There is much epidemiological evidence that a diet rich in fruits and vegetables could lower the risk of certain cancers. The effect has been attributed, in part, to natural polyphenols. Besides, numerous studies have demonstrated that natural polyphenols could be used for the prevention and treatment of cancer. Potential mechanisms included antioxidant, anti-inflammation as well as the modulation of multiple molecular events involved in carcinogenesis. The current review summarized the anticancer efficacy of major polyphenol classes (flavonoids, phenolic acids, lignans and stilbenes) and discussed the potential mechanisms of action, which were based on epidemiological, in vitro, in vivo and clinical studies within the past five years.

https://www.mdpi.com/2072-6643/8/8/515/pdf

Natural Polyphenols for Prevention and Treatment of Cancer

Berberine: new perspectives for old remedies.

// Weidong Li 1,3,* , Shakir M. Saud 2,3,* , Matthew R. Young 3 , Guohong Chen 4 , Baojin Hua 1 1 Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China 2 Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA 3 Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA 4 Department of Urinary Surgery, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China * These authors have contributed equally to this work Correspondence to: Baojin Hua, email: // Guohong Chen, email: // Keywords : AMP activated kinase, cancer, prevention, treatment Received : February 02, 2015 Accepted : February 26, 2015 Published : March 20, 2015 Abstract AMP-activated protein kinase (AMPK) is an important mediator in maintaining cellular energy homeostasis. AMPK is activated in response to a shortage of energy. Once activated, AMPK can promote ATP production and regulate metabolic energy. AMPK is a known target for treating metabolic syndrome and type-2 diabetes; however, recently AMPK is emerging as a possible metabolic tumor suppressor and target for cancer prevention and treatment. Recent epidemiological studies indicate that treatment with metformin, an AMPK activator reduces the incidence of cancer. In this article we review the role of AMPK in regulating inflammation, metabolism, and other regulatory processes with an emphasis on cancer, as well as, discuss the potential for targeting AMPK to treat various types of cancer. Activation of AMPK has been found to oppose tumor progression in several cancer types and offers a promising cancer therapy. This review evaluates the evidence linking AMPK with tumor suppressor function and analyzes the molecular mechanisms involved. AMPK activity opposes tumor development and progression in part by regulating inflammation and metabolism.

/pdf/targeting-ampk-for-cancer-prevention-and-treatment-jzmvchwaqd.pdf

Targeting AMPK for cancer prevention and treatment

Ever present hurdles for the discovery of new drugs for cancer therapy have necessitated the development of the alternative strategy of drug repurposing, the development of old drugs for new therapeutic purposes. This strategy with a cost-effective way offers a rare opportunity for the treatment of human neoplastic disease, facilitating rapid clinical translation. With an increased understanding of the hallmarks of cancer and the development of various data-driven approaches, drug repurposing further promotes the holistic productivity of drug discovery and reasonably focuses on target-defined antineoplastic compounds. The “treasure trove” of non-oncology drugs should not be ignored since they could target not only known but also hitherto unknown vulnerabilities of cancer. Indeed, different from targeted drugs, these old generic drugs, usually used in a multi-target strategy may bring benefit to patients. In this review, aiming to demonstrate the full potential of drug repurposing, we present various promising repurposed non-oncology drugs for clinical cancer management and classify these candidates into their proposed administration for either mono- or drug combination therapy. We also summarize approaches used for drug repurposing and discuss the main barriers to its uptake.

/pdf/overcoming-cancer-therapeutic-bottleneck-by-drug-repurposing-26m168lv8z.pdf

Overcoming cancer therapeutic bottleneck by drug repurposing

Synergy effects of herb extracts: pharmacokinetics and pharmacodynamic basis.

Berberine-induced AMPK activation inhibits the metastatic potential of melanoma cells via reduction of ERK activity and COX-2 protein expression

Tumor hypoxia is considered the best validated target in clinical oncology because of its significant contribution to chemotherapy failure and drug resistance. As an approach to target hypoxia, we assessed the potential of quercetin, a flavonoid widely distributed in plants, as a anticancer agent under hypoxic conditions and examined its pharmacological mechanisms by primarily focusing on the role of AMP-activated protein kinase (AMPK). Quercetin significantly attenuated tumor growth in an HCT116 cancer xenograft in vivo model with a substantial reduction of AMPK activity. In a cell culture system, quercetin more dramatically induced apoptosis of HCT116 cancer cells under hypoxic conditions than normoxic conditions, and this was tightly associated with inhibition of hypoxia-induced AMPK activity. An in vitro kinase assay demonstrated that quercetin directly inhibits AMPK activity. Inhibition of AMPK by expressing a dominant-negative form resulted in an increase of apoptosis under hypoxia, and a constitutively active form of AMPK effectively blocked quercetin-induced apoptosis under hypoxia. Collectively, our data suggest that quercetin directly inhibits hypoxia-induced AMPK, which plays a protective role against hypoxia. Quercetin also reduced the activity of hypoxia-inducible factor-1 (HIF-1), a major transcription factor for adaptive cellular response to hypoxia. Moreover, quercetin sensitized HCT116 cancer cells to the anticancer drugs cisplatin and etoposide under hypoxic conditions. Our findings suggest that AMPK may serve as a novel target for overcoming tumor hypoxia-associated negative aspects.

