Targeting the AMP-Activated Protein Kinase for Cancer Prevention and Therapy.

Introduction

Despite the advances in biomedical research and clinical applications, cancer remains a leading cause of death worldwide. Given the limitations of conventional chemotherapeutics, including serious toxicities and reduced quality of life for patients, the development of safe and efficacious alternatives with known mechanism of action is much needed. In recent years, there has been increasing interest in the potential cancer chemopreventive properties of diet-derived agents, and many studies suggest that prevention of cancer through dietary intervention may hold promise. It is estimated that an average of 35% of human cancers (certain types up to 70%) can be attributed to diet ( 1 ), and epidemiological research has shown a link in the geographical distribution of cancer incidence to specific diet consumption. According to the World Health Organization report 2002, there are at least 2.7 million deaths globally per year, which are primarily attributable to low fruit and vegetable intake ( 2 ). This is not surprising, as the National Cancer Institute identified about 35 plant-based foods that possess anti-cancer benefits, including garlic, soybeans, ginger, onion, turmeric, tomatoes, and cruciferous vegetables (broccoli, cabbage, cauliflower, and Brussels sprouts). Furthermore, the chemopreventive efficacy of these diet constituents has been demonstrated in vitro and in vivo . The substantial anticarcinogenic and antimutagenic properties of these tested dietary agents can be attributed to the non-nutritive components of these foods, termed phytochemicals. There could be more than 100 different phytochemicals in just a single serving of vegetables ( 2 ), and they can be extracted for therapeutic purposes. Since phytochemicals have not been shown to have any known toxicities, they can be considered as an alternative to the conventional chemotherapy that may be harmful. A number of phytochemicals have been found to have notable efficacy in preclinical models of carcinogenesis, such as those of colorectum, breast, lung, and hematological origin. These include epigallocatechin gallate (EGCG) from tea, the flavonoids quercetin and genistein from onions and soya, respectively, curcumin in curry spice and resveratrol from red grapes ( 3 ). Chemopreventive phytochemicals can block the initiation or reverse the promotion of carcinogenesis and impede the progression of precancerous cells into malignant ones. A substantial progress has been made in identifying the signal transduction pathways involved in the antineoplastic effects of these substances, such as MAPK, MEK, PI3K, AP-1, COX-2, JNK, ERK, AP-1, and p53 ( 3 – 8 ). Elucidating the molecular mechanisms of phytochemicals fortifies the possibility in developing safe and effective preventative and therapeutic agents for cancer. In this review, we highlight (1) the role of the energy sensing enzyme AMP-activated protein kinase (AMPK) ( 9 – 11 ) in the prevention and treatment of cancer and (2) the recent developments in this budding field that suggest AMPK as a new molecular target in the prevention and treatment of cancer by phytochemicals.

Function and Regulation of AMPK

AMP-activated protein kinase is a well-conserved energy sensor that plays a key role in the regulation of protein and lipid metabolism in response to changes in fuel availability ( 9 – 11 ). AMPK exists as heterotrimeric complexes comprising a catalytic α-subunit and regulatory β- and γ-subunits. In mammals, each subunit occurs as multiple isoforms encoded by multiple genes that can be assembled to form up to 12 heterotrimeric combinations ( 12 ). Although AMPK is traditionally thought to play a major role in the regulation of cellular metabolism, it is now widely recognized to have antineoplastic efficacy and as a target for chemotherapy. A key characteristic of tumor cells is their ability to rapidly grow and divide, thus requiring a tremendous demand for energy. An extensive body of evidence has demonstrated that AMPK inhibits essentially all anabolic pathways that promote cell growth, such as synthesis of fatty acid, phospholipid, protein, and ribosomal RNA synthesis ( 12 , 13 ). Thus, it is not surprising that AMPK antagonizes cancer cell growth. The first hint that AMPK may be linked to cancer was provided by the finding that liver kinase B1 (LKB1), a known tumor suppressor, acted as an upstream kinase of AMPK ( 14 , 15 ). LKB1 is mutated in the inherited cancer disorder Peutz–Jeghers syndrome and in many lung and cervical cancers, suggesting that AMPK could play a role in tumor suppression ( 16 , 17 ).

Activators of AMPK

AMP-activated protein kinase can be activated by various types of metabolic stress that lead to ATP depletion, such as conditions of low nutrient supply or prolonged exercise, or via an increase in intracellular Ca 2+ concentration ( 9 ). The upstream kinases, LKB1 and calcium/calmodulin-dependent protein kinase kinase-β (CaMKKβ) activate AMPK by phosphorylating Thr172 in the activation loop of the catalytic α-subunit ( 18 – 20 ). The finding that CaMKKβ can also activate AMPK, independently of LKB1, broadened the potential for AMPK to be used for therapy in cancers that have mutant LKB1 and thus low AMPK activation. Loss of function of the tumor suppressor LKB1 occurs in 30–50% of lung adenocarcinomas. Memmott et al. ( 21 ) found that lipid-based AKT inhibitors, phosphatidylinositol ether lipid analogs (PIA), activate AMPK independently of LKB1 in LKB1-mutant non-small cell lung cancer (NSCLC) cell lines. The more well-known activators of AMPK include several pharmacological agents that stimulate the LKB1 pathway. Metformin, the most widely prescribed Type-2 diabetes drug for more than 30 years, has been shown to activate AMPK in an LKB1-dependent manner ( 22 , 23 ). Metformin mimics an energetic stress because it inhibits the mitochondrial complex I in hepatocytes and cancer cells which leads to the decrease in intracellular ATP and an increase in glycolysis and lactate production ( 24 , 25 ). Consistent with this, diabetic patients treated with metformin had a lower incidence of cancer compared to those on other medications ( 26 ). In light of this, other retrospective studies have been performed, one of which showed that breast cancer patients on metformin for diabetes responded significantly better to chemotherapy than other diabetic patients not on metformin and non-diabetic patients ( 27 ). Since then, several studies have shown that metformin exerts antineoplastic effects in other cancer cells and animal models. Phenformin, a biguanide more potent than metformin, and A-769662, a direct AMPK activator developed by Abbott also delayed tumorigenesis in a mouse cancer model ( 28 ). 5-Amino-1-β-Dffff-ribofuranosyl-imidazole-4-carboxamide, or AICAR, is an analog of AMP and widely used to activate AMPK in experiments. Interestingly, AMPK is also activated by ionizing radiation (IR) in lung, prostate, and breast cancer cells, independent of LKB1. This suggests that AMPK may play a role as a target for radiosensitization of human cancer cells ( 29 ). Since the discovery of antineoplastic effects of AMPK, the number of patents describing potential AMPK activators has grown rapidly ( 30 , 31 ). Among the most recent developments is the activation of AMPK by naturally occurring dietary constituents and plant products, to be reviewed in the latter part of this article.

