 2016 ; 8 : 3063 – 74 . 10.21037/jtd.2016.11.08 28066584 PMC5179405

163. Khwairakpam AD Monisha J Banik K Choudhary H Sharma A Bordoloi D Chemoresistance in brain cancer and different chemosensitization approaches . In: Kunnumakkara AB Bordoloi D Monisha J editors. Cancer cell chemoresistance and chemosensitization . Singapore : World Scientific ; 2018 . pp. 107 – 27 .

164. Bhuvanalakshmi G Gamit N Patil M Arfuso F Sethi G Dharmarajan A Stemness, pluripotentiality, and Wnt antagonism: sFRP4, a Wnt antagonist mediates pluripotency and stemness in glioblastoma . Cancers (Basel). 2018 ; 11 : 25 . 10.3390/cancers11010025 PMC6356444 30591679

165. Thakur KK Bordoloi D Kunnumakkara AB. Alarming burden of triple-negative breast cancer in India . Clin Breast Cancer. 2018 ; 18 : e393 – 9 . 10.1016/j.clbc.2017.07.013 28801156

166. Shanmugam MK Ahn KS Hsu A Woo CC Yuan Y Tan KHB Thymoquinone inhibits bone metastasis of breast cancer cells through abrogation of the CXCR4 signaling axis . Front Pharmacol. 2018 ; 9 : 1294 . 10.3389/fphar.2018.01294 30564115 PMC6288203

167. Liu L Ahn KS Shanmugam MK Wang H Shen H Arfuso F Oleuropein induces apoptosis via abrogating NF-κB activation cascade in estrogen receptor-negative breast cancer cells . J Cell Biochem. 2019 ; 120 : 4504 – 13 . 10.1002/jcb.27738 30260018

168. Wang C Kar S Lai X Cai W Arfuso F Sethi G Triple negative breast cancer in Asia: an insider’s view . Cancer Treat Rev. 2018 ; 62 : 29 – 38 . 10.1016/j.ctrv.2017.10.014 29154023

169. Bhuvanalakshmi G Basappa Rangappa KS Dharmarajan A Sethi G Kumar AP Breast cancer stem-like cells are inhibited by Diosgenin, a steroidal saponin, by the attenuation of the Wnt β-Catenin signaling via the Wnt antagonist secreted frizzled related protein-4 . Front Pharmacol. 2017 ; 8 : 124 . 10.3389/fphar.2017.00124 28373842 PMC5357646

170. Mohan CD Srinivasa V Rangappa S Mervin L Mohan S Paricharak S Trisubstituted-imidazoles induce apoptosis in human breast cancer cells by targeting the oncogenic PI3K/Akt/mTOR signaling pathway . PLoS One. 2016 ; 11 : e0153155 . 10.1371/journal.pone.0153155 27097161 PMC4838272

171. Jia LY Shanmugam MK Sethi G Bishayee A. Potential role of targeted therapies in the treatment of triple-negative breast cancer . Anticancer Drugs. 2016 ; 27 : 147 – 55 . 10.1097/CAD.0000000000000328 26682525

172. Choudhuri R Degraff W Gamson J Mitchell JB Cook JA. Guggulsterone-mediated enhancement of radiosensitivity in human tumor cell lines . Front Oncol. 2011 ; 1 : 19 . 10.3389/fonc.2011.00019 22649756 PMC3355920

173. Silva J Dasgupta S Wang G Krishnamurthy K Ritter E Bieberich E. Lipids isolated from bone induce the migration of human breast cancer cells . J Lipid Res. 2006 ; 47 : 724 – 33 . 10.1194/jlr.M500473-JLR200 16439808

174. Xu HB Li L Liu GQ. Reversal of multidrug resistance by guggulsterone in drug-resistant MCF-7 cell lines . Chemotherapy. 2011 ; 57 : 62 – 70 . 10.1159/000321484 21282948

