Modulating the JAK/STAT pathway with natural products: potential and challenges in cancer therapy.

Introduction

According to the 2024 Cancer Statistics update by the American Cancer Society around 2,001,140 new cancer cases and 611,720 cancer deaths are projected to occur in the United States [ 1 ]. Cancer is a diverse group of diseases that is associated with uncontrolled, rapid, and aberrant cell proliferation. Despite significant advancements in chemotherapy strategies, no single medication has shown efficacy across all cancer types. Several challenges hinder effective cancer treatment and drug development, including issues with drug delivery to tumors, systemic side effects, and the emergence of drug resistance, where cancer cells become unresponsive to treatment [ 2 ]. In light of the pressing need to develop methods for predicting the severity of diagnoses, similar approaches have been explored in other areas of healthcare, such as the use of artificial intelligence to forecast the severity of COVID-19 infections, demonstrating the potential of integrating clinical, biological, and imaging data for accurate predictions [ 3 ]. Drug resistance can occur due to several reasons, including drug expulsion by cancer cells, decreased sensitivity to drugs, or cellular changes rendering drugs less effective. Collectively, these factors cause significant barriers to successful cancer treatment [ 4 ]. The evolution of genetic technology, notably the sequencing of the human genome, has transformed our grasp of cancer. This advancement has unveiled the genetic alterations driving cancer initiation, progression, and treatment response. Armed with this understanding, researchers have identified novel therapeutic targets, offering exciting avenues for the creation of groundbreaking cancer therapies [ 5 ]. Phytochemicals, derived from a variety of natural sources, have shown significant potential in cancer therapy due to their ability to modulate key signaling pathways, inhibit tumor growth, and enhance the efficacy of conventional treatments [ 2 , 4 – 7 ]. Targeted therapies represent a significant advancement in cancer treatment, as they are designed to hinder cancer development and spread by targeting specific molecules or pathways crucial for cancer progression [ 8 ]. These therapies play a pivotal role in the development of chemotherapy drugs and form the foundation of precision medicine [ 2 ]. Tumor development is the outcome of a complex interplay between genetic and non-genetic alterations, which impart traits such as uncontrolled growth and metastasis. Key signaling pathways like JAK/STAT and Notch play crucial roles in this process, capable of transforming healthy cells into cancerous ones [ 9 ]. These pathways are integral to a multitude of cellular and biological functions and dysregulated due to mutations or inactivation of tumor suppressor genes [ 6 ]. The JAK/STAT signaling pathway is involved in stem cell maintenance, hematopoiesis, inflammatory responses, and signal transmission from cytokines and growth factors through specific transmembrane receptor families [ 7 , 10 ]. STAT dimers regulate the transcription of genes responsible for diverse functions, including cell differentiation, proliferation, apoptosis, inflammation, self-renewal, immune response suppression against tumors, cell motility, and stress response [ 8 ]. In addition to conventional treatment approaches, researchers are investigating a novel strategy utilizing natural products. These plant-derived bioactive compounds are being explored for their potential therapeutic advantages in cancer treatment. However, their effectiveness in cancer therapy necessitates thorough validation [ 9 , 11 ]. Studies suggest that natural products demonstrate a reduced incidence of adverse effects compared to conventional chemotherapy and have fewer detrimental impacts on vital organs such as the liver, heart, adrenal glands [ 12 ] and kidneys [ 13 ]. Numerous phytochemicals have been documented to modulate the JAK/STAT signaling pathway through diverse mechanisms [ 14 ]. Natural products have the ability to target multiple sites within the JAK/STAT pathway, inhibiting its activity by reducing the production of cytokines and growth factors [ 15 , 16 ]. Certain phytomolecules have been observed to exert their effects by hindering the phosphorylation of JAK proteins prior to STAT activation or by impeding the dimerization of STAT, thereby preventing the transfer of STAT dimers into the nucleus. The STAT family includes seven members: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6, each with distinct roles in cellular processes. STAT1 and STAT2 are key players in antiviral defense through interferon signalling [ 17 , 28 ]. STAT3 and STAT5 are heavily involved in cell proliferation, survival, and immune regulation, often associated with cancer development. STAT4 drives Th1 immune responses, while STAT6 regulates IL-4 and IL-13 signaling in allergic pathways. These proteins are essential in tumor progression and represent important targets for therapeutic intervention [ 17 , 28 ]. Consequently, inhibiting STAT-DNA binding directly obstructs JAK/STAT-regulated gene transcription. Computational approaches, mainly molecular docking based virtual screening employ to discover the potential lead anti-cancer compounds that target various biological targets like JAK/STAT proteins. Literature evidence suggests that several in silico studies indicate flavonoid as promising anti-cancer scaffold [ 17 ]. Studies suggests that pharmaco-informatics approach was applied to profile and design some Curcumin compounds as potent anticancer agent [ 18 ]. Resveratrol [ 19 ], Apigenin [ 20 ], Silibinin, Emodin [ 21 ], Caffeic acid, Thymoquinone [ 22 ], Garcinol [ 23 ], and Epigallocatechin gallate (EGCG) [ 24 ] are explored for their anti-cancer properties using molecular dynamic simulations and network pharmacology studies. The in silico analysis of pentacyclic triterpenes have reported to have anti-tumor activity [ 25 ]. Ursolic acid is a triterpene acid with anti-cancer activity which inhibit multiple stages of tumor formation and low toxicity profile. The molecular docking studies suggests that ursolic acid exhibits anti tumor activity against various types of cancers [ 26 , 27 ]. This review highlights the therapeutic roles of specific phytochemicals, such as Curcumin, Resveratrol, Apigenin, Silibinin, Ursolic acid, Emodin, Caffeic acid, Thymoquinone, Garcinol, and Epigallocatechin gallate (EGCG), in inhibiting the JAK/STAT signaling pathway. The mechanisms and anticancer effects of these phytochemicals, along with their potential as inhibitors in various types of cancers, are discussed.

Methodology

The literature search was comprehensive, encompassing databases such as PubMed, ScienceDirect, SpringerLink, Scopus, and Google Scholar. The search strategy included the use of specific keywords and MeSH terms such as "Cancer," "Chemotherapy," "JAK," "STAT," "Phytochemicals," "Natural Products," and "Clinical Studies," combined with Boolean operators (AND, OR, NOT) to refine the search (e.g., "Cancer AND JAK/STAT AND Phytochemicals"). Only peer-reviewed papers from reputable journals indexed in Scopus or PubMed were included, ensuring the reliability and quality of the sources. The inclusion criteria were as follows: peer-reviewed papers from reputable journals indexed in Scopus or PubMed, studies published in English, research articles focusing on the modulation of the JAK/STAT pathway by natural products in cancer, articles providing preclinical or clinical data, and studies published within the last 10 years to ensure relevance. The exclusion criteria included conference abstracts, books, book chapters, unpublished works, non-English publications, articles lacking full-text availability, studies not directly related to JAK/STAT signaling in cancer, and duplicates identified during the screening process. A total of 8750 full-text scientific papers were initially selected. After duplicate removal, 5849 articles were screened for eligibility. Based on the inclusion and exclusion criteria, 784 full-text articles were considered eligible. Following further filtering, 66 full-text articles were included in the manuscript. The most representative data has been summarized in tables and figures to provide a clear and concise overview of the findings (Fig. 1 ). Fig. 1 Flowchart of literature selection process for review on natural products modulating the JAK/STAT pathway in cancer. The process involved several stages: identification, screening, eligibility, and inclusion. A total of 8750 records were initially identified from databases such as PubMed, ScienceDirect, PubMed Central, and Google Scholar using specific keywords and MeSH terms. After duplicate removal, 5849 records remained. Of these, 1345 records were screened based on specificity, originality, relevance of information, and adequacy of data. Following further analysis, 784 full-text articles were evaluated for eligibility. Ultimately, 66 articles met the inclusion criteria and were included in the review. Exclusion criteria comprised articles with repeated information, lack of specificity, and incomplete data

The effect of activation of the Janus kinase (JAK)-signal transducer and activator of the transcription (STAT) signaling mechanism in normal and malignant cells