Downstream targets of AMPK

One of the major growth regulatory pathways controlled by LKB1–AMPK is the mammalian target of rapamycin (mTOR) pathway (Figure 1 ). The mTOR pathway controls various biological processes that are important for normal functioning of the cell via cell-cycle progression, survival, migration, transcription, translation, and metabolism. AMPK is linked with the phosphatidylinositol 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/protein kinase B (AKT) pathway and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) cascades – all known for being frequently dysregulated in cancer. mTOR can be activated downstream of the PI3K-AKT and Ras-Raf-MEK-ERK signaling pathways ( 32 ), which converge on TSC1-TSC2 ( 33 ). Moreover, AMPK has been shown to be necessary for cell-cycle arrest at the G1 phase during limited nutrient supply, via phosphorylation of the tumor suppressors p53 ( 34 , 35 ) and p27 ( 36 ). The mTOR complex also controls AMPK-mediated autophagy ( 37 ), a cellular process in which the cell breaks down its own organelles and cytosolic components to ensure sufficient metabolites during starvation states. Under certain circumstances, autophagic cells may engage a specific mode of cell death called type II cell death or autophagic cell death (ACD). A number of studies have revealed the role of AMPK in ACD of cancer cells ( 38 , 39 ). The most upstream components of the autophagy pathway include Atg1 (ULK1 in mammals) and its regulatory subunits Atg13 and Atg17 ( 40 ). The mTOR/Raptor pathway is thought to suppress ULK1 and ULK2 and their regulatory subunits ( 41 ), while AMPK phosphorylates ULK1, leading to autophagy-mediated cancer cell death. Furthermore, AMPK has been shown to downregulate the expression of cyclooxygenase (COX)-2, which contributes to the pathophysiological progression of certain human cancers and inflammatory disorders ( 42 ). AMPK is required for the expression of xeroderma pigmentosum C (XPC) to promote DNA repair following UV damage ( 43 ).

Role of AMPK in Cancer Cell Lines and Animal Models of Cancer

Since the AMPK cascade has emerged as an important pathway implicated in cancer control, many discoveries have been made in the past decade revealing robust anti-cancer effects of AMPK in vitro and in vivo , including animal cancer models of breast, lung, colorectum, skin, and hematological malignancies. We review the role of AMPK in major cancers, as outlined below.

Breast cancer

Observations that diabetics treated with biguanide drugs have a reduced risk of developing cancer have prompted an enthusiasm for these agents as anti-cancer therapies. Metformin, which activates AMPK, was shown to inhibit cell proliferation and induce apoptosis in the triple-negative breast cancer cell line, as well as the estrogen receptor (ER) α-positive and the human epidermal receptor (HER) 2-positive cell lines. Moreover, synergistic inhibition of the G1 phase of the cell cycle was demonstrated by the combination treatment of metformin and chemotherapeutic agents carboplatin, paclitaxel, and doxorubicin ( 44 ). Moreover, a novel small molecule AMPK activator, OSU-53 derived from inactive peroxisome proliferator-activated receptor gamma (PPARγ), was reported to inhibit the proliferation of the triple-negative breast cancer, a disease for which there are limited therapeutic options ( 45 ). Phenformin, a stronger biguanide than metformin and also a direct activator of AMPK, was demonstrated to be effective in the prevention and treatment of ER-positive and receptor triple-negative xenografts in immunocompromised mice ( 46 ). In another study, AICAR and phenformin elicited clear anti-proliferative effects in ER-positive, ER-negative, and triple-negative breast cancer cell lines ( 47 ).

Lung cancer

AMP-activated protein kinase is considered a potential prognostic and therapeutic target for lung cancer. In tumors from patients with resected non-small cell lung cancer (NSCLC), the expression of proteins in the AMPK pathway, including pLKB1, AMPK, p -Acetyl-CoA, pTSC2, was inversely correlated with NSCLC recurrence ( 48 ). Consistent with this, another study showed a significant association between high phosphorylated AMPK (pAMPK) expression levels with increased overall survival and recurrence-free survival in patients with NSCLC, especially those with adenocarcinoma ( 49 ). Never smokers also showed significantly higher levels of pAMPK compared to former and current smokers. In NSCLC cells in vitro , LKB1/AMPK signaling was shown to negatively regulate mTOR activity and contribute to cell growth inhibition in response to 2-deoxyglucose (2-DG), which mimics energy stress ( 50 ). Moreover, metformin treatment led to increased apoptosis in human lung cancer cell lines (A549 and NCI-H1299) and significantly inhibited cell proliferation in a dose- and time-dependent manner, which was confirmed by results from A549 tumor xenografts in nude mice ( 51 ). Similarly, A/J mice treated with oral metformin after exposure to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) showed a 72% reduction in tumor burden compared to the control mice, which correlated with decreased cellular proliferation and marked inhibition of mTOR in the tumors ( 52 ).

Hematological cancers

AMP-activated protein kinase has been shown to inhibit cancer cell growth in various hematological cancers. In acute lymphoblastic leukemia (ALL) cell lines, AICAR induced dose- and time-dependent cell growth inhibition ( 53 ), leading to increased AKT phosphorylation and decreased mTOR phosphorylation ( 54 ). When used in combination with methotrexate or pemetrexed, AMPK showed a synergistic cytotoxic effect and cell growth inhibition ( 53 ). Sengupta et al. ( 55 ) reported that the apoptotic effect of AMPK was mediated by activation of the p38 MAPK pathway, increased expression of cell-cycle inhibitory proteins p27 and p53, and the downstream effects of the mTOR pathway. In B-cell chronic lymphocytic leukemia (B-CLL) cells, AMPK-induced apoptosis in a p53-independent manner ( 56 ). In mantle cell lymphoma (MCL), a clinically aggressive B-cell non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) and overexpression of cyclin D1, stimulation of the AMPK kinase activity using AICAR inhibited phosphorylation of critical downstream effectors of mTOR signaling, such as 4E-BP1 and ribosomal protein s6 (rps6) ( 57 ). In BCR-ABL-expressing chronic myeloid leukemia (CML) precursors and ALL cells that are positive for the Philadelphia chromosome (Ph+), metformin, and AICAR suppressed the mTOR pathway and cell growth ( 58 ). Lastly, induction of the LKB1/AMPK tumor suppressor pathway demonstrates a strong potential for the treatment of acute myeloid leukemia (AML). Green et al. showed that the LKB1/AMPK/TSC tumor suppressor axis could lead to a specific inhibition of the mammalian target of rapamycin (mTOR) catalytic activity, inducing 4E-BP1 dephosphorylation, which inhibits the initiation step of mRNA translation. Metformin consequently reduced the recruitment of mRNA molecules encoding oncogenic proteins to the polysomes, resulting in a strong anti-leukemic activity against primary AML cells while sparing normal hematopoiesis ex vivo and significantly reducing the growth of AML cells in nude mice ( 59 ).