175. Buhrmann C Yazdi M Popper B Kunnumakkara AB Aggarwal BB Shakibaei M. Induction of the epithelial-to-mesenchymal transition of human colorectal cancer by human TNF-β (Lymphotoxin) and its reversal by resveratrol . Nutrients. 2019 ; 11 : 704 . 10.3390/nu11030704 PMC6471988 30917533

176. Buhrmann C Kunnumakkara AB Popper B Majeed M Aggarwal BB Shakibaei M. Calebin A potentiates the effect of 5-FU and TNF-β (Lymphotoxin α) against human colorectal cancer cells: potential role of NF-κB . Int J Mol Sci. 2020 ; 21 : 2393 . 10.3390/ijms21072393 PMC7177530 32244288

177. Peng Z Raufman JP Xie G. Src-mediated cross-talk between farnesoid X and epidermal growth factor receptors inhibits human intestinal cell proliferation and tumorigenesis . PLoS One. 2012 ; 7 : e48461 . 10.1371/journal.pone.0048461 23119029 PMC3485230

178. Bordoloi D Banik K Khwairakpam AD Sharma A Monisha J Sailo BL Different approaches to overcome chemoresistance in esophageal cancer . In: Kunnumakkara AB Bordoloi D Monisha J editors. Cancer cell chemoresistance and chemosensitization . Singapore : World Scientific ; 2018 . pp. 241 – 66 .

179. Guan B Li H Yang Z Hoque A Xu X. Inhibition of farnesoid X receptor controls esophageal cancer cell growth in vitro and in nude mouse xenografts . Cancer. 2013 ; 119 : 1321 – 9 . 10.1002/cncr.27910 23280144 PMC3604152

180. Guan B Hoque A Xu X. Amiloride and guggulsterone suppression of esophageal cancer cell growth in vitro and in nude mouse xenografts . Front Biol (Beijing). 2014 ; 9 : 75 – 81 . 10.1007/s11515-014-1289-z 24999355 PMC4079079

181. Elkashty OA Ashry R Tran SD. Head and neck cancer management and cancer stem cells implication . Saudi Dent J. 2019 ; 31 : 395 – 416 . 10.1016/j.sdentj.2019.05.010 31700218 PMC6823822

182. Sawhney M Rohatgi N Kaur J Shishodia S Sethi G Gupta SD Expression of NF-kappaB parallels COX-2 expression in oral precancer and cancer: association with smokeless tobacco . Int J Cancer. 2007 ; 120 : 2545 – 56 . 10.1002/ijc.22657 17354234

183. Lee JH Rangappa S Mohan CD Basappa Sethi G Lin ZX Rangappa KS Ahn KS. Brusatol, a Nrf2 inhibitor targets STAT3 signaling cascade in head and neck squamous cell carcinoma . Biomolecules. 2019 ; 9 : 550 . 10.3390/biom9100550 PMC6843503 31575007

184. Behera AK Kumar M Shanmugam MK Bhattacharya A Rao VJ Bhat A Functional interplay between YY1 and CARM1 promotes oral carcinogenesis . Oncotarget. 2019 ; 10 : 3709 – 24 . 10.18632/oncotarget.26984 31217904 PMC6557205

185. Selvi RB Swaminathan A Chatterjee S Shanmugam MK Li F Ramakrishnan GB Inhibition of p300 lysine acetyltransferase activity by luteolin reduces tumor growth in head and neck squamous cell carcinoma (HNSCC) xenograft mouse model . Oncotarget. 2015 ; 6 : 43806 – 18 . 10.18632/oncotarget.6245 26517526 PMC4791268

186. Li F Shanmugam MK Siveen KS Wang F Ong TH Loo SY Garcinol sensitizes human head and neck carcinoma to cisplatin in a xenograft mouse model despite downregulation of proliferative biomarkers . Oncotarget. 2015 ; 6 : 5147 – 63 . 10.18632/oncotarget.2881 25762616 PMC4467139

187. Li F Shanmugam MK Chen L Chatterjee S Basha J Kumar AP Garcinol, a polyisoprenylated benzophenone modulates multiple proinflammatory signaling cascades leading to the suppression of growth and survival of head and neck carcinoma . Cancer Prev Res (Phila). 2013 ; 6 : 843 – 54 . 10.1158/1940-6207.CAPR-13-0070 23803415

188. Thakur KK Bordoloi D Prakash J Monisha J Roy NK Kunnumakkara AB. Different chemosensitization approaches for the effective management of HNSCC . In: Kunnumakkara AB Bordoloi D Monisha J editors. Cancer cell chemoresistance and chemosensitization . Singapore : World Scientific ; 2018 . pp. 399 – 423 .