The JAK/STAT pathway is an essential signaling mechanism. that controls several biological activities such as immune regulation and development, cell proliferation and differentiation, cell migration, apoptosis, hematopoiesis of myeloid and non-myeloid cells, and adipogenesis.The investigation into cellular responses to interferons (IFNs) has unveiled the JAK/STAT pathway. These discoveries have illuminated a cellular signaling framework that remains consistent across various species, spanning from slime molds to mammals [ 28 ]. Several studies have shown that autoimmune disorders and multiple malignancies are associated with the deregulation of the JAK/STAT pathway [ 29 , 30 ]. The JAK/STAT signaling system consists of three main components: the cellular receptors, the JAK proteins, and the STAT proteins. The JAK proteins are a group of non-receptor tyrosine kinases consisting of four members: JAK1, JAK2, JAK3, and TYK2. These proteins have molecular weights that range from 120 to 140 kDa. JAK1, JAK2, and TYK2 are widely distributed in all tissues, whereas JAK3 is mostly found in hematopoietic cells, bone marrow, and lymphoid system [ 30 , 31 ]. The JAK protein possesses seven homology domains, often known as JH domains or JAK homology domains. The JH1 domain, sometimes referred to as the Kinase domain, is the first domain that begins with a carboxy terminus consisting of 250 amino acid residues. The JH1 encodes a kinase protein that catalyzes the phosphorylation of the substrate molecule. The Pseudokinase domain, JH2, exhibits structural similarity to JH1 but lacks any kinase activity. The JH2 domain modulates the function of the kinase domain. The SH2 domain consists of the JH3 domain and half of the JH4 domain. The FERM (four-point one ezrin radixin, moesin) domain is formed by the combination of one-half of the JH4 domain, JH5, JH6, and JH7. The fundamental role of the FERM domain is to facilitate the interaction between JAK kinases and the intracellular Box 1 region of cytokine receptors. The interaction between FERM and cytokine receptors is enabled by the SH2 domain, which acts as the specific location for binding with the intracellular Box 2 of cytokine receptors (Fig. 2 a) [ 28 , 30 ]. The STAT family in mammals consists of seven members: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6. The functions of STAT proteins are regulated by six distinct domains, which are arranged in a certain order from the N-terminus to the C-terminus. These domains include the N-terminal domain and coil, helix domain, DNA binding domain, connection domain, SH2 domain, and transcription-activation domain [ 30 , 31 ]. The amino terminal domain promotes STAT dimer formation and enables the subsequent binding of transcription factors. The coiled domain comprises a four-helix bundle and regulates the nuclear import and export mechanisms. The connection domain, also known as the link domain, serves to connect the DNA-binding domain with the SH2 domain. It plays an integral part in controlling the transcription of STAT1. The DNA-binding domain is the crucial area that directs the binding of each STAT molecule to the DNA in the regulatory region of the target gene. The SH2 domain is situated at the dimer interface and has a high degree of conservation across STAT molecules (Fig. 2 b). It plays an essential role in STAT signaling by facilitating the binding of STATs to the active receptor complex [ 30 , 32 , 33 ]. Fig. 2 Structural domains of JAK and STAT proteins. The figure illustrates the structural domains of Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) proteins. a Shows the JAK protein structure, highlighting its seven JAK homology (JH) domains. The FERM domain (JH7 to JH4) facilitates the binding of JAK to the Box1 portion of the cytokine receptor. The SH2 domain (part of JH4 and JH3) aids in the binding of the FERM domain to the cytokine receptor. The Pseudokinase domain (JH2) regulates the activity of the kinase domain, while the Kinase domain (JH1) is responsible for the phosphorylation of cytokines and downstream STAT molecules. b Details the STAT protein structure, displaying its six distinct domains. The N-Terminal domain promotes the formation of STAT dimers. The Coiled-coil domain assists in binding to regulatory proteins. The DNA binding domain identifies and binds to the DNA sequence of the target gene, while the Linker domain connects the DNA binding domain with the SH2 domain. The SH2 domain facilitates the tyrosine phosphorylation of STAT proteins, and the Tyrosine activation domain is crucial for the transcriptional activation of target genes, containing key phosphorylation sites for tyrosine and serine

The activation of the JAK/STAT signaling pathway is triggered by a wide range of ligands, such as cytokines, growth hormones, growth factors, and their corresponding receptors, interferons, and interleukins [ 31 ]. In healthy cells, the canonical JAK/STAT system is activated when cytokines bind to their specific transmembrane receptors. This binding then stimulates the JAK/STAT signaling pathway, which in turn initiates other intracellular signal transduction processes [ 34 ]. The cytokine binds to the corresponding receptor and activates the JAK protein through ligand-associated receptor dimerization [ 28 ]. The interaction between a cytokine and its receptor leads to JAK protein activation and induces the phosphorylation of tyrosine residues on the receptor, leading to the creation of a docking site for STATs. At the docking site, the JAK protein phosphorylates and activates its primary substrate STAT. The phosphorylation of STAT results in the formation of dimers with other STAT family members, which exhibit common SH2 domains [ 30 , 34 ]. Subsequently, the dimer undergoes nuclear translocation where it selectively binds to the targeted DNA sequences, thereby facilitating the transcription process of the target genes (Fig. 3 ). STAT proteins can be activated through pathways other than JAK-dependent activation, like epidermal growth factor (EGF), platelet-derived growth factor (PDGF), extracellular signal-regulated kinase (ERK), protein kinase C, and mitogen-activated protein kinase (MAPK) [ 31 , 34 ]. In addition to its role in regular physiological processes, the JAK/STAT signaling system plays an essential role in various disease conditions, including cancer [ 29 ]. The aberrant activation of the JAK/STAT pathway stimulates the progression of tumors. Abnormal activation occurs when the ligand constantly binds to its receptor or when the tyrosine kinase is improperly activated [ 9 ]. Multiple studies have shown the involvement of STAT3 in tumor progression. STAT3 plays a crucial part in the malignant change that occurs as a result of the activation of oncogenic proteins Src and Ras. Src facilitates the process of incorporating a phosphate group to tyrosine and increases the potential of STAT3 to activate gene transcription. Ras phosphorylates STAT3 at Serine 727, a crucial step for its mitochondrial localization. Therefore, mitochondrial STAT3 plays a role in driving the oncogenic transformation of Ras by facilitating a metabolic shift [ 35 ]. The JAK/STAT pathway plays a significant role in various stages of tumor growth, particularly invasion and metastasis [ 6 , 36 ]. Studies have shown that the JAK/STAT pathway can activate various downstream signaling systems, including the MAPK and PI3K/AKT, TGF-β, Notch signaling, and NF-κB pathways [ 30 ]. Blocking the JAK/STAT signaling system can inhibit the expression of target genes that control vital cellular processes and prevent tumor cells from apoptosis and invasion. Thus, inhibiting JAK/STAT signaling could impede the progression of preneoplastic lesions into a malignant tumor. Fig. 3 Regulation of the JAK/STA signaling pathway. (1) The cytokine binds itself to the corresponding receptor and activates the JAK molecule through ligand-associated receptor dimerization. (2) The binding between cytokine and its receptor causes transphosphorylation of the JAK protein. (3) JAK activation causes tyrosine residues on the receptor to become phosphorylated, which opens up a docking site for STATs. (4) The JAK protein phosphorylates and activates its primary substrate, STAT, at the docking site and forms STAT dimers. (5) Subsequently, the dimer undergoes translocation into the nucleus where it (6) selectively binds to the targeted DNA sequences, thereby facilitating the transcription process of the target genes. DNA deoxyribonucleic acid, JAK Janus Kinase, STAT signal transducer and activator of transcription

An overview of the therapeutic potential of natural products that modulate the JAK/STAT signaling mechanism