Skin cancer

The role of AMPK in UVB-induced skin cancer is still only beginning to be understood and depends on the type of skin cancer. AMPK activators phenformin and AICAR were shown to inhibit the cell growth of both BRAF-mutant or NRAS-mutant melanoma cell, due to cell-cycle arrest in either the G0/G1 or the S phase, associated with an increased expression of the p21 cell-cycle inhibitor ( 60 ). However, another study revealed that BRAF-mutant melanoma cells are resistant to metformin in vitro , while metformin accelerates their growth in vivo . Surprisingly, metformin inhibited tumor growth when vascular endothelial growth factor (VEGF) signaling was inhibited. Thus, VEGF inhibitors and metformin synergized to suppress the growth of BRAF-mutant tumors ( 61 ). The role of AMPK in basal cell carcinoma remains unclear. In a study by Byekova et al. ( 62 ) LKB1 and pAMPK expression was shown to be upregulated in UVB-induced murine BCC and in human skin tumor keratinocytes. Paradoxically, persistent mTOR activation was also observed. Metformin was effective in activating the LKB1/AMPK pathway only in HaCaT keratinocytes but not in human carcinoma A431 cells, suggesting a complex regulatory mechanism for the persistent mTOR activation in murine BCCs. In contrast, Zhang and Bowden reported that UVB irradiation, a strong carcinogen for non-melanoma skin cancer, reduced activation of AMPK and LKB1, leading to increased Cox-2 mRNA stability, which may contribute to cancer development ( 63 ). Furthermore, our recent studies showed that the AMPK pathway is down-regulated in human and mouse squamous cell carcinomas and that its activators AICAR and metformin increased the expression of the DNA repair protein xeroderma pigmentosum C (XPC) and UVB-induced DNA repair in mouse skin and in normal human epidermal keratinocytes ( 43 ). Furthermore, in UVB-damaged tumor-bearing mice, both topical and systemic metformin prevented the formation of new tumors and suppressed growth of established tumors, demonstrating that AMPK acts as a tumor suppressor in the skin by promoting DNA repair and controlling cell proliferation ( 43 ).

Activation of AMPK by Phytochemicals

It was not until about 5 years ago that AMPK began to be recognized as a target for various phytochemicals. In this section, we review the studies that have demonstrated the role of AMPK in the chemopreventive effects of phytochemicals (Table 1 ), the majority of which have been reported in the last few years.

Curcumin

Curcumin (diferuloylmethane), a yellow pigment present in the rhizome of turmeric ( Curcuma longa L.), is one of most extensively investigated phytochemicals in the field of chemoprevention and is used in early clinical trials as a novel anti-cancer agent. Curcumin has been shown to suppress tumor progression in various animal models of cancer ( 64 – 67 ). Recently, AMPK was found to be a new molecular target of curcumin (Figure 2 ). Pan et al. ( 67 ) showed that activation of AMPK by curcumin has shown to be responsible for the cytotoxic effects of curcumin ovarian cancer cells. In another study, stimulation of AMPK by curcumin resulted in the downregulation of PPAR (peroxisome proliferator-activated receptor)-g in 3T3-L1 adipocytes and a decrease in COX-2 in MCF-7 cells ( 65 ). Application of a synthetic AMPK activator also supported the evidence that AMPK acts as an upstream signal of PPARγ in 3T3-L1 adipocytes. In cancer cells, AMPK was found to act as a regulator of ERK1/2, p38, and COX-2. Thus, activation of AMPK by curcumin and its downstream targets such as PPAR-g, MAP kinases, and COX-2 is important in regulating adipocytes and cancer cells ( 66 ). Consistent with this study, curcumin activated AMPK to induce apoptosis and limit proliferation of colon cancer cells via the inhibition of AKT and COX-2 ( 66 ). Thus, curcumin is a potent stimulator of AMPK leading to chemoprevention.

Resveratrol

Resveratrol (3,4′,5-trihydroxy-trans-stilbene) is a type of natural phenol that is present in grapes and a key antioxidant ingredient in red wine. The consumption of red wine has been correlated with the reduction of mortality rates from cardiovascular diseases and certain cancers. Moreover, anti-cancer, anti-inflammatory, blood sugar-lowering, and other beneficial cardiovascular effects of resveratrol have been reported in animal models and human clinical trials ( 68 – 71 ). One of the earliest findings of its anti-cancer effects was in 1997, in which topical resveratrol applications prevented skin cancer development in mice treated with a carcinogen ( 72 ). There have since been many studies demonstrating the anti-cancer activity of resveratrol in animal models ( 73 ). AMPK is now a recognized target of resveratrol that mediates its anti-cancer effects (Figure 3 ). In 2007, Hwang et al. ( 74 ) showed that resveratrol activates AMPK and induces apoptosis of chemoresistant HT-29 colon cancer cells and identified that reactive oxygen species (ROS) acted as an upstream regulator of AMPK. Resveratrol was also found to activate AMPK, leading to the suppression of NF-κB-dependent COX-2, a pathway implicated in cancer development ( 75 ). Moreover, resveratrol-induced autophagy-mediated cell death in imatinib-sensitive and – resistant CML cells. AMPK knockdown or mTOR overexpression impaired resveratrol-induced autophagy, suggesting that AMPK activation and mTOR inhibition is important for autophagy-mediated cancer cell death ( 76 ). Resveratrol also increased sensitivity to standard chemotherapies, thus reducing the required dosage of potentially toxic substances in prostate cancer, glioblastoma, and breast cancer cells ( 77 – 79 ). A series of screening resveratrol methylated derivatives was performed, and trans-3,4-dimethoxystilbene (3,4-DMS) was found to effectively inhibit endothelial cell proliferation, migration, tube formation, and endogenous neovascularization. Moreover, 3,4-DMS induced autophagy in endothelial cells through AMPK activation and downstream inhibition of the mTOR signaling pathway ( 80 ). As outlined in this section, evidence for the chemopreventive potential of resveratrol is growing, as the various molecular mechanisms of its action via AMPK is being elucidated.

Flavonoids and related compounds

Flavonoids can be found in many different sources, including soy, berries, tea, wine, beer, chocolate, many vegetables, and most fruits. While there are several 1000 types, they can be categorized as flavones (quercetin, fisetin, luteolin), isoflavonoids (genistein, deguelin), and neoflavonoids ( 81 ). Epidemiological evidence reveals a lower incidence of prostate cancer in Asian countries, where soy products are more frequently consumed than in Western countries. The chemopreventive effects of a soy isoflavonoid genistein can be attributed to its ability to activate AMPK (Figure 4 ) and PTEN, leading to the induction of the antioxidant enzymes manganese superoxide dismutase and catalase ( 82 ). In another study, genistein was demonstrated to potentiate arsenic trioxide-induced apoptosis in human leukemia cells by activation of AMPK ( 83 ). Moreover, anthocyanin – belonging to the family of flavones that occurs in all tissues of higher plants, including leaves, stems, roots, flowers, and fruits – is shown to be a powerful activator of AMPK. Lee and Park ( 84 ) demonstrated that anthocyanin activates AMPK, leading to a reduction in mTOR phosphorylation and ultimately inhibiting cancer cell growth. Fisetin, a flavonoid, activates AMPK to induce apoptosis in multiple myeloma cells ( 85 ), inhibits PI3K/AKT and mTOR and activates AMPK in non-small cell lung cancer ( 86 ), and induces autophagy-mediated cell death by activating AMPK and suppressing mTOR in prostate cancer cells ( 87 ). Quercetin induces apoptosis via AMPK activation and p53 in HT-29 colon cancer cells ( 88 ) and suppresses cell viability via AMPK-induced Hsp70 and EGFR downregulation ( 89 ). Apigenin induces AMPK, inhibiting mTOR and further inducing autophagy in both HaCaT cell line and primary normal human epidermal keratinocytes. This effect was independent of AKT and LKB1 but dependent on CaMMKβ ( 90 ). Luteolin showed its anti-tumor effects in an in vivo tumor model, in which its activation of AMPK reduced tumor volume in a tumor xenograft model ( 91 ). Deguelin, a plant-derived rotenoid with cancer chemopreventive activity, was shown to inhibit UVB-induced skin carcinogenesis with the SKh-1 hairless mouse model. Topically applied deguelin significantly inhibited the multiplicity of UVB-induced skin tumors by activating AMPK ( 92 ). Celastrol, another antioxidant flavonoid, suppressed the viability of breast cancer MCF-7 cells in an AMPK-dependent fashion. Celastrol also induced an increase in ROS levels, leading to AMPK phosphorylation and increased the pro-apoptotic p53 in an AMPK-dependent manner ( 93 ). Chrysin, a naturally occurring flavone chemically extracted from the passion flowers Passiflora caerulea and Passiflora incarnata , leads to growth inhibition and apoptosis of lung cancer cells via AMPK activation and inhibition of AKT/mTOR ( 94 ). Thus, flavonoids and related compounds act as direct activators of AMPK and demonstrate their promising potential to be used as chemotherapeutic agents.