Quercetin enhances hypoxia-mediated apoptosis via direct inhibition of AMPK activity in HCT116 colon cancer

As solid tumors outgrow the surrounding vasculature, they encounter microenvironments with a limited supply of nutrients. Therefore, in order to survive, tumor cells need to adapt to glucose-deprived environments. In the present study, we examined the signaling pathways that lead to cancer cell survival in response to glucose deprivation. We primarily focused on the roles of adenosine monophosphate-activated protein kinase (AMPK), its upstream kinase LKB1 and c-Jun N-terminal kinase (JNK). Herein, we showed that in DU145 human prostate carcinomas, glucose deprivation activated JNK with biphasic kinetics. We demonstrated that the early phase of JNK activation promoted cell survival, whereas the late phase of JNK activation induced apoptosis. Our data further showed that AMPK relayed a survival signal transmitted by early activation of JNK and that the sustained AMPK signal in turn inhibited the proapoptotic property of JNK via a negative feedback mechanism involving reactive oxygen species. We induced this negative feedback inhibition by expressing LKB1 ectopically in DU145 cells. In conclusion, our results demonstrated how AMPK controls the molecular mechanism underlying the differential biological functions of JNK, and they also provided a novel explanation for the antiapoptotic role of LKB1.

/pdf/amp-kinase-signaling-determines-whether-c-jun-n-terminal-4n7sn7h4l2.pdf

AMP kinase signaling determines whether c-Jun N-terminal kinase promotes survival or apoptosis during glucose deprivation.

N-myc downstream-regulated gene 2 (NDRG2), which is known to have tumor suppressor functions, is frequently down-regulated in breast cancers and potentially involved in preventing the migration and invasion of malignant tumor cells. In the present study, we examined the inhibitory effects of NDRG2 overexpression, specifically focusing on the role of cyclooxygenase-2 (COX-2) in the migration of breast cancer cells. NDRG2 overexpression in MDA-MB-231 cells inhibited the expression of the COX-2 mRNA and protein, the transcriptional activity of COX-2, and prostaglandin E2 (PGE2) production, which were induced by a treatment with phorbol-12-myristate-13-acetate (PMA). Nuclear transcription factor-κB (NF-κB) signaling attenuated by NDRG2 expression resulted in a decrease in PMA-induced COX-2 expression. Interestingly, the inhibition of COX-2 strongly suppressed PMA-stimulated migration and invasion in MDA-MB-231-NDRG2 cells. Moreover, siRNA-mediated knockdown of NDRG2 in MCF7 cells increased the COX-2 mRNA and protein expression levels and the PMA-induced COX-2 expression levels. Consistent with these results, the migration and invasion of MCF7 cells treated with NDRG2 siRNA were significantly enhanced following treatment with PMA. Taken together, our data show that the inhibition of NF-κB signaling by NDRG2 expression is able to suppress cell migration and invasion through the down-regulation of COX-2 expression.

NDRG2 controls COX-2/PGE₂-mediated breast cancer cell migration and invasion.

Kazinol C is a 1,3-diphenylpropane, obtained from Broussonetia kazinoki, that has been employed in folk medicine as an edema suppressant. It exerts beneficial effects in oxidative stress-related diseases, such as cancer. However, the molecular mechanism involved in the anticancer effects remains to be determined. AMP-activated protein kinase (AMPK) has emerged as a possible anticancer target molecule. The present study investigated the effect of kazinol C on AMPK activation as well as subsequent HT-29 colon cancer cell viability, apoptosis and migration. Kazinol C markedly induced AMPK phosphorylation and significantly attenuated HT-29 colon cancer cell growth and viability. Compound C, as a well‑known AMPK inhibitor, blocked the kazinol C-induced cell death, and stable transduction of dominant-negative (DN) AMPK in colon cancer cells also inhibited kazinol C-induced cell apoptosis. In addition, kazinol C inhibited HT-29 cell migration and anchorage-independent growth. AMPK inhibition using stable transduction with DN AMPK significantly abrogated the kazinol C-induced inhibition of cancer cell migration. Thus, AMPK is a critical and novel regulator of kazinol C-mediated cancer cell apoptosis and inhibition of migration, suggesting that AMPK is a prime cancer target.

/pdf/kazinol-c-from-broussonetia-kazinoki-activates-amp-activated-1ezfdn48t1.pdf

Hak-Su Kim

Papers

Berberine-induced AMPK activation inhibits the metastatic potential of melanoma cells via reduction of ERK activity and COX-2 protein expression

Quercetin enhances hypoxia-mediated apoptosis via direct inhibition of AMPK activity in HCT116 colon cancer

AMP kinase signaling determines whether c-Jun N-terminal kinase promotes survival or apoptosis during glucose deprivation.

NDRG2 controls COX-2/PGE₂-mediated breast cancer cell migration and invasion.

Kazinol C from Broussonetia kazinoki activates AMP-activated protein kinase to induce antitumorigenic effects in HT-29 colon cancer cells.