Several phytochemicals have been reported to modulate the JAK/STAT signaling pathway through various mechanisms. Natural products can target many sites of action within the JAK/STAT pathway and impede its activity by decreasing the production of cytokines and growth factors. Certain phytomolecules have been found to exert their effects by blocking the process of JAK phosphorylation just before STAT activation, or by impeding the dimerization of STAT and thus hindering the transport of the STAT dimer into the nucleus. Therefore, blocking the direct binding of STAT to DNA inhibits the JAK/STAT-regulated gene transcription. In this context, we described the mechanisms and anticancer effects of selected phytochemicals like Curcumin, Resveratrol, Apigenin, Silibinin, Ursolic acid, Emodin, Caffeic acid, Thymoquinone, Garcinol, Epigallocatechin gallate (EGCG) which works as the inhibitors of the JAK/STAT signaling pathways, with an emphasis on their therapeutic use in different cancer types (Tables 1 and 2 ). Table 1 The tabular column represents the preclinical studies of selected Natural products that modulate the JAK/STAT signaling pathway Tested compound Mechanism of action Experimental model Observation Concentration/Dose References Curcumin Inhibits STAT3 phosphorylation BCPAP and TPC-1 cell line in vitro • Inhibiting antiapoptotic genes • Stimulating proapoptotic genes • Inhibition of PTC cell migration 10 µM, 20 µM and 40 µM of curcumin for 24 h [ 37 ] Six- to eight-week-old male athymic nude mice • increased sensitivity of xenograft tumors containing CAFs to 5-fluorouracil by increasing apoptosis • Ensures synergistic activity of curcumin with 5-fluorouracil treatment 100 µg/g body weight [ 38 ] HepG2 cell line in vitro • Decreased STAT3 expression in HepG2 cells • inhibited growth and migration of liver cancer cells • Mechanism involves blocking cancer cell cycle in the S phase, inducing cell death 20, 40 and 60 μmol for 48 h [ 39 ] Dimethylbenz-(a)anthracene (DMBA)-induced ovarian cancer in female Wistar Rats in vivo • Co-treatment reduced ovarian tumor volume and weight • Decreased JAK expression and STAT3 phosphorylation • It also lowered IL-6 concentrations Unmodified curcumin (100 mg/kg bw every day) Nanocurcumin (100 mg/kg bw every day) [ 40 ] Human Osteosarcoma cell line (MG-63) in vitro Xenograft model (MG-63 injected BALB/c nude mice) in vivo • Curcumin reduced cell proliferation, migration, and invasion in MG-63 osteosarcoma cells • It induced G0/G1 phase arrest • Curcumin triggered apoptosis by inhibiting the phosphorylated JAK2/STAT3 pathway In vitro: 0, 10 or 20 μM of curcumin In vivo: 50 mg/kg/day [ 41 ] TPC-1 and SW1736 pancreatic cell lines in vitro • Reduced cell viability, clonality, and metastatic traits in PTC cell lines • Increased apoptosis • Downregulated Bcl-2 and upregulated Bax expression • Decreased p-JAK2 and p-STAT3 protein levels in treated cells 10 μM and 20 μM [ 42 ] Resveratrol Blocks the STAT1 phosphorylation Human glioblastoma cell lines LN-229 and U87-MG in vitro • Reduced the Sox2 expression • Blocked the activation of Akt and STAT3 induced by CAF-CM 20 µM [ 43 ] Silibinin Suppresses the activation of STAT3 phosphorylation H460 and PC9 cell lines in vitro • Dose-dependently inhibited Y705 STAT3 phosphorylation in H2228 cells • Suppressed acquired feedback hyperactivation of Y705 STAT3 in H3122CR cells 100 µmol/L [ 44 ] • EC cell lines Ishikawa and RL-952 in vitro • BALB/c female nude mice in vivo • Induced cell cycle arrest and apoptosis in endometrial cancer cells, confirmed by TUNEL assay • Suppressed STAT3 activation 50 mg/kg, 100 mg/kg, 150 mg/kg, 200 mg/kg [ 45 ] Apigenin Suppresses the JAK and STAT phosphorylation Blocks the transfer of STAT dimers into the nucleus Doxorubicin resistant MCF-7 and MCF-7R cell line in vitro • Effectively inhibited the phosphorylation and activation of JAK2 and STAT3 proteins in both MCF-7 and MCF-7R cell lines 0–100 µM [ 46 ] Ursolic acid Suppresses JAK2/STAT3 A549 and H460 cell lines in vitro • Inhibits the JAK/STAT pathway and downregulates VEGF, PD-L1, and MMPs • Binds to epidermal growth factor receptors (EGFRs) and reduces phosphorylated EGFRs, which activate the Jak/Stat pathway 1 to 100 µM for 24 [ 47 ] Hep3B, HEPG2, SSMC-7721 and Huh7 cell lines in vitro Xenograft tumor model in mice in vivo • Modulates JAK2 and STAT3 phosphorylation in liver carcinoma • Suppresses nuclear STAT activation 60mg/kg [ 48 ] Caffeic acid Inhibition of STAT3 phosphorylation PC-3 cell line in vitro • Inhibits STAT3 phosphorylation, suppressing proliferation in human prostate cancer PC-3 cells • Reduces PC-3 proliferation, lowers STAT3 levels, enhances apoptosis 15 μM [ 49 ] human colonic carcinoma HT29 and human breast cancer MDA-MB-231 cell lines, mice breast cancer 4T1 cells in vitro • Resveratrol-caffeic acid hybrids targeting both acetylation and phosphorylation of STAT3 to inhibit cell proliferation • Compound 7d showed excellent STAT3 inhibition, 50-fold more potent than resveratrol and caffeic acid 1–5 μM [ 50 ] Thymoquinone Inhibits the STAT3 phosphorylation HGC27, BGC823, and SGC7901 cells in vitro • Inhibits the STAT3 phosphorylation in multiple myeloma cells 0, 10, 25, 50, 75, 100, 125 μmol/L [ 51 ] MV4-11 cells in vitro • Exhibits anti-cancer activity against leukemia, suppressing K562 cell growth dose and time-dependently • Decreases PI3K, Akt, and mTOR activity while upregulating PTEN expression, leading to suppression of JAK/STAT 5.5 μM [ 52 ] Eca-109 cells in vitro • Enhances cisplatin's proapoptotic effect in esophageal cancer cells (Eca-109) by inhibiting the JAK/STAT pathway • Enhances cisplatin's proapoptotic effect in esophageal cancer cells (Eca-109) by inhibiting the JAK/STAT pathway 100 μM [ 53 ] Epigallocatechin gallate (EGCG) Induce apoptosis by blocking JAK3/STAT3 signaling K562 cell line in vitro • Suppresses the production of cancer-causing proteins Bcr/Ab by blocking the p38-MAPK/JNK and JAK2/STAT3/AKT signalling pathways 50 μM [ 54 ] Human metastatic melanoma cell lines, 1205Lu, HS294T and A375 in vitro Six-week-old female C57BL/6 mice in vivo • Inhibits interferon-gamma-induced PD-L1 and PD-L2 expression and JAK-STAT signaling in human and mouse metastatic melanoma cells • Inhibits the phosphorylation of STAT1, resulting in the downregulation of the transcriptional regulator IRF1 that controls the expression of PD-L1 and PD-L2 In vitro : 10 μM In vivo : 50mg/kg [ 55 ] U251 human glioblastoma cells in vitro • Activates fatal caspases, inhibits JAK3/STAT3 signaling, and regulates cell cycle regulatory proteins • Induces apoptosis and inhibits cell growth similar to EGFR-TKIs 1, 5, and 10 μg/mL [ 56 ] Emodin stimulates phosphorylation of STAT1 protein, decreasing the phosphorylation of STAT3 Human pancreatic cancer cell lines PANC-1 and BxPC-3 in vitro tumor growth model using BALB/c nude mice in vivo • Enhances EGFR inhibitor anti-tumor activity in pancreatic cells, promoting Afatinib-induced cell death by altering the STAT3 signaling pathway • It exhibits a strong EGFR inhibitory effect and reduces p-STAT3 protein expression when combined with afatinib In vitro : 30, 60 and 90 μM In vivo : 50 mg/kg/day [ 57 ] Human CoCa cells (DLD-1 and COLO-20) and normal colon epithelial cells (CCD 841 CoN in vitro • Reduced cell viability in colon cancer cells DLD-1 and COLO-20, inducing dose-dependent cell death • Adversely affects STAT signaling pathways linked to cell growth, differentiation, and Bcl-2 family expression or function 0,10, 20, 40 and 80 μM [ 58 ] HCC cell lines (Hep3B, HepG2, SK-HEP-1, Huh7, PLC/PRF5) in vitro Tumor Xenograft model: BALB/c-nude mice in vivo • Induces synergistic effects with sorafenib, causing cell cycle arrest in the G1 phase and apoptosis • Suppresses sterol regulatory element-binding protein-2 (SREBP-2) transcriptional activity, blocking cholesterol biosynthesis and AKT signaling In vitro:20 µM In vivo: 10 mg/kg/day [ 59 ] Garcinol Reducing the expression of STAT3/STAT5A The human U-87 MG (ATCC® HTB-14™) (ATCC, Manassas, VA, USA) and GBM8401 GBM cell lines in vitro • Suppresses growth, invasion, and migration of glioblastoma cells (U-87 MG and GBM8401) in a dose-dependent manner • Modulates the hsa-miR-181d/STAT3 and hsa-miR-181d/STAT5A ratios in glioblastoma cells 2.5 µM or 5 µM [ 60 ] Table 2 Summary of clinical trials of natural products targeting various cancer types: phases, observations, and outcomes Natural product Disease condition Clinical trial Phase Observation Clinical trial number Curcumin Gastric cancer Phase II b • Randomized study with two arms: curcumin and placebo • Comparison of changes in gastric mucosal DNA damage • Exploration of associations between proinflammatory cytokine genotype status and outcomes NCT02782949 Advanced/inoperable pancreatic cancer Phase III • Results: Four out of eleven patients had stable disease, six experienced tumor progression • Time to tumor progression: Ranged from 1 to 12 months, with a median of 2.5 months • Overall survival: Ranged from 1 to 24 months, median of 5 months • Low compliance with a high dose of oral curcumin (8,000 mg/day), when taken with gemcitabine, may limit effectiveness NCT00486460 Colon cancer Phase I • Investigation of plant exosomes' capability to deliver curcumin to normal and colon cancer tissue • Challenge: Limited bioavailability of curcumin, even at high doses • Study design: Characterization of exosomally delivered curcumin's effect on immune modulation, cellular metabolism, and phospholipid profile in normal and malignant colon cells • Exploration of curcumin's impact on cytokine production, immune cell changes, and glucose metabolism in selected subjects NCT01294072 Resveratrol Colorectal cancer Phase I • Assessment of safety, pharmacokinetics, and pharmacodynamics of SRT501 in colorectal cancer subjects with hepatic metastases • Study aim: Determine safety, tolerability, and pharmacokinetic profile of SRT501 administered once daily for 14 days • Study design: Administration of SRT501 or placebo followed by surgical removal of metastatic liver disease for evaluation NCT00920803 Silibinin Multiple brain metastasis Phase I • Investigate the effectiveness of whole-brain radiotherapy (WBRT) alone vs. WBRT combined with Silibinin for brain metastases • Silibinin-phytosome treatment tolerated with mild side effects (diarrhea, asymptomatic grade 2 hyperbilirubinemia) • A high concentration of Silibinin-phytosome was reported, and low levels in prostate tissues NCT05793489 Single brain metastasis Phase II • Evaluation of Silibinin's effectiveness in preventing intracranial recurrence post-complete removal of single brain metastasis from NSCLC or BC NCT05689619 Hepatocellular carcinoma PHASE I • Evaluate the use of Siliphos in advanced liver cancer patients NCT01129570 Apigenin Colorectal cancer Phase II • Aims to prove dietary supplementation with bioflavonoids reduces colorectal cancer recurrence • Effects assessed by analyzing serum concentrations of Apigenin and EGCG NCT00609310 Ursolic acid Prostate cancer PHASE 0 • Evaluation of synergistic effects of curcumin and ursolic acid on molecular pathways in the prostate • The study aims to assess the safety and pharmacokinetics of the combination • Measurement of number, frequency, duration, and relation of toxicity events • Assessment of peak serum concentration of substances NCT04403568 Caffeic acid Squamous esophageal cell cancer Phase III • Investigation of caffeic acid's effectiveness and safety in treating advanced esophageal squamous cell cancer (ESCC) in Chinese patients • Caffeic acid targets and inhibits the expression of oncogene GASC1, implicated in esophageal cancer progression • Primary endpoint: Overall survival • Secondary endpoint: Progression-free survival NCT04648917 Thymoquinone Potential premalignant lesion Phase II • Evaluate the chemo-preventive effect of thymoquinone on oral potentially malignant lesions • Thymoquinone could potentially prevent malignant transformation in oral lesions NCT03208790 Epigallocatechin gallate Colon or rectal carcinoma Phase II • Evaluate the safety and effectiveness of oral EGCG treatment NCT06314113 Hepatocellular carcinoma Phase II • Evaluate the efficacy and safety of EGCG as a chemotherapeutic agent against liver cancer • Primary Endpoint: Comparison of change in Prognostic Liver Secretome signature score (PLSec) test before and after 24-week treatment period • Secondary Endpoints: Recording adverse event profiles and comparing changes in quality of life between treatment arms NCT06015022