Epigallocatechin gallate

Epigallocatechin-3-gallate, EGCG, a green tea-derived polyphenol, has been shown to suppress cancer cell proliferation and interfere with the several signaling pathways and induce apoptosis. EGCG treatment of HT-29 colon cancer cells resulted in a strong activation of AMPK and an inhibition of COX-2 expression (Figure 5 ). Treatment with an AMPK inhibitor completely abolished the inhibition of COX-2 by EGCG. Also, AMPK activation was accompanied by a reduction of VEGF and glucose transporter, Glut-1 in EGCG-treated cancer cells. These findings support the regulatory role of AMPK in COX-2 expression in EGCG-treated cancer cells ( 95 ). Moreover, analogs of EGCG have been synthesized and found to be more potent AMPK activators than metformin and EGCG. Activation of AMPK by these EGCG analogs resulted in the inhibition of cell proliferation, up-regulation of the cyclin-dependent kinase inhibitor p21, downregulation of the mTOR pathway, and suppression of stem cell population in human breast cancer cells. This study suggests that specific and more potent AMPK activators can be derived from natural and synthetic sources and be used for chemotherapy ( 96 ). In a model of diethylnitrosamine-induced liver tumorigenesis in obese and diabetic mice, EGCG improved liver steatosis and activated AMPK in the liver, suggesting that EGCG may prevent obesity-related liver tumorigenesis ( 97 ). EGCG, therefore, may be useful in the chemoprevention of liver tumorigenesis in obese individuals by the activation of AMPK, consistent with the reported effects of metformin. EGCG is known to play a critical role in growth inhibition and apoptosis in hepatocellular carcinoma cell lines. Furthermore, EGCG was shown to enhance the anti-tumor activity of 5-fluorouracil (5-FU), one of the most commonly used chemotherapeutic drugs, suggesting that EGCG may be used as an adjunct therapy for the treatment of advanced-stage liver cancer ( 98 ).

Phytochemicals belonging to other category

Berberine, a traditional plant alkaloid used in Ayurvedic and Chinese medicine for its antimicrobial and antiprotozoal properties, strongly increased AMPK phosphorylation via ROS production, leading to inhibition of tumor cell adhesion, tumor invasion, and the expression of epithelial to mesenchymal transition (EMT)-related genes. Furthermore, berberine inhibited the metastatic potential of melanoma cells through a decrease in ERK activity and protein levels of cyclooxygenase-2 (COX-2) by a berberine-induced AMPK activation ( 99 ). In another study, berberine was shown to inhibit migration of colon cancer cells in an AMPK-dependent manner ( 100 ). Furthermore, 24-hydroxyursolic acid from persimmon, capsaicin, and p-HPEA-EDA, a phenolic compound of virgin olive oil, activate AMPK and inhibit cell survival in HT-29 colon cancer cells ( 100 – 103 ).

Conclusion and Future Considerations

In summary, the use of phytochemicals derived from dietary agents holds promise in the prevention and treatment of cancer, and AMPK is one of the major pathways activated by many phytochemicals. Not only do phytochemicals activate AMPK to increase cancer cell apoptosis and inhibit cell proliferation, but they have also been shown to be effective in reducing the toxicity associated with standard chemotherapy by increasing the sensitivity of cancer cells to drugs. While the majority of the studies on AMPK that we reported in this review demonstrate that it is an antineoplastic agent, some evidence suggests the role of AMPK in promoting cancer. This warrants further investigation. As AMPK exists as different heterotrimeric compound consisting of various isoforms, it is conceivable that different contexts of stimulation may lead to disparate consequences. There are other phytochemicals that have been reported to activate AMPK, such as Honokiol ( 104 ), that have been shown to have consequences other than cancer prevention. Thus, it seems that AMPK can be used not only as a chemotherapeutic agent but also to protect from injury, diabetes, or inflammatory diseases.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

1 Doll R Peto R The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today . J Natl Cancer Inst ( 1981 ) 66 : 1191 – 308 7017215

2 Surh YJ Cancer chemoprevention with dietary phytochemicals . Nat Rev Cancer ( 2003 ) 3 : 768 – 80 10.1038/nrc1189 14570043

3 Manson MM Cancer prevention – the potential for diet to modulate molecular signalling . Trends Mol Med ( 2003 ) 9 : 11 – 8 10.1016/S1471-4914(02)00002-3 12524205

4 Agarwal R Cell signaling and regulators of cell cycle as molecular targets for prostate cancer prevention by dietary agents . Biochem Pharmacol ( 2000 ) 60 : 1051 – 9 10.1016/S0006-2952(00)00385-3 11007941

5 Ashendel CL Diet, signal transduction and carcinogenesis . J Nutr ( 1995 ) 125 : 686S – 91 7884552 10.1093/jn/125.suppl_3.686S

6 Gescher A Pastorino U Plummer SM Manson MM Suppression of tumour development by substances derived from the diet-mechanisms and clinical implications . Br J Clin Pharmacol ( 1998 ) 45 : 1 – 12 10.1046/j.1365-2125.1998.00640.x 9489587 PMC1873997

7 Kong AN Yu R Hebbar V Chen C Owuor E Hu R Signal transduction events elicited by cancer prevention compounds . Mutat Res ( 2001 ) 48 ( 0-481 ): 231 – 41 11506817 10.1016/s0027-5107(01)00182-8

8 Manson MM Gescher A Hudson EA Plummer SM Squires MS Prigent SA Blocking and suppressing mechanisms of chemoprevention by dietary constituents . Toxicol Lett ( 2000 ) 11 ( 2-113 ): 499 – 505 10.1016/S0378-4274(99)00211-8 10720772