189. Li C Zang Y Sen M Leeman-Neill RJ Man DS Grandis JR Bortezomib up-regulates activated signal transducer and activator of transcription-3 and synergizes with inhibitors of signal transducer and activator of transcription-3 to promote head and neck squamous cell carcinoma cell death . Mol Cancer Ther. 2009 ; 8 : 2211 – 20 . 10.1158/1535-7163.MCT-09-0327 19638453 PMC2768047

190. Singh AK Roy NK Anip A Banik K Monisha J Bordoloi D Different methods to inhibit chemoresistance in hepatocellular carcinoma . In: Kunnumakkara AB Bordoloi D Monisha J editors. Cancer cell chemoresistance and chemosensitization . Singapore : World Scientific ; 2018 . pp. 373 – 98 .

191. Swamy SG Kameshwar VH Shubha PB Looi CY Shanmugam MK Arfuso F Targeting multiple oncogenic pathways for the treatment of hepatocellular carcinoma . Target Oncol. 2017 ; 12 : 1 – 10 . 10.1007/s11523-016-0452-7 27510230

192. Sethi G Chatterjee S Rajendran P Li F Shanmugam MK Wong KF Inhibition of STAT3 dimerization and acetylation by garcinol suppresses the growth of human hepatocellular carcinoma in vitro and in vivo . Mol Cancer. 2014 ; 13 : 66 . 10.1186/1476-4598-13-66 24655440 PMC3998115

193. Mohan CD Bharathkumar H Bulusu KC Pandey V Rangappa S Fuchs JE Development of a novel azaspirane that targets the Janus kinase-signal transducer and activator of transcription (STAT) pathway in hepatocellular carcinoma in vitro and in vivo . J Biol Chem. 2014 ; 289 : 34296 – 307 . 10.1074/jbc.M114.601104 25320076 PMC4256360

194. Dai X Ahn KS Kim C Siveen KS Ong TH Shanmugam MK Ascochlorin, an isoprenoid antibiotic inhibits growth and invasion of hepatocellular carcinoma by targeting STAT3 signaling cascade through the induction of PIAS3 . Mol Oncol. 2015 ; 9 : 818 – 33 . 10.1016/j.molonc.2014.12.008 25624051 PMC5528777

195. Rajendran P Li F Shanmugam MK Vali S Abbasi T Kapoor S Honokiol inhibits signal transducer and activator of transcription-3 signaling, proliferation, and survival of hepatocellular carcinoma cells via the protein tyrosine phosphatase SHP-1 . J Cell Physiol. 2012 ; 227 : 2184 – 95 . 10.1002/jcp.22954 21792937

196. Rajendran P Li F Manu KA Shanmugam MK Loo SY Kumar AP γ-Tocotrienol is a novel inhibitor of constitutive and inducible STAT3 signalling pathway in human hepatocellular carcinoma: potential role as an antiproliferative, pro-apoptotic and chemosensitizing agent . Br J Pharmacol. 2011 ; 163 : 283 – 98 . 10.1111/j.1476-5381.2010.01187.x 21198544 PMC3087132

197. Tan SM Li F Rajendran P Kumar AP Hui KM Sethi G. Identification of beta-escin as a novel inhibitor of signal transducer and activator of transcription 3/Janus-activated kinase 2 signaling pathway that suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells . J Pharmacol Exp Ther. 2010 ; 334 : 285 – 93 . 10.1124/jpet.110.165498 20378717