Curcumin

Curcumin is a naturally occurring flavonoid that is present in the rhizome plant Curcuma longa . It possesses a wide range of pharmacological actions [ 61 ]. Curcumin is reported to have anti-inflammatory, anticancer, antidiabetes, antioxidant, hepatoprotective and cardioprotective actions. Also, curcumin reduces cholesterol and lipid levels, reduces blood glycemic levels, prevents ischemic or reperfusion injury, and acts as a therapeutic agent against several neurological disorders [ 13 , 62 ]. Moreover, curcumin can modify many signaling mechanisms. It demonstrates anti-cancer effects via regulating many cancer related genes (EGR-1, c-Myc, Bcl-XL, NF-κB, and p53), as well as transcription factors (NF-κB, STAT3, and AP-1), and protein enzymes like COX and LOX [ 63 , 64 ]. Studies report that curcumin can regulate the JAK/STAT signaling pathway. It inhibits the STAT3 phosphorylation, It prevents the translocation of STAT3 dimer from the cytoplasm into the nucleus of cancer cells [ 9 ].

In vitro and in vivo studies

Khan et al. reported that curcumin suppressed papillary thyroid cancer cell survival through caspase-mediated cell death. Curcumin reduced the expression of STAT3 through dephosphorylation of Tyr705 residue. Furthermore, the PTC cell lines, BCPAP, and TPC-1 were cotreated with cisplatin and curcumin. From the study results, curcumin and cisplatin exhibited synergistic activity that enhanced the cytotoxic effects by suppressing JAK/STAT3 activity, inhibiting antiapoptotic genes, and stimulating proapoptotic genes. Curcumin also hindered colony formation and downregulated matrix metalloproteinases, which inhibited PTC cell migration [ 26 ]. A study by Ham et al. reports curcumin reduced the cancer-associated fibroblast (CAF) mediated activation of JAK/STAT3 signaling mechanism in gastric cells.The in vivo studies indicated that curcumin enhanced the susceptibility of xenograft tumors containing cancer-associated fibroblasts (CAFs) to 5-fluorouracil by inducing apoptosis, without any other adverse effects. This study demonstrates the beneficial effect of curcumin and 5-fluorouracil treatment in a xenograft model of gastric cancer [ 38 ]. The activation of the JAK/STAT pathway is facilitated by noncoding RNA, leading to an increased tumor progression. The intergenic long non-coding RNA (lncRNA) LINC00346 located on chromosome 13q34 is expressed at higher levels in hepatocellular carcinoma (HCC). The presence of LINC00346 and activation of the JAK/STAT signaling pathway contributes to the development of cancerous cells by inhibiting apoptosis and promoting cell division [ 65 ]. Curcumin decreased the expression of STAT3 in HepG2 cells and hindered the proliferation of liver cancer cells by causing cell death through the inhibition of the cancer cell cycle in the S phase [ 39 ].. Another study reported by Sandhiutami et al. shows that administering nano curcumin and cisplatin (as cotreatment) reduced tumor volume. Also, cisplatin and nano curcumin co-treatment suppressed JAK expression, and reduced IL-6 production, and phosphorylation of STAT3 [ 40 ]. Curcumin dose-dependently reduced the cell proliferation, migration, and invasion in the osteosarcoma cell line (MG-63) cell line and induced G0/G1 phase arrest. Curcumin produced apoptosis by inhibiting the phosphorylated JAK2/STAT3 pathway [ 41 ]. Curcumin suppresses cell proliferation and invasion in papillary thyroid carcinoma (PTC). Dose-dependent action of curcumin reduced the cell viability, clonality, and metastatic characteristics in PTC cell lines, TPC-1, and SW1736. Curcumin at a concentration of 10 and 20 µm blocked the G2/M phase with increased apoptosis, downregulated the expression of Bcl-2, and upregulated Bax in PTC cell lines. The study also reports curcumin treatment decreased the p-JAK2 and p-STAT3 protein expressions in TPC-1 and SW1736 cells [ 42 ]. Therefore, curcumin inhibits the activity of phosphorylated JAK and STAT proteins, thereby exerting its anti-tumor effects. Additionally, curcumin has the potential to enhance the efficacy of the current chemotherapeutic treatment, which is an important benefit.