9 Hardie DG Adenosine monophosphate-activated protein kinase: a central regulator of metabolism with roles in diabetes, cancer, and viral infection . Cold Spring Harb Symp Quant Biol ( 2011 ) 76 : 155 – 64 10.1101/sqb.2011.76.010819 22071265

10 Hardie DG Ross FA Hawley SA AMPK: a nutrient and energy sensor that maintains energy homeostasis . Nat Rev Mol Cell Biol ( 2012 ) 13 : 251 – 62 10.1038/nrm3311 22436748 PMC5726489

11 Steinberg GR Kemp BE AMPK in health and disease . Physiol Rev ( 2009 ) 89 : 1025 – 78 10.1152/physrev.00011.2008 19584320

12 Hardie DG AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy . Nat Rev Mol Cell Biol ( 2007 ) 8 : 774 – 85 10.1038/nrm2249 17712357

13 Hoppe S Bierhoff H Cado I Weber A Tiebe M Grummt I AMP-activated protein kinase adapts rRNA synthesis to cellular energy supply . Proc Natl Acad Sci U S A ( 2009 ) 106 : 17781 – 6 10.1073/pnas.0909873106 19815529 PMC2764937

14 Hawley SA Boudeau J Reid JL Mustard KJ Udd L Makela TP Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade . J Biol ( 2003 ) 2 : 28 10.1186/1475-4924-2-28 14511394 PMC333410

15 Woods A Johnstone SR Dickerson K Leiper FC Fryer LG Neumann D LKB1 is the upstream kinase in the AMP-activated protein kinase cascade . Curr Biol ( 2003 ) 13 : 2004 – 8 10.1016/j.cub.2003.10.031 14614828

16 Hemminki A Markie D Tomlinson I Avizienyte E Roth S Loukola A A serine/threonine kinase gene defective in Peutz–Jeghers syndrome . Nature ( 1998 ) 391 : 184 – 7 10.1038/34432 9428765

17 Sanchez-Cespedes M Parrella P Esteller M Nomoto S Trink B Engles JM Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung . Cancer Res ( 2002 ) 62 : 3659 – 62 12097271

18 Hawley SA Pan DA Mustard KJ Ross L Bain J Edelman AM Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase . Cell Metab ( 2005 ) 2 : 9 – 19 10.1016/j.cmet.2005.05.009 16054095

19 Hurley RL Anderson KA Franzone JM Kemp BE Means AR Witters LA The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases . J Biol Chem ( 2005 ) 280 : 29060 – 6 10.1074/jbc.M503824200 15980064

20 Woods A Dickerson K Heath R Hong SP Momcilovic M Johnstone SR Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells . Cell Metab ( 2005 ) 2 : 21 – 33 10.1016/j.cmet.2005.06.005 16054096

21 Memmott RM Gills JJ Hollingshead M Powers MC Chen Z Kemp B Phosphatidylinositol ether lipid analogues induce AMP-activated protein kinase-dependent death in LKB1-mutant non small cell lung cancer cells . Cancer Res ( 2008 ) 68 : 580 – 8 10.1158/0008-5472.CAN-07-3091 18199555 PMC3558831

22 Dykens JA Jamieson J Marroquin L Nadanaciva S Billis PA Will Y Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro . Toxicol Appl Pharmacol ( 2008 ) 233 : 203 – 10 10.1016/j.taap.2008.08.013 18817800

23 Shaw RJ Lamia KA Vasquez D Koo SH Bardeesy N Depinho RA The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin . Science ( 2005 ) 310 : 1642 – 6 10.1126/science.1120781 16308421 PMC3074427

24 Ben Sahra I Laurent K Giuliano S Larbret F Ponzio G Gounon P Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells . Cancer Res ( 2010 ) 70 : 2465 – 75 10.1158/0008-5472.CAN-09-2782 20215500

25 El-Mir MY Nogueira V Fontaine E Averet N Rigoulet M Leverve X Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I . J Biol Chem ( 2000 ) 275 : 223 – 8 10.1074/jbc.275.1.223 10617608

26 Evans JM Donnelly LA Emslie-Smith AM Alessi DR Morris AD Metformin and reduced risk of cancer in diabetic patients . BMJ ( 2005 ) 330 : 1304 – 5 10.1136/bmj.38415.708634.F7 15849206 PMC558205

27 Jiralerspong S Palla SL Giordano SH Meric-Bernstam F Liedtke C Barnett CM Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer . J Clin Oncol ( 2009 ) 27 : 3297 – 302 10.1200/JCO.2009.19.6410 19487376 PMC2736070

28 Huang X Wullschleger S Shpiro N McGuire VA Sakamoto K Woods YL Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice . Biochem J ( 2008 ) 412 : 211 – 21 10.1042/BJ20080557 18387000

29 Sanli T Rashid A Liu C Harding S Bristow RG Cutz JC Ionizing radiation activates AMP-activated kinase (AMPK): a target for radiosensitization of human cancer cells . Int J Radiat Oncol Biol Phys ( 2010 ) 78 : 221 – 9 10.1016/j.ijrobp.2010.03.005 20615625

30 Giordanetto F Karis D Direct AMP-activated protein kinase activators: a review of evidence from the patent literature . Expert Opin Ther Pat ( 2012 ) 22 : 1467 – 77 10.1517/13543776.2012.743994 23136886

31 Yun H Ha J AMP-activated protein kinase modulators: a patent review (2006 - 2010) . Expert Opin Ther Pat ( 2011 ) 21 : 983 – 1005 10.1517/13543776.2011.577069 21548715

32 Dazert E Hall MN mTOR signaling in disease . Curr Opin Cell Biol ( 2011 ) 23 : 744 – 55 10.1016/j.ceb.2011.09.003 21963299

33 Manning BD Cantley LC Rheb fills a GAP between TSC and TOR . Trends Biochem Sci ( 2003 ) 28 : 573 – 6 10.1016/j.tibs.2003.09.003 14607085

34 Imamura K Ogura T Kishimoto A Kaminishi M Esumi H Cell cycle regulation via p53 phosphorylation by a 5’-AMP activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, in a human hepatocellular carcinoma cell line . Biochem Biophys Res Commun ( 2001 ) 287 : 562 – 7 10.1006/bbrc.2001.5627 11554766

35 Jones RG Plas DR Kubek S Buzzai M Mu J Xu Y AMP-activated protein kinase induces a p53-dependent metabolic checkpoint . Mol Cell ( 2005 ) 18 : 283 – 93 10.1016/j.molcel.2005.03.027 15866171

36 Liang J Shao SH Xu ZX Hennessy B Ding Z Larrea M The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis . Nat Cell Biol ( 2007 ) 9 : 218 – 24 10.1038/ncb1537 17237771

37 Mihaylova MM Shaw RJ The AMPK signalling pathway coordinates cell growth, autophagy and metabolism . Nat Cell Biol ( 2011 ) 13 : 1016 – 23 10.1038/ncb2329 21892142 PMC3249400

38 Puissant A Auberger P AMPK- and p62/SQSTM1-dependent autophagy mediate Resveratrol-induced cell death in chronic myelogenous leukemia . Autophagy ( 2010 ) 6 : 655 – 7 10.4161/auto.6.5.12126 20458181