198. Bharti AC Shishodia S Reuben JM Weber D Alexanian R Raj-Vadhan S Nuclear factor-kappaB and STAT3 are constitutively active in CD138+ cells derived from multiple myeloma patients, and suppression of these transcription factors leads to apoptosis . Blood. 2004 ; 103 : 3175 – 84 . 10.1182/blood-2003-06-2151 15070700

199. Shishodia S Amin HM Lai R Aggarwal BB. Curcumin (diferuloylmethane) inhibits constitutive NF-kappaB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma . Biochem Pharmacol. 2005 ; 70 : 700 – 13 . 10.1016/j.bcp.2005.04.043 16023083

200. Siveen KS Mustafa N Li F Kannaiyan R Ahn KS Kumar AP Thymoquinone overcomes chemoresistance and enhances the anticancer effects of bortezomib through abrogation of NF-κB regulated gene products in multiple myeloma xenograft mouse model . Oncotarget. 2014 ; 5 : 634 – 48 . 10.18632/oncotarget.1596 24504138 PMC3996662

201. Arora L Kumar AP Arfuso F Chng WJ Sethi G. The role of signal transducer and activator of transcription 3 (STAT3) and its targeted inhibition in hematological malignancies . Cancers (Basel). 2018 ; 10 : 327 . 10.3390/cancers10090327 PMC6162647 30217007

202. Samudio I Konopleva M Safe S McQueen T Andreeff M. Guggulsterones induce apoptosis and differentiation in acute myeloid leukemia: identification of isomer-specific antileukemic activities of the pregnadienedione structure . Mol Cancer Ther. 2005 ; 4 : 1982 – 92 . 10.1158/1535-7163.MCT-05-0247 16373713

203. Harikumar KB Kunnumakkara AB Sethi G Diagaradjane P Anand P Pandey MK Resveratrol, a multitargeted agent, can enhance antitumor activity of gemcitabine in vitro and in orthotopic mouse model of human pancreatic cancer . Int J Cancer. 2010 ; 127 : 257 – 68 . 10.1002/ijc.25041 19908231 PMC3090706

204. Kunnumakkara AB Guha S Krishnan S Diagaradjane P Gelovani J Aggarwal BB. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products . Cancer Res. 2007 ; 67 : 3853 – 61 . 10.1158/0008-5472.CAN-06-4257 17440100

205. Dhillon N Aggarwal BB Newman RA Wolff RA Kunnumakkara AB Abbruzzese JL Phase II trial of curcumin in patients with advanced pancreatic cancer . Clin Cancer Res. 2008 ; 14 : 4491 – 9 . 10.1158/1078-0432.CCR-08-0024 18628464

206. Kunnumakkara AB Sung B Ravindran J Diagaradjane P Deorukhkar A Dey S {Gamma}-tocotrienol inhibits pancreatic tumors and sensitizes them to gemcitabine treatment by modulating the inflammatory microenvironment . Cancer Res. 2010 ; 70 : 8695 – 705 . 10.1158/0008-5472.CAN-10-2318 20864511 PMC2970705

207. Kunnumakkara AB Sung B Ravindran J Diagaradjane P Deorukhkar A Dey S Zyflamend suppresses growth and sensitizes human pancreatic tumors to gemcitabine in an orthotopic mouse model through modulation of multiple targets . Int J Cancer. 2012 ; 131 : E292 – 303 . 10.1002/ijc.26442 21935918 PMC3288649

208. Harikumar KB Kunnumakkara AB Ochi N Tong Z Deorukhkar A Sung B A novel small-molecule inhibitor of protein kinase D blocks pancreatic cancer growth in vitro and in vivo . Mol Cancer Ther. 2010 ; 9 : 1136 – 46 . Erratum in: Mol Cancer Ther. 2010;9:2153. 10.1158/1535-7163.MCT-09-1145 20442301 PMC2905628

209. Lee JY Lee KT Lee JK Lee KH Jang KT Heo JS Farnesoid X receptor, overexpressed in pancreatic cancer with lymph node metastasis promotes cell migration and invasion . Br J Cancer. 2011 ; 104 : 1027 – 37 . 10.1038/bjc.2011.37 21364590 PMC3065277