Clinical studies

The National Cancer Institute is currently conducting a clinical study ( NCT02782949 ) to examine the efficacy of curcumin in preventing gastric malignancy in patients diagnosed with chronic atrophic gastritis or gastric intestinal metaplasia.Patients will be randomized into two arms, one receiving curcumin and the other receiving a placebo. The study will compare changes in gastric mucosal DNA damage and explore associations between proinflammatory cytokine genotype status and outcomes. Another clinical trial ( NCT00486460 ) examined the efficacy of curcumin and gemcitabine in patients with advanced pancreatic cancer. The findings indicated that 36.4% of the patients had stable disease, whereas 54.5% of the patients underwent tumor progression. The duration of tumor progression varied between 1 and 12 months, with a median of 2.5 months. The overall survival ranged between 1 and 24 months, with a median of 5 months. The study also discovered that low compliance to high dosages of oral curcumin (8000 mg/day) when combined with systemic gemcitabine could restrict the efficacy of curcumin in producing a widespread impact. However, further investigation was required to assess the potential of alternative curcumin formulations in augmenting the impact of chemotherapy in cancer patients. A clinical trial ( NCT02782949 ) was conducted to investigate the ability of plant exosomes to deliver curcumin to normal and colon cancer tissue. However, the limited bioavailability of curcumin, even at high doses, was a challenge. The study design involved characterizing the effect of exosomally delivered curcumin on immune modulation, cellular metabolism, and phospholipid profile in normal and malignant colon cells. Additionally, the study explored the effect of curcumin on cytokine production, immune cell changes, and glucose metabolism in selected subjects.

Resveratrol

Resveratrol is a natural compound derived from plants that exhibits anti-inflammatory and antioxidant properties [ 63 ]. Resveratrol, chemically known as trans -3,5,4′-trihydroxystilbene abundantly present in berries, grapes, and peanuts. Multiple studies reported resveratrol exhibit anticancer effects [ 66 ]. Resveratrol is reported to alter the JAK/STAT pathway by blocking the phosphorylation of STAT1 protein. Resveratrol is said to reduce the activity of anti-apoptotic genes and induce cell death within the cancer cells [ 9 ].

In vitro and in vivo studies

Zhang et al. reported the anti-tumor effect of resveratrol against glioblastoma. Resveratrol inhibited the cell viability in glioblastoma cell lines, LN-229 and U87-MG. The network pharmacology study reported a close connection between the anti-tumor effect of resveratrol and the JAK/STAT pathway. Resveratrol treatment lowered the NLRP3 expression through the JAK2/STAT3 pathway [ 42 ]. Another study by Suh et al. found that resveratrol inhibited the proliferation, migration, and invasion of human breast cancer cells treated with Cancer-associated fibroblast-conditioned media (CAF-CM). Also, resveratrol decreased the expression of Sox2 and inhibited the activation of Akt and STAT3 that was induced by CAF-CM in breast cancer cells. Resveratrol exhibited anti-cancer properties against osteosarcoma cells in both in vitro and in vivo conditions. The results indicate that resveratrol contributed to the suppression of JAK2/STAT3 signaling and decreased the production of several cytokine molecules that activate the JAK/STAT pathway [ 67 ].

Clinical studies

A clinical trial ( NCT00920803 ) was carried out to evaluate the safety, pharmacokinetics and pharmacodynamics of SRT501 (micronized resveratrol) in individuals with colorectal cancer and liver metastases. Micronization allows increased drug absorption, thus increasing availability.The objective of the study was to assess the safety and tolerability of SRT501 when given once daily for 14 days, as well as to characterize its pharmacokinetic profile. The study design involved the administration of SRT501 or placebo, followed by surgical removal of metastatic liver disease for evaluation. The eligibility criteria included factors such as not receiving chemotherapy within six weeks before the study, having a life expectancy exceeding 3 months, and being physically able to comply with SRT501 dosing [ 68 ]. Another study by Patel et al. suggested that daily administration of resveratrol at 0.5 g and 1.0 g can lead to levels in the human colorectum that are sufficient to potentially have pharmacological effects. The study found that resveratrol may have a slight reduction in cell proliferation, which is consistent with its potential chemo-preventive efficacy in colorectal cancer. However, it is important to interpret the results with caution due to differences in sample size and surgical procurement methods. Further clinical evaluation is needed to determine the full potential of resveratrol as a substitute for non-steroidal anti-inflammatory drugs and selective COX inhibitors in preventing colorectal cancer [ 69 ].

Silibinin

In vitro and in vivo studies

Silibinin, also called as Silybin is a major bioactive compound present in the plant milk thistle. It is a nonsteroidal anti-inflammatory drug with potent hepatoprotective, and antioxidant/anti-inflammatory action. Moreover, Silibinin exhibits anti-cancer properties when administered in conjugation with conventional chemotherapeutic agents [ 9 , 44 ]. Silibinin induced cell cycle arrest and promoted apoptosis in endometrial cancer cells. The apoptotic effect inducedby Silibinin was validated with TUNEL assay kit. During tumorigenesis, STAT3 is activated and silibinin effectively inhibits the activation of STAT3 phosphorylation and regulates the expression of downstream genes associated with cell cycle and death in endometrial cancer cells. Furthermore, Silibinin lowered the levels of intranuclear SREBP1, an essential modulator of lipid metabolism within the nucleus, and decreased the formation of triglycerides in endometrial cancer cells. Treatment with silibinin led to a decrease in the expression levels of SREBP1 and its associated genes that are involved in lipid metabolism [ 45 ]. Soto et al. reported that silibinin primarily acts by inhibiting STAT3 through a unique, bimodal mechanism that involves targeting the Src Homology-2 domain (SH2) for STAT3 dimerization and the DNA-binding domain (DBD) for STAT3 DNA binding.The study depicts that Silibinin reduced the activation of tyrosine (Y705) phosphorylation in GFP-STAT3 genetic fusions without causing significant changes in the kinase activity of the upstream kinases JAK1 and JAK2. Also, they conducted a comparative computational analysis using docking and molecular dynamics simulations on a variety of structurally distinct STAT3 inhibitors. Silibinin was expected to show a distinctive way of strongly adhering to the SH2 domain, partially coinciding with the area occupied by other direct STAT3 inhibitors, hence indirectly preventing Y705 phosphorylation [ 70 ].

Clinical studies

A study conducted by the IstitutoClinicoHumanitas focused on the occurrence of brain metastasis in adults by modulating the STAT3 pathway ( NCT05793489 ). The purpose of the study is to investigate the effectiveness of whole-brain radiotherapy (WBRT) alone versus WBRT combined with Silibinin. The study aims to determine if the addition of Silibinin to WBRT can improve outcomes for patients with brain metastases. It is a Phase I clinical trial that involves two study arms: (i) An experimental arm where patients undergo WBRT concomitant to Silibinin, and (ii) A control arm where patients undergo WBRT alone. Another study investigated the effects of a large dosage of Silibinin-phytosome in malesdiagnosed with prostate carcinoma. From the study reports, the Silibinin-phytosome treatment was found to be tolerated with mild side effects like diarrhea and asymptomatic grade 2 hyperbilirubinemia. Also, from the blood samples high concentration of the Silibinin-phytosome was reported, but low levels were found in the prostate tissues. The study indicates that Silibinin's reduced tissue uptake may be due to its short half-life, the small duration of therapy in this case, or an active mechanism that removes silibinin from the prostate [ 71 ]. A Phase II Randomized, Multicenter trial conducted by the Azienda Ospedaliera Città della Salute e della Scienza di Torino evaluates the efficacy of Silibinin in preventing intracranial recurrence following the total removal of a single brain metastasis from either breast cancer (BC) or non-small cell lung cancer (NSCLC). The primary purpose of the study is to assess the safety and effecasy of Silibinin as a preventive treatment for intracranial recurrence after gross-total resection of single brain metastasis from NSCLC ( NCT05689619 ). Another trial sponsored by Abby Siegel in collaboration with the Lotte and John Hecht Memorial Foundation evaluated the use of Siliphos in patients with advanced liver cancer. It involved three participants and had a non-randomized design. The trial was open-label, meaning there was no masking or blinding. The study did not provide any results ( NCT01129570 ).