39 Puissant A Robert G Auberger P Targeting autophagy to fight hematopoietic malignancies . Cell Cycle ( 2010 ) 9 : 3470 – 8 10.4161/cc.9.17.13048 20703092

40 Mizushima N Levine B Cuervo AM Klionsky DJ Autophagy fights disease through cellular self-digestion . Nature ( 2008 ) 451 : 1069 – 75 10.1038/nature06639 18305538 PMC2670399

41 Kamada Y Funakoshi T Shintani T Nagano K Ohsumi M Ohsumi Y Tor-mediated induction of autophagy via an Apg1 protein kinase complex . J Cell Biol ( 2000 ) 150 : 1507 – 13 10.1083/jcb.150.6.1507 10995454 PMC2150712

42 Lala PK Chakraborty C Role of nitric oxide in carcinogenesis and tumour progression . Lancet Oncol ( 2001 ) 2 : 149 – 56 10.1016/S1470-2045(00)00256-4 11902565

43 Wu CL Qiang L Han W Ming M Viollet B He YY Role of AMPK in UVB-induced DNA damage repair and growth control . Oncogene ( 2013 ) 32 : 2682 – 9 10.1038/onc.2012.279 22751115 PMC3465498

44 Liu H Scholz C Zang C Schefe JH Habbel P Regierer AC Metformin and the mTOR inhibitor everolimus (RAD001) sensitize breast cancer cells to the cytotoxic effect of chemotherapeutic drugs in vitro . Anticancer Res ( 2012 ) 32 : 1627 – 37 22593441

45 Lee KH Hsu EC Guh JH Yang HC Wang D Kulp SK Targeting energy metabolic and oncogenic signaling pathways in triple-negative breast cancer by a novel adenosine monophosphate-activated protein kinase (AMPK) activator . J Biol Chem ( 2011 ) 286 : 39247 – 58 10.1074/jbc.M111.264598 21917926 PMC3234749

46 Appleyard MV Murray KE Coates PJ Wullschleger S Bray SE Kernohan NM Phenformin as prophylaxis and therapy in breast cancer xenografts . Br J Cancer ( 2012 ) 106 : 1117 – 22 10.1038/bjc.2012.56 22361631 PMC3304424

47 El-Masry OS Brown BL Dobson PR Effects of activation of AMPK on human breast cancer cell lines with different genetic backgrounds . Oncol Lett ( 2012 ) 3 : 224 – 8 22740885 10.3892/ol.2011.458 PMC3362498

48 Nanjundan M Byers LA Carey MS Siwak DR Raso MG Diao L Proteomic profiling identifies pathways dysregulated in non-small cell lung cancer and an inverse association of AMPK and adhesion pathways with recurrence . J Thorac Oncol ( 2010 ) 5 : 1894 – 904 10.1097/JTO.0b013e3181f2a266 21124077 PMC3374718

49 William WN Kim JS Liu DD Solis L Behrens C Lee JJ The impact of phosphorylated AMP-activated protein kinase expression on lung cancer survival . Ann Oncol ( 2012 ) 23 : 78 – 85 10.1093/annonc/mdr036 21430184 PMC3276321

50 Dong LX Sun LL Zhang X Pan L Lian LJ Chen Z Negative regulation of mTOR activity by LKB1-AMPK signaling in non-small cell lung cancer cells . Acta Pharmacol Sin ( 2013 ) 34 : 314 – 8 10.1038/aps.2012.143 23178462 PMC4011621

51 Wu N Gu C Gu H Hu H Han Y Li Q Metformin induces apoptosis of lung cancer cells through activating JNK/p38 MAPK pathway and GADD153 . Neoplasma ( 2011 ) 58 : 482 – 90 10.4149/neo_2011_06_482 21895401

52 Memmott RM Mercado JR Maier CR Kawabata S Fox SD Dennis PA Metformin prevents tobacco carcinogen – induced lung tumorigenesis . Cancer Prev Res (Phila) ( 2010 ) 3 : 1066 – 76 10.1158/1940-6207.CAPR-10-0055 20810672 PMC3192328

53 Kuznetsov JN Leclerc GJ Leclerc GM Barredo JC AMPK and Akt determine apoptotic cell death following perturbations of one-carbon metabolism by regulating ER stress in acute lymphoblastic leukemia . Mol Cancer Ther ( 2011 ) 10 : 437 – 47 10.1158/1535-7163.MCT-10-0777 21262957 PMC3053424

54 Leclerc GM Leclerc GJ Fu G Barredo JC AMPK-induced activation of Akt by AICAR is mediated by IGF-1R dependent and independent mechanisms in acute lymphoblastic leukemia . J Mol Signal ( 2010 ) 5 : 15 10.1186/1750-2187-5-15 20863384 PMC2955666

55 Sengupta TK Leclerc GM Hsieh-Kinser TT Leclerc GJ Singh I Barredo JC Cytotoxic effect of 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) on childhood acute lymphoblastic leukemia (ALL) cells: implication for targeted therapy . Mol Cancer ( 2007 ) 6 : 46 10.1186/1476-4598-6-46 17623090 PMC1948012

56 Campas C Lopez JM Santidrian AF Barragan M Bellosillo B Colomer D Acadesine activates AMPK and induces apoptosis in B-cell chronic lymphocytic leukemia cells but not in T lymphocytes . Blood ( 2003 ) 101 : 3674 – 80 10.1182/blood-2002-07-2339 12522004

57 Drakos E Atsaves V Li J Leventaki V Andreeff M Medeiros LJ Stabilization and activation of p53 downregulates mTOR signaling through AMPK in mantle cell lymphoma . Leukemia ( 2009 ) 23 : 784 – 90 10.1038/leu.2008.348 19225536

58 Vakana E Altman JK Glaser H Donato NJ Platanias LC Antileukemic effects of AMPK activators on BCR-ABL-expressing cells . Blood ( 2011 ) 118 : 6399 – 402 10.1182/blood-2011-01-332783 22021366 PMC3236122

59 Green AS Chapuis N Maciel TT Willems L Lambert M Arnoult C The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation . Blood ( 2010 ) 116 : 4262 – 73 10.1182/blood-2010-02-269837 20668229

60 Petti C Vegetti C Molla A Bersani I Cleris L Mustard KJ AMPK activators inhibit the proliferation of human melanomas bearing the activated MAPK pathway . Melanoma Res ( 2012 ) 22 : 341 – 50 10.1097/CMR.0b013e3283544929 22588166

61 Martin MJ Hayward R Viros A Marais R Metformin accelerates the growth of BRAF V600E-driven melanoma by upregulating VEGF-A . Cancer Discov ( 2012 ) 2 : 344 – 55 10.1158/2159-8290.CD-11-0280 22576211 PMC3364710

62 Byekova YA Herrmann JL Xu J Elmets CA Athar M Liver kinase B1 (LKB1) in the pathogenesis of UVB-induced murine basal cell carcinoma . Arch Biochem Biophys ( 2011 ) 508 : 204 – 11 10.1016/j.abb.2011.01.006 21272562 PMC3072754