210. Kohyama A Yokoyama R Dibwe DF El-Mekkawy S Meselhy MR Awale S Synthesis of guggulsterone derivatives as potential anti-austerity agents against PANC-1 human pancreatic cancer cells . Bioorg Med Chem Lett. 2020 ; 30 : 126964 . 10.1016/j.bmcl.2020.126964 32057581

211. Ahn DW Seo JK Lee SH Hwang JH Lee JK Ryu JK Enhanced antitumor effect of combination therapy with gemcitabine and guggulsterone in pancreatic cancer . Pancreas. 2012 ; 41 : 1048 – 57 . 10.1097/MPA.0b013e318249d62e 22513291

212. Zhang J Sikka S Siveen KS Lee JH Um JY Kumar AP Cardamonin represses proliferation, invasion, and causes apoptosis through the modulation of signal transducer and activator of transcription 3 pathway in prostate cancer . Apoptosis. 2017 ; 22 : 158 – 68 . 10.1007/s10495-016-1313-7 27900636

213. Lee JH Kim C Baek SH Ko JH Lee SG Yang WM Capsazepine inhibits JAK/STAT3 signaling, tumor growth, and cell survival in prostate cancer . Oncotarget. 2017 ; 8 : 17700 – 11 . 10.18632/oncotarget.10775 27458171 PMC5392279

214. Zhang J Ahn KS Kim C Shanmugam MK Siveen KS Arfuso F Nimbolide-induced oxidative stress abrogates STAT3 signaling cascade and inhibits tumor growth in transgenic adenocarcinoma of mouse prostate model . Antioxid Redox Signal. 2016 ; 24 : 575 – 89 . 10.1089/ars.2015.6418 26649526

215. Kim C Cho SK Kapoor S Kumar A Vali S Abbasi T β-Caryophyllene oxide inhibits constitutive and inducible STAT3 signaling pathway through induction of the SHP-1 protein tyrosine phosphatase . Mol Carcinog. 2014 ; 53 : 793 – 806 . 10.1002/mc.22035 23765383

216. Muralimanoharan SB Kunnumakkara AB Shylesh B Kulkarni KH Haiyan X Ming H Butanol fraction containing berberine or related compound from nexrutine inhibits NFkappaB signaling and induces apoptosis in prostate cancer cells . Prostate. 2009 ; 69 : 494 – 504 . 10.1002/pros.20899 19107816 PMC2674392

217. Heymach JV Shackleford TJ Tran HT Yoo SY Do KA Wergin M Effect of low-fat diets on plasma levels of NF-κB-regulated inflammatory cytokines and angiogenic factors in men with prostate cancer . Cancer Prev Res (Phila). 2011 ; 4 : 1590 – 8 . 10.1158/1940-6207.CAPR-10-0136 21764858 PMC3438697

218. Xiao D Singh SV. z-Guggulsterone, a constituent of Ayurvedic medicinal plant Commiphora mukul, inhibits angiogenesis in vitro and in vivo . Mol Cancer Ther. 2008 ; 7 : 171 – 80 . 10.1158/1535-7163.MCT-07-0491 18202020

219. Koo JH Rhee KS Koh HW Jang HY Park BH Park JW. Guggulsterone inhibits melanogenesis in B16 murine melanoma cells by downregulating tyrosinase expression . Int J Mol Med. 2012 ; 30 : 974 – 8 . 10.3892/ijmm.2012.1057 22797252

220. Verma N Singh SK Gupta RC. Simultaneous determination of the stereoisomers of guggulsterone in serum by high-performance liquid chromatography . J Chromatogr B Biomed Sci Appl. 1998 ; 708 : 243 – 8 . 10.1016/s0378-4347(97)00626-9 9653969

221. Verma N Singh SK Gupta RC. Pharmacokinetics of guggulsterone after intravenous and oral administration in rats . Pharm Pharmacol Comm. 1999 ; 5 : 349 – 54 . 10.1211/146080899128734956