Apigenin

In vitro and in vivo studies

Apigenin is an endogenous flavonoid that is abundantly present in fruits, vegetables, herbs, and plant-derived beverages which can suppress different kinds of human cancers, including prostate cancer, lung cancer, breast cancer, colorectal cancer, liver cancer, melanoma, glioma, osteosarcoma, leukemia, ovarian cancer, pancreatic cancer, and cervical cancer [ 72 ]. The anti-tumor activity is achieved by reducing cell migration and promoting cell apoptosis, and cellular immunity [ 73 ]. Apigenin exhibited anticancer effects by inhibiting the JAK/STAT pathway and lowering the expressions of phosphorylated JAK1, JAK2, and STAT3 proteins in breast cancer (BT-474) cells [ 74 ]. Apigenin triggered apoptosis in colon cancer cells by inhibiting the phosphorylation of STAT3, resulting in the downregulation of the antiapoptotic proteins Mcl-1 and Bcl-xL [ 46 ].

Clinical studies

A clinical trial was conducted by Technische Universität Dresden ( NCT00609310 ) to prove that dietary supplementation with bioflavonoids can reduce the recurrence rate of colorectal cancer. In the study, the investigators compare the effects of bioflavonoids and a placebo in a double-blind randomized trial. The participants will receive a standardised bioflavonoid supplement known as Flavo-Natin ® . The formulation consists of 200 mg chamomile and green tea extract, which naturally contains bioflavonoids (2%) along with vitamins and folic acid. The participants will undergo a 3-year monitoring period, during which the impact of the treatment will be assessed by analyzing the serum concentrations of apigenin and epigallocatechin gallate (EGCG) in the patients.

Ursolic acid

In vitro and in vivo studies

Ursolic acid, also known as 3β-hydroxy-urs-12-en-28-oic acid, is a common secondary metabolite found in various parts of herbal plants such as pomace, cork, flowers, sprouts, leaf, and bark. It belongs to a group of terpenoids called ursane-type five-ring terpenoids. Around 2.95% Ursolic acid is reported to be present in the leaves of Rosmarinus officinalis. Recently, for the first time, Ursolic acid was identified in commercially available dry fruits and edible wild mushrooms [ 75 ]. Ursolic acid plays a crucial role in modulating the JAK/STAT pathway. It inhibits the activation of Src and JAK kinases by interfering with the phosphorylation process, hence blocking the activation of STAT3 in prostate cancer cells. In addition, ursolic acid also declined the development of xenografted prostate cancer in a mouse model by lowering the activation of STAT3 [ 9 ]. Through apoptosis regulation, ursolic acid prevents colorectal cancer. Several reports demonstrate ursolic acid effectively reduces the anti-apoptotic activity of the JAK2 protein, further decreases the activity of STAT3, and blocks their translocation towards the nucleus. As a result, the compound prevents the activation of genes that promote resistance to cell death in colorectal cancer [ 76 , 77 ]. In a study reported by Kang et al. ursolic acid suppressed the JAK/STAT pathway and reduced the expression of VEGF, PD-L1, and MMPs. Ursolic acid interacts with the epidermal growth factor receptors (EGFRs) and reduces the number of phosphorylated EGFRs in cells, which are responsible for initiating the Jak/Stat pathway. The byproducts originating from the JAK/STAT pathway were responsible for the activation of VEGF, MMPs, and PD-L1, all of which regulate cell proliferation, angiogenesis, and metastasis [ 47 ]. In liver carcinoma, ursolic acid modulates the phosphorylation of JAK2 and STAT3 proteins. The study found that ursolic acid specifically hindered INF-induced STAT3 from activating in the Hep3 cell line. The ursolic acidalso suppressed nuclear STAT activation. Furthermore, ursolic acid administration resulted in increased expression levels of genes that promote cell death, inhibiting tumor growth in live organisms [ 48 ].

Clinical studies

A clinical study conducted by the University of Texas Health Science Centre, evaluated the synergistic effects of two natural products, curcumin, and ursolic acid, on different biochemical pathways in the the prostate cancer ( NCT04403568 ). The study evaluate the safety, pharmacokinetics, and toxicity of the curcumin and ursolic acid combination. The study will also analyse the peak serum metabolite concentration required to validate the appropriate molecular mechanism.

Caffeic acid

In vitro and in vivo studies

Caffeic acid is widely present in fruits, vegetables, tea, coffee, oils, and other sources. Caffeic acid and its derivatives have been utilized for many decades due to its inherent therapeutic and medicinal characteristics. Caffeic acid exhibits a broad spectrum of biological and pharmacological characteristics, including antioxidant, anti-inflammatory, anticancer, and neuroprotective actions [ 78 ]. Caffeic acid inhibited the proliferation of human prostate cancer cells (PC-3 cells) mediated by STAT3 phosphorylation. The treatment suppressed decreased the PC-3 cell proliferation and induced cell death. Caffeic acid also reduced the PC-3 cell migration and invasion [ 49 ]. Cytokines, hormones, or growth factors bind to the receptors on the cell membrane. The receptor binding triggers STAT3 activation and results in the phosphorylation of STAT3 at the tyrosine 705 residue (Tyr705). The substitution of Lys685 with arginine has been observed to interfere with the production of STAT3 dimers, hence blocking STAT3-DNA and initiating the transcription of oncogenes in response to cytokine stimulation. Using this hypothesis Li et al. synthesized two series of resveratrol-caffeic acid hybrids which target to block both acetylation and phosphorylation of STAT3 protein to inhibit the proliferation of malignant cells. From the series of hybrids, compound 7d exerted excellent STAT3 inhibition with 50-fold better potency than resveratrol and caffeic acid (Supplementary file). To ensure the possible binding mode, molecular docking analysis was performed. Based on the results, it was found that Compound 7d is anticipated to connect with the SH2 domain of STAT3, hence preventing the formation of dimers and the activation of STAT3 [ 50 ].

Clinical studies

A clinical study conducted by the first affiliated hospital of Henan University of Science and Technology investigates the effectiveness and safety of caffeic acid in treating advanced esophageal squamous cell cancer (ESCC) in Chinese patients. From the study findings, caffeic acid targets and inhibits the expression of a specific gene called GASC1, an oncogene present in the progression of esophageal cancer. The study will involve 80 patients who have failed previous chemotherapy or chemoradiotherapy treatments. Half of the patients will receive caffeic acid treatment, while the other half will receive a placebo. The patients will be followed up for one year, and they may also receive other anti-cancer therapies during the study. The primary endpoint of the study is overall survival, and the secondary endpoint is progression-free survival ( NCT04648917 ).