63 Zhang J Bowden GT UVB irradiation regulates Cox-2 mRNA stability through AMPK and HuR in human keratinocytes . Mol Carcinog ( 2008 ) 47 : 974 – 83 10.1002/mc.20450 18449856

64 Beevers CS Chen L Liu L Luo Y Webster NJ Huang S Curcumin disrupts the Mammalian target of rapamycin-raptor complex . Cancer Res ( 2009 ) 69 : 1000 – 8 10.1158/0008-5472.CAN-08-2367 19176385 PMC4307947

65 Lee YK Lee WS Hwang JT Kwon DY Surh YJ Park OJ Curcumin exerts antidifferentiation effect through AMPKalpha-PPAR-gamma in 3T3-L1 adipocytes and antiproliferatory effect through AMPKalpha-COX-2 in cancer cells . J Agric Food Chem ( 2009 ) 57 : 305 – 10 10.1021/jf802737z 19093868

66 Lee YK Park SY Kim YM Park OJ Regulatory effect of the AMPK-COX-2 signaling pathway in curcumin-induced apoptosis in HT-29 colon cancer cells . Ann N Y Acad Sci ( 2009 ) 1171 : 489 – 94 10.1111/j.1749-6632.2009.04699.x 19723094

67 Pan W Yang H Cao C Song X Wallin B Kivlin R AMPK mediates curcumin-induced cell death in CaOV3 ovarian cancer cells . Oncol Rep ( 2008 ) 20 : 1553 – 9 19020741

68 Biasutto L Mattarei A Zoratti M Resveratrol and health: the starting point . Chembiochem ( 2012 ) 13 : 1256 – 9 10.1002/cbic.201200193 22581673

69 Constant J Alcohol, ischemic heart disease, and the French paradox . Clin Cardiol ( 1997 ) 20 : 420 – 4 10.1002/clc.4960200504 9134271 PMC6656249

70 Fremont L Biological effects of resveratrol . Life Sci ( 2000 ) 66 : 663 – 73 10.1016/S0024-3205(99)00410-5 10680575

71 Tome-Carneiro J Larrosa M Gonzalez-Sarrias A Tomas-Barberan FA Garcia-Conesa MT Espin JC Resveratrol and clinical trials: the crossroad from in vitro studies to human evidence . Curr Pharm Des ( 2013 ). [Epub ahead of print]. 23448440 10.2174/13816128113199990407 PMC3782695

72 Jang M Cai L Udeani GO Slowing KV Thomas CF Beecher CW Cancer chemopreventive activity of resveratrol, a natural product derived from grapes . Science ( 1997 ) 275 : 218 – 20 10.1126/science.275.5297.218 8985016

73 Baur JA Sinclair DA Therapeutic potential of resveratrol: the in vivo evidence . Nat Rev Drug Discov ( 2006 ) 5 : 493 – 506 10.1038/nrd2060 16732220

74 Hwang JT Kwak DW Lin SK Kim HM Kim YM Park OJ Resveratrol induces apoptosis in chemoresistant cancer cells via modulation of AMPK signaling pathway . Ann N Y Acad Sci ( 2007 ) 1095 : 441 – 8 10.1196/annals.1397.047 17404056

75 Yi CO Jeon BT Shin HJ Jeong EA Chang KC Lee JE Resveratrol activates AMPK and suppresses LPS-induced NF-kappaB-dependent COX-2 activation in RAW 264.7 macrophage cells . Anat Cell Biol ( 2011 ) 44 : 194 – 203 10.5115/acb.2011.44.3.194 22025971 PMC3195823

76 Puissant A Robert G Fenouille N Luciano F Cassuto JP Raynaud S Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62/SQSTM1 expression and AMPK activation . Cancer Res ( 2010 ) 70 : 1042 – 52 10.1158/0008-5472.CAN-09-3537 20103647

77 Castillo-Pichardo L Dharmawardhane SF Grape polyphenols inhibit Akt/mammalian target of rapamycin signaling and potentiate the effects of gefitinib in breast cancer . Nutr Cancer ( 2012 ) 64 : 1058 – 69 10.1080/01635581.2012.716898 23061908 PMC4286176

78 Rashid A Liu C Sanli T Tsiani E Singh G Bristow RG Resveratrol enhances prostate cancer cell response to ionizing radiation. Modulation of the AMPK Akt and mTOR pathways . Radiat Oncol ( 2011 ) 6 : 144 10.1186/1748-717X-6-144 22029423 PMC3217881

79 Yuan Y Xue X Guo RB Sun XL Hu G Resveratrol enhances the antitumor effects of temozolomide in glioblastoma via ROS-dependent AMPK-TSC-mTOR signaling pathway . CNS Neurosci Ther ( 2012 ) 18 : 536 – 46 10.1111/j.1755-5949.2012.00319.x 22530672 PMC6493617

80 Zhang L Jing H Cui L Li H Zhou B Zhou G 3,4-Dimethoxystilbene, a resveratrol derivative with anti-angiogenic effect, induces both macroautophagy and apoptosis in endothelial cells . J Cell Biochem ( 2013 ) 114 : 697 – 707 10.1002/jcb.24411 23059970

81 Kandaswami C Lee LT Lee PP Hwang JJ Ke FC Huang YT The antitumor activities of flavonoids . In vivo ( 2005 ) 19 : 895 – 909 16097445

82 Park CE Yun H Lee EB Min BI Bae H Choe W The antioxidant effects of genistein are associated with AMP-activated protein kinase activation and PTEN induction in prostate cancer cells . J Med Food ( 2010 ) 13 : 815 – 20 10.1089/jmf.2009.1359 20673057

83 Sanchez Y Amran D Fernandez C de Blas E Aller P Genistein selectively potentiates arsenic trioxide-induced apoptosis in human leukemia cells via reactive oxygen species generation and activation of reactive oxygen species-inducible protein kinases (p38-MAPK, AMPK) . Int J Cancer ( 2008 ) 123 : 1205 – 14 10.1002/ijc.23639 18546268

84 Lee YK Park OJ Regulation of mutual inhibitory activities between AMPK and Akt with quercetin in MCF-7 breast cancer cells . Oncol Rep ( 2010 ) 24 : 1493 – 7 21042744 10.3892/or_00001010

85 Jang KY Jeong SJ Kim SH Jung JH Kim JH Koh W Activation of reactive oxygen species/AMP activated protein kinase signaling mediates fisetin-induced apoptosis in multiple myeloma U266 cells . Cancer Lett ( 2012 ) 319 : 197 – 202 10.1016/j.canlet.2012.01.008 22261340

86 Khan N Afaq F Khusro FH Mustafa Adhami V Suh Y Mukhtar H Dual inhibition of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin . Int J Cancer ( 2012 ) 130 : 1695 – 705 10.1002/ijc.26178 21618507 PMC3267899

87 Suh Y Afaq F Khan N Johnson JJ Khusro FH Mukhtar H Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells . Carcinogenesis ( 2010 ) 31 : 1424 – 33 10.1093/carcin/bgq115 20530556 PMC2915634

88 Kim HJ Kim SK Kim BS Lee SH Park YS Park BK Apoptotic effect of quercetin on HT-29 colon cancer cells via the AMPK signaling pathway . J Agric Food Chem ( 2010 ) 58 : 8643 – 50 10.1021/jf101510z 20681654