222. Bhatta RS Kumar D Chhonker YS Jain GK. Simultaneous estimation of E- and Z-isomers of guggulsterone in rabbit plasma using liquid chromatography tandem mass spectrometry and its application to pharmacokinetic study . Biomed Chromatogr. 2011 ; 25 : 1054 – 60 . 10.1002/bmc.1574 21268049

223. Chhonker YS Chandasana H Mukkavilli R Prasad YD Laxman TS Vangala S Assessment of in vitro metabolic stability, plasma protein binding, and pharmacokinetics of E- and Z-guggulsterone in rat . Drug Test Anal. 2016 ; 8 : 966 – 75 . 10.1002/dta.1885 26608935

224. Yang D Yang J Shi D Xiao D Chen YT Black C Hypolipidemic agent Z-guggulsterone: metabolism interplays with induction of carboxylesterase and bile salt export pump . J Lipid Res. 2012 ; 53 : 529 – 39 . 10.1194/jlr.M014688 22246918 PMC3276476

225. Chhonker YS Chandasana H Bala V Mukkavilli R Kumar D Vangala S In-vitro metabolism, CYP profiling and metabolite identification of E- and Z-guggulsterone, a potent hypolipidmic agent . J Pharm Biomed Anal. 2018 ; 160 : 202 – 11 . 10.1016/j.jpba.2018.06.047 30099292

226. Balhara A Ladumor M Singh DK Praneetha P Preethi J Pokharkar S In vitro evaluation of reactive nature of E- and Z-guggulsterones and their metabolites in human liver microsomes using UHPLC-Orbitrap mass spectrometer . J Pharm Biomed Anal. 2020 ; 186 : 113275 . 10.1016/j.jpba.2020.113275 32247160

227. Singh AK Roy NK Bordoloi D Padmavathi G Banik K Khwairakpam AD Orai-1 and Orai-2 regulate oral cancer cell migration and colonisation by suppressing Akt/mTOR/NF-κB signalling . Life Sci. 2020 ; 261 : 118372 . 10.1016/j.lfs.2020.118372 32882268

228. Roy NK Monisha J Padmavathi G Lalhruaitluanga H Kumar NS Singh AK Isoform-specific role of akt in oral squamous cell carcinoma . Biomolecules. 2019 ; 9 : 253 . 10.3390/biom9070253 PMC6681224 31252679

229. Parama D Boruah M Kumari Y Rana V Banik K Harsha C Diosgenin, a steroidal saponin, and its analogues: effective therapies against different chronic diseases . Life Sci . 2020 : 118182 . 10.1016/j.lfs.2020.118182 32781063

230. Bordoloi D Banik K Padmavathi G Vikkurthi R Harsha C Roy NK TIPE2 induced the proliferation, survival, and migration of lung cancer cells through modulation of Akt/mTOR/NF-κBsignaling cascade . Biomolecules. 2019 ; 9 : 836 . 10.3390/biom9120836 PMC6995575 31817720

231. Monisha J Roy NK Padmavathi G Banik K Bordoloi D Khwairakpam AD NGAL is downregulated in oral squamous cell carcinoma and leads to increased survival, proliferation, migration and chemoresistance . Cancers (Basel). 2018 ; 10 : 228 . 10.3390/cancers10070228 PMC6071146 29996471

232. Aggarwal BB Sethi G Ahn KS Sandur SK Pandey MK Kunnumakkara AB Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution . Ann N Y Acad Sci. 2006 ; 1091 : 151 – 69 . 10.1196/annals.1378.063 17341611

233. Goel A Kunnumakkara AB Aggarwal BB. Curcumin as “Curecumin”: from kitchen to clinic . Biochem Pharmacol. 2008 ; 75 : 787 – 809 . 10.1016/j.bcp.2007.08.016 17900536

234. Anand P Thomas SG Kunnumakkara AB Sundaram C Harikumar KB Sung B Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature . Biochem Pharmacol. 2008 ; 76 : 1590 – 611 . 10.1016/j.bcp.2008.08.008 18775680