Thymoquinone

In vitro and in vivo studies

Thymoquinone, chemically referred to as 2-methyl-5-isopropyl-1,4-benzoquinone, is a biologically active substance found in black seed ( Nigella sativa ). Several studies have shown that thymoquinone possesses a wide range of beneficial benefits, including antidiabetic, analgesic, antihypertensive, antimicrobial, anti-inflammatory, bronchodilatory, gastroprotective, hepatoprotective, immunomodulatory, spasmolytic, renal-protective, antioxidant, and antineoplastic properties [ 79 ]. Thymoquinone inhibited STAT3 phosphorylation in multiple myeloma cells, U266 and RPMI 8226 [ 51 ]. Al-Rawashde et al. reported the anti-cancer activity of thymoquinone against leukemia. Thymoquinone effectively suppressed the growth of K562 cells in a dose and time-dependent manner. Thymoquinone significantly decreased the activity of PI3K, Akt, and mTOR and upregulated the expression of PTEN. This led to a notable suppression of JAK/STAT and PI3K/Akt/mTOR signaling pathways. Thymoquinone can block the JAK/STAT and PI3K/Akt/mTOR pathways, suppressing myeloid leukemia cell growth. This indicates that thymoquinone may have promising anti-leukemic effects on both acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) cells [ 52 ]. Thymoquinone enhances the proapoptotic effect of cisplatin in the Eca-109 cells (Human Esophageal cancer cell line) by suppressing the JAK/STAT pathway. The study validates the chemosensitization effect of thymoquinone when used in co-treatment with cisplatin, which inhibits the activity of the JAK2/STAT3 signaling pathway. Thymoquinone suppressed esophageal cancer cell growth in a dose-dependent mannerand the inhibitory effect of thymoquinone combined with cisplatin was more significant. The study findings suggest that thymoquinone in cotreatment with cisplatin blocked the JAK2 phosphorylation and obstructed the phosphorylation of STAT3 by retaining the JAK2 activity. Furthermore, the STAT3-regulated mitochondrial apoptotic mechanism and treatment with thymoquinone cisplatin combination upregulated the Bax protein and downregulated the Bcl-2, Survivin, Cyclin D1, and caspase-3, 7, 9 proteins [ 53 ].

Clinical studies

Thymoquinone is an active constituent found in Nigella sativa with potent anti cancer activities. A randomized, controlled trial conducted by Cairo University in Egypt evaluated the chemo-preventive effect of thymoquinone on oral potentially malignant lesions. The study included 48 patients who were randomly assigned to receive either Nigella Sativa buccal tablets or a placebo. The intervention lasted for three months, and the results suggest that thymoquinone may potentially prevent malignant transformation in these oral lesions ( NCT03208790 ).

Epigallocatechin gallate (EGCG)

In vitro and in vivo studies

Epigallocatechin Gallate (EGCG), a type of catechin present in tea (Camellia sinensis (L.) Kuntze), has shown a significant effect in combating many forms of tumors due to its promising anticancer properties. In a study reported by Xiao et al. EGCG was found to suppress cell proliferation and induce apoptosis in chronic myeloid leukemia cells. The compound suppressed the production of cancer-causing proteins, Bcr/Abl, by reducing the activity of the p38-MAPK/JNK and JAK2/STAT3/AKT signaling pathways [ 54 ]. EGCG inhibited the interferon-gamma (IFN-γ)-induced PD-L1 and PD-L2 expression and JAK-STAT signaling in human (1205Lu, HS294T and A375) and mouse (B16F10) metastatic melanoma cells. EGCG exhibited anti-tumor activity by blocking the STAT1 phosphorylation, thereby downregulating the PD-L1/PD-L2 transcriptional regulator IRF1. From the in vivo studies EGCG induced tumor-inhibitory activity through CD8 + T cells and the inhibitory effect of EGCG was comparable to anti-PD-1 therapy [ 55 ]. In addition, EGCG was found to induce apoptosis and inhibit cell proliferation as EGFR-TKIs by regulating the expression of cell cycle regulatory proteins, inhibiting JAK3/STAT3 signalling, and activating lethal caspases. EGCG inhibits the process of EGFR dimerization and its activation, and it binds to EGF to prevent EGFR phosphorylation. Furthermore, EGCG hampers the proliferation of glioblastoma cells by triggering telomere shrinkage, enhancing DNA harm via γ-H2AX histone phosphorylation, fostering the development of micronuclei, and producing telomere dysfunction [ 56 ].

Clinical studies

A clinical study conducted by the University of Palermo ( NCT06314113 ) evaluates the safety and effectiveness of oral EGCG treatment for Low-grade Cervical Lesions (L-SIL) associated with HPV infection in women. It is a retrospective cohort study currently in the recruiting phase. It aims to assess the efficacy of oral EGCG treatment in reducing L-SIL associated with HPV infection. Another similar trial aims to study the effects of EGCG in patients with colon or rectal cancer who have not received any prior treatments. The trial is in the early phase and recruiting participants in Texas. The inclusion criteria include having resectable cancer and being a candidate for surgical resection without planned neoadjuvant chemotherapy. The trial will assess the hematologic, biochemical, and organ function of participants. A Phase II randomized controlled trial ( NCT06015022 ) conducted by the University of Texas Southwestern Medical Center evaluates the efficacy and safety of EGCG as a chemotherapeutic agent against liver cancer. The study will involve a total of 60 participants who will be randomly assigned to different treatment arms. The treatment efficacy will be assessed by comparing the change in the Prognostic Liver Secretome signature score (PLSec) test, a serum biomarker, before and after the 24-week treatment period. The changes in the PLSec test will be compared between the treatment arms as the primary endpoint. In addition to the primary endpoint, the study will also record the adverse event profiles and compare the changes in quality of life between the treatment arms as secondary endpoints. If optionally paired liver biopsy tissues are obtained, the study will determine changes in tissue-based HCC risk biomarkers and immunohistochemical markers of cell proliferation, neoplasm, senescence, and fibrogenesis. The study will also evaluate changes in the FIB-4 index and liver stiffness measurement and their association with incident HCC during the study period as exploratory endpoints. The study is currently in not recruiting phase.

Emodin

In vitro and in vivo studies

Emodin, chemically known as 1,3,8-trihydroxy-6-methyl anthraquinone is obtained from the roots and barks of various plants like Japanese knotweed, buckthorn, and rhubarb ( Rheum Palmatum ). It is also explicitly extracted from other sources like different varieties of aloe plants and fungi species [ 80 ]. He et al. reported emodin as an effective human 26S proteasome inhibitor. Emodin improved intracellular protein ubiquitination and inhibited the human 26S proteasome's caspase and chymotrypsin-like activities. Emodin increased the inhibitory effect of interferon α/β (IFN-α/β) on cell proliferation by promoting the phosphorylation of STAT1 protein, reducing the phosphorylation of STAT3, and enhancing the synthesis of endogenous gene activated by IFN-α. Furthermore, it impeded the ubiquitination process that was initiated by IFN-α and the degradation of type I interferon receptor 1 (IFNAR1). Moreover, it increased the suppressive effect of IFN-α on the proliferation of HeLa cells and diminished tumor growth in Huh7 hepatocellular carcinoma-bearing mice [ 81 ]. In pancreatic cells, emodin enhanced the anti-tumor activity of EGFR inhibitors and promotedAfatinib-induced cell death by altering the STAT3 signaling pathway. Emodin in combination with afatinib reduced the pancreatic cell clones and further validation by MTT assay confirms that emodin significantly reduced the pancreatic cancer cell proliferation. Furthermore, the combination of emodin with afatinib exhibited a potent inhibitory effect on EGFR and decreased the protein expression of p-STAT3. The tumor xenograft mice model confirms that emodin and afatinib synergistically function against pancreatic cancer by controlling the expression of STAT3 [ 57 ]. Emodin reduced the cell viability in colon cancer cells, DLD-1 and COLO-20, and induced cell death in a dose-dependent manner. Emodin activated the caspases, which regulated the Bcl-2 protein family and decreased the mitochondrial membrane potential, resulting in the death of colon cancer cells [ 58 ]. Emodin adversely affects STAT signaling pathways, which are associated with cell growth, differentiation, and the expression or function of the Bcl-2 family [ 58 ]. Emodin improved the chemotherapeutic efficacy of Sorafenib in various liver cancer cell lines, including HepG2, Hep3B, Huh7, SK-HEP-1, and PLC/PRF5. Emodin inhibits the transcriptional activity of sterol regulatory element-binding protein-2 (SREBP-2) and disrupts cholesterol production and oncogenic protein kinase B (AKT) signaling. Furthermore, the suppression of AKT signaling and cholesterol production impeded the activation of STAT3. Furthermore, emodin exhibited a synergistic impact by causing cell cycle arrest, specifically in the G1 phase, and inducing apoptosis when taken in conjunction with sorafenib. The xenograft animal models using HepG2 or SK-HEP-1 cells demonstrated that the co-administration of emodin and sorafenib successfully inhibited tumor growth. Overall, the findings suggest that the concurrent use of emodin and sorafenib holds potential as an effective therapeutic approach for individuals with advanced HCC [ 59 ].