89 Jung JH Lee JO Kim JH Lee SK You GY Park SH Quercetin suppresses HeLa cell viability via AMPK-induced HSP70 and EGFR down-regulation . J Cell Physiol ( 2010 ) 223 : 408 – 14 10.1002/jcp.22049 20082303

90 Tong X Smith KA Pelling JC Apigenin, a chemopreventive bioflavonoid, induces AMP-activated protein kinase activation in human keratinocytes . Mol Carcinog ( 2012 ) 51 : 268 – 79 10.1002/mc.20793 21538580

91 Hwang JT Park OJ Lee YK Sung MJ Hur HJ Kim MS Anti-tumor effect of luteolin is accompanied by AMP-activated protein kinase and nuclear factor-kappaB modulation in HepG2 hepatocarcinoma cells . Int J Mol Med ( 2011 ) 28 : 25 – 31 10.3892/ijmm.2011.667 21468539

92 Gills JJ Kosmeder J 2nd Moon RC Lantvit DD Pezzuto JM Effect of deguelin on UVB-induced skin carcinogenesis . J Chemother ( 2005 ) 17 : 297 – 301 16041863 10.1179/joc.2005.17.3.297

93 Kim JH Lee JO Lee SK Kim N You GY Moon JW Celastrol suppresses breast cancer MCF-7 cell viability via the AMP-activated protein kinase (AMPK)-induced p53-polo like kinase 2 (PLK-2) pathway . Cell Signal ( 2013 ) 25 : 805 – 13 10.1016/j.cellsig.2012.12.005 23266469

94 Shao JJ Zhang AP Qin W Zheng L Zhu YF Chen X AMP-activated protein kinase (AMPK) activation is involved in chrysin-induced growth inhibition and apoptosis in cultured A549 lung cancer cells . Biochem Biophys Res Commun ( 2012 ) 423 : 448 – 53 10.1016/j.bbrc.2012.05.123 22659738

95 Hwang JT Ha J Park IJ Lee SK Baik HW Kim YM Apoptotic effect of EGCG in HT-29 colon cancer cells via AMPK signal pathway . Cancer Lett ( 2007 ) 247 : 115 – 21 10.1016/j.canlet.2006.03.030 16797120

96 Chen D Pamu S Cui Q Chan TH Dou QP Novel epigallocatechin gallate (EGCG) analogs activate AMP-activated protein kinase pathway and target cancer stem cells . Bioorg Med Chem ( 2012 ) 20 : 3031 – 7 10.1016/j.bmc.2012.03.002 22459208 PMC3334407

97 Shimizu M Sakai H Shirakami Y Yasuda Y Kubota M Terakura D Preventive effects of (-)-epigallocatechin gallate on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db Mice . Cancer Prev Res (Phila) ( 2011 ) 4 : 396 – 403 10.1158/1940-6207.CAPR-10-0331 21372039

98 Yang XW Wang XL Cao LQ Jiang XF Peng HP Lin SM Green tea polyphenol epigallocatechin-3-gallate enhances 5-fluorouracil-induced cell growth inhibition of hepatocellular carcinoma cells . Hepatol Res ( 2012 ) 42 : 494 – 501 10.1111/j.1872-034X.2011.00947.x 22221825

99 Kim HS Kim MJ Kim EJ Yang Y Lee MS Lim JS Berberine-induced AMPK activation inhibits the metastatic potential of melanoma cells via reduction of ERK activity and COX-2 protein expression . Biochem Pharmacol ( 2012 ) 83 : 385 – 94 10.1016/j.bcp.2011.11.008 22120676

100 Park JJ Seo SM Kim EJ Lee YJ Ko YG Ha J Berberine inhibits human colon cancer cell migration via AMP-activated protein kinase-mediated downregulation of integrin beta1 signaling . Biochem Biophys Res Commun ( 2012 ) 426 : 461 – 7 10.1016/j.bbrc.2012.08.091 22943849

101 Khanal P Oh WK Thuong PT Cho SD Choi HS 24-Hydroxyursolic acid from the leaves of the Diospyros kaki (Persimmon) induces apoptosis by activation of AMP-activated protein kinase . Planta Med ( 2010 ) 76 : 689 – 93 10.1055/s-0029-1240678 19960411

102 Khanal P Oh WK Yun HJ Namgoong GM Ahn SG Kwon SM p-HPEA-EDA, a phenolic compound of virgin olive oil, activates AMP-activated protein kinase to inhibit carcinogenesis . Carcinogenesis ( 2011 ) 32 : 545 – 53 10.1093/carcin/bgr001 21216846

103 Kim YM Hwang JT Kwak DW Lee YK Park OJ Involvement of AMPK signaling cascade in capsaicin-induced apoptosis of HT-29 colon cancer cells . Ann N Y Acad Sci ( 2007 ) 1095 : 496 – 503 10.1196/annals.1397.053 17404062

104 Harada S Kishimoto M Kobayashi M Nakamoto K Fujita-Hamabe W Chen HH Honokiol suppresses the development of post-ischemic glucose intolerance and neuronal damage in mice . J Nat Med ( 2012 ) 66 : 591 – 9 10.1007/s11418-011-0623-x 22261858

105 Lin JN Lin VC Rau KM Shieh PC Kuo DH Shieh JC Resveratrol modulates tumor cell proliferation and protein translation via SIRT1-dependent AMPK activation . J Agric Food Chem ( 2010 ) 58 : 1584 – 92 10.1021/jf9035782 19928762

106 Lee YK Lee WS Kim GS Park OJ Anthocyanins are novel AMPKalpha1 stimulators that suppress tumor growth by inhibiting mTOR phosphorylation . Oncol Rep ( 2010 ) 24 : 1471 – 7 21042741 10.3892/or_00001007

107 Ding D Zhang B Meng T Ma Y Wang X Peng H Novel synthetic baicalein derivatives caused apoptosis and activated AMP-activated protein kinase in human tumor cells . Org Biomol Chem ( 2011 ) 9 : 7287 – 91 10.1039/c1ob06094e 21901221

108 Lin YC Hung CM Tsai JC Lee JC Chen YL Wei CW Hispidulin potently inhibits human glioblastoma multiforme cells through activation of AMP-activated protein kinase (AMPK) . J Agric Food Chem ( 2010 ) 58 : 9511 – 7 10.1021/jf1019533 20698539

109 Choi Y Lee JH The combination of tephrosin with 2-deoxy-D-glucose enhances the cytotoxicity via accelerating ATP depletion and blunting autophagy in human cancer cells . Cancer Biol Ther ( 2011 ) 12 : 989 – 96 10.4161/cbt.12.11.18364 22123175 PMC3280917

110 Park IJ Lee YK Hwang JT Kwon DY Ha J Park OJ Green tea catechin controls apoptosis in colon cancer cells by attenuation of H 2 O 2 -stimulated COX-2 expression via the AMPK signaling pathway at low-dose H 2 O 2 . Ann N Y Acad Sci ( 2009 ) 1171 : 538 – 44 10.1111/j.1749-6632.2009.04698.x 19723101