235. Anand P Sundaram C Jhurani S Kunnumakkara AB Aggarwal BB. Curcumin and cancer: an “old-age” disease with an “age-old” solution . Cancer Lett. 2008 ; 267 : 133 – 64 . 10.1016/j.canlet.2008.03.025 18462866

236. Kunnumakkara AB Bordoloi D Padmavathi G Monisha J Roy NK Prasad S Curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases . Br J Pharmacol. 2017 ; 174 : 1325 – 48 . 10.1111/bph.13621 27638428 PMC5429333

237. Kunnumakkara AB Diagaradjane P Guha S Deorukhkar A Shentu S Aggarwal BB Curcumin sensitizes human colorectal cancer xenografts in nude mice to gamma-radiation by targeting nuclear factor-kappaB-regulated gene products . Clin Cancer Res. 2008 ; 14 : 2128 – 36 . 10.1158/1078-0432.CCR-07-4722 18381954

238. Bhutani M Pathak AK Nair AS Kunnumakkara AB Guha S Sethi G Capsaicin is a novel blocker of constitutive and interleukin-6-inducible STAT3 activation . Clin Cancer Res. 2007 ; 13 : 3024 – 32 . 10.1158/1078-0432.CCR-06-2575 17505005

239. Pandey MK Sandur SK Sung B Sethi G Kunnumakkara AB Aggarwal BB. Butein, a tetrahydroxychalcone, inhibits nuclear factor (NF)-kappaB and NF-kappaB-regulated gene expression through direct inhibition of IkappaBalpha kinase beta on cysteine 179 residue . J Biol Chem. 2007 ; 282 : 17340 – 50 . 10.1074/jbc.M700890200 17439942

240. Kunnumakkara AB Diagaradjane P Anand P Harikumar KB Deorukhkar A Gelovani J Curcumin sensitizes human colorectal cancer to capecitabine by modulation of cyclin D1, COX-2, MMP-9, VEGF and CXCR4 expression in an orthotopic mouse model . Int J Cancer. 2009 ; 125 : 2187 – 97 . 10.1002/ijc.24593 19623659

241. Pandey MK Sung B Kunnumakkara AB Sethi G Chaturvedi MM Aggarwal BB. Berberine modifies cysteine 179 of IkappaBalpha kinase, suppresses nuclear factor-kappaB-regulated antiapoptotic gene products, and potentiates apoptosis . Cancer Res. 2008 ; 68 : 5370 – 9 . 10.1158/0008-5472.CAN-08-0511 18593939

242. Sung B Kunnumakkara AB Sethi G Anand P Guha S Aggarwal BB. Curcumin circumvents chemoresistance in vitro and potentiates the effect of thalidomide and bortezomib against human multiple myeloma in nude mice model . Mol Cancer Ther. 2009 ; 8 : 959 – 70 . 10.1158/1535-7163.MCT-08-0905 19372569 PMC2694943

243. Harikumar KB Kunnumakkara AB Ahn KS Anand P Krishnan S Guha S Modification of the cysteine residues in IkappaB alpha kinase and NF-kappaB (p65) by xanthohumol leads to suppression of NF-kappaB-regulated gene products and potentiation of apoptosis in leukemia cells . Blood . 2009 , 113 : 2003 – 13 . 10.1182/blood-2008-04-151944 18952893 PMC2947354

244. Nair AS Shishodia S Ahn KS Kunnumakkara AB Sethi G Aggarwal BB. Deguelin, an Akt inhibitor, suppresses IkappaBalpha kinase activation leading to suppression of NF-kappaB-regulated gene expression, potentiation of apoptosis, and inhibition of cellular invasion . J Immunol. 2006 ; 177 : 5612 – 22 . 10.4049/jimmunol.177.8.5612 17015749

245. Buhrmann C Shayan P Banik K Kunnumakkara AB Kubatka P Koklesova L Targeting NF-κBsignaling by calebin A, a compound of turmeric, in multicellular tumor microenvironment: potential role of apoptosis induction in CRC cells . Biomedicines. 2020 ; 8 : 236 . 10.3390/biomedicines8080236 PMC7460490 32708030