Garcinol

In vitro and in vivo studies

Garcinol is a natural product derived from the dried rind of the Garcinia indica fruit. It is classified under polyisoprenylated benzophenone [ 82 ]. A study conducted by Liu et al. found that garcinol efficiently inhibited the growth, invasion, and migration of glioblastoma cells (U-87 MG and GBM8401) in a dose-dependent manner by regulating the hsa-miR-181d/STAT3 and hsa-miR-181d/STAT5A ratios in glioblastoma cells [ 60 ]. Garcinol was found to decrease the growth of glioblastoma tumors in an in vivo study using an immunocompromised mouse model by reducing the expression of STAT3/STAT5A, increasing the apoptotic ratio of Bax/Bcl-XL, and decreasing the Ki-67 proliferation index [ 83 ].

Limitations and clinical gaps

The primary limitation of the current research is the relatively limited number of comprehensive clinical trials validating the efficacy of natural products in modulating the JAK/STAT signaling pathway in human subjects. Despite abundant preclinical data, the translation to clinical settings remains inadequate. Additionally, many natural products, such as curcumin , suffer from poor bioavailability, requiring high doses to achieve therapeutic levels in the body. This can lead to compliance issues and potential side effects. Although curcumin has gained significant attention for its broad therapeutic benefits, poor solubility, and low bioavailaibity due its rapid degradation in the body has limited its clinical utility. However, nanoparticle-based drug delivery strategies offer promising solutions to overcome these challenges and enhance curcumin's effectiveness in various clinical applications. One strategy to overcome these challenges is to encapsulate natural plant metabolites within biodegradable and biocompatible nanoparticles (NPs). A CD44-targeted drug delivery system was created by covalently attaching hyaluronic acid to propylene glycol-based ethosomes (HA-ES). The HA-ES were further coated with a hyaluronic acid gel network, which minimized curcumin leakage and release. This approach enhanced the targeted delivery of curcumin to inflamed psoriatic skin, where CD44 protein is overexpressed, thereby improving its therapeutic efficacy in the affected area [ 84 ]. Similarly, the therapeutic potential of resveratrol , apigenin , Silibinin , and emodin has been extensively studied, but bioavailability issues hinder their clinical translation. Resveratrol is chemically unstable and degrades when exposed to UV light, temperature fluctuations, pH changes, and oxidative enzymes. Encapsulation and controlled release of resveratrol using various carriers have emerged as promising strategies to overcome its low bioavailability. A notable approach involved using transferrin-modified polyethylene glycol liposomes (Tf-RES-L) as a delivery system for resveratrol. Compared to free drugs, these functionalized, drug-loaded liposomes significantly enhanced apoptosis in glioblastoma multiforme (GBM) cells by activating the caspase 3/7 pathway [ 85 ].

Apigenin and Silibinin suffer from poor water solubility, a key physicochemical limitation that leads to low oral bioavailability. Emodin undergoes significant first-pass metabolism in the liver and intestines, further restricting its oral bioavailability. Caffeic acid is known for its poor solubility and degradation under neutral or alkaline conditions. Similarly, thymoquinone, garcinol , and Epigallocatechin Gallate (EGCG) demonstrate reduced stability, limited bioavailability, and lower absorption rates. These challenges can be addressed using nanotechnology-based drug delivery systems. Studies indicate that encapsulating natural products allows tissue-specific targeted delivery, improves water dispersibility, enhances chemical stability, and boosts bioavailability. Various delivery systems are available for encapsulating resveratrol, including liposomes, niosomes, nano emulsions, nano particles (NPs), and dendrimers. The clinical gaps include a lack of long-term studies assessing the efficacy and safety of natural products in cancer therapy. Most studies focus on short-term outcomes, leaving gaps in understanding the long-term benefits and potential risks associated with prolonged use. Comprehensive pharmacokinetic and pharmacodynamic studies are needed to better understand the absorption, distribution, metabolism, and excretion of natural products, which is crucial for optimizing their therapeutic use and minimizing adverse effects. Additionally, there is a need for more research into patient-specific responses to natural products, considering genetic, epigenetic, and environmental factors, as personalized approaches could enhance the effectiveness of phytochemical-based therapies. Establishing standardized methods for the extraction, preparation, and quality control of natural products is essential to ensure consistent therapeutic outcomes and facilitate regulatory approval. Further research is required to explore the synergistic mechanisms between natural products and existing cancer therapies, as understanding these interactions could lead to the development of more effective combination treatments. Addressing these limitations and clinical gaps through rigorous research and well-designed clinical trials will be critical in harnessing the full therapeutic potential of natural products for cancer treatment.

Conclusion and future perspectives

The consumption of nutritional and medicinal plants that contain active phytoconstituents usually results in low or insignificant side effects, contrary to synthetic drugs. Thus, scientific validation of natural products relies on confirming their safety through toxicity studies conducted on various preclinical animal models. In this review, we have selected ten different phytochemicals (Curcumin, Resveratrol, Apigenin, Silibinin, Ursolic Acid, Emodin, Caffeic Acid, Thymoquinone, Garcinol, Epigallocatechin Gallate) based on their demonstrated anti-tumor potential in various clinical studies. Most of these natural products inhibit the activation of JAK/STAT by reducing the phosphorylation of JAK and/or STAT proteins, or by blocking the movement of STAT dimers to their target genes. The development of tumors often involves the abnormal activation of the JAK/STAT pathway. Existing literature focuses on preclinical and clinical studies investigating the effects of phytochemicals on altering the JAK/STAT signaling system. Further research is necessary to explore the long-term effects of phytochemical usage, the suppression of the JAK/STAT pathway, the efficacy of natural compounds in cancer prevention among high-risk populations, and the potential synergies when combining them with existing chemotherapy and diverse phytoconstituents. The extensive research findings presented in this review underscore the potential of natural products as therapeutics for combating cancer and highlight the importance of incorporating phytochemicals into human trials. Nonetheless, given considerations of adverse reactions and the development of chemoresistance, further investigation into phytochemicals is crucial for effectively addressing the global cancer crisis.

Supplementary Information

Supplementary Material 1.

Abbreviations

Acute myeloid leukemia

Breast cancer

B-cell lymphoma 2

Breakpoint cluster region/abelson murine leukemia

Cancer-Associated Fibroblasts

Cyclooxygenase

DNA-binding domain

Deoxyribonucleic acid

Endometrial cancer

Epigallocatechin gallate

Epidermal growth factor receptor

Extracellular signal-regulated kinase

Esophageal squamous cell cancer

Four-point One Ezrin Radixin Moesin

Hepatocellular carcinoma

Interferon

Interleukin

Janus Kinase

JAK homology

Mitogen-activated protein kinase

Myeloid cell leukemia 1

Mammalian target of rapamycin

Nuclear factor kappa-light-chain-enhancer of activated B cells

Non-small cell lung cancer

Platelet-derived growth factor

Phosphoinositide 3-kinase

Papillary thyroid cancer

Src homology 2

Sterol regulatory element-binding protein 1

Signal transducer and activator of transcription

Transforming growth factor beta

Vascular endothelial growth factor

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Bhagyalakshmi Nair, Anjana Menon and M. Rithwik Kalidas have contributed equally.

Acknowledgements

We acknowledge the support of the Amrita Vishwa Vidyapeetham SEED grant to L.R.N. (K-PHAR-24-722). The authors would like to express their gratitude to Dr. Irina Zamfir, MD, RCP London, Basildon University Hospital UK for providing professional English editing of this manuscript and for editorial support.

Author contributions

B.N., A.M., R.K.M, L.R.N., D.C., J. S.-R. made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or in all these areas that is revising or critically reviewing the article; giving final approval of the version to be published; agreeing on the journal to which the article has been submitted; and confirming to be accountable for all aspects of the work. All authors have read and agreed to the published version of the manuscript. The authors confirm that no paper mill and artificial intelligence was used.

Funding

Not applicable.

Availability of data and materials

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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