Metformin and Hepatic Carcinogenesis

Pollak, Michael; González-Angulo, Ana M.

doi:10.1158/1940-6207.capr-12-0080

Cited by 8 publications

(3 citation statements)

References 23 publications

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“…38) One of the pharmacological AMPK activators, AICAR, induces hepatocellular cancer cell death, 39) suggesting that activating AMPK could be a potential therapeutic target for HCC. In this study, we demonstrated that CrT1 increases AMPK activation (Figs.…”

Section: )mentioning

confidence: 99%

An ent-Kaurane Diterpenoid from Croton tonkinensis Induces Apoptosis by Regulating AMP-Activated Protein Kinase in SK-HEP1 Human Hepatocellular Carcinoma Cells

Sul

Lee

Young

et al. 2013

Biological & Pharmaceutical Bulletin

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Hepatocellular carcinoma (HCC) is the most common type of liver cancer with high mortality worldwide. Traditional chemotherapy for HCC is not widely accepted by clinical practitioners because of its toxic side effects. Thus, there is a need to identify chemotherapeutic drugs against HCC. AMP-activated protein kinase (AMPK) is a biologic sensor for cellular energy status that acts a tumor suppressor and a potential cancer therapeutic target. The traditional Vietnamese medicinal plant Croton tonkinensis shows cytotoxicity in various cancer cells; however, its anticancer mechanism remains unclear. In this study, we determined whether the ent-kaurane diterpenoid ent-18-acetoxy-7β-hydroxy kaur-15-oxo-16-ene (CrT1) isolated from this plant plays a role as a chemotherapeutic drug targeting AMPK. CrT1 blocked proliferation in dose-and time-dependent manners in human hepatocellular carcinoma SK-HEP1 cells. CrT1 induced sub-G 1 arrest and caspase-dependent apoptosis. CrT1 activated caspase-3, -7, -8, -9, and poly(ADP-ribose) polymerase, and its effect was inhibited by z-VAD-fmk suppressing caspase-3 cleavage. CrT1 induced increases in p53 and Bax levels but decreased Bcl 2 levels. In addition, CrT1 resulted in increased translocation of cytochrome c into the cytoplasm. We showed that CrT1-activated AMPK activation was followed by modulating the mammalian target of rapamycin/p70S6K pathway and was inactivated by treating cells with compound C. Treatment with CrT1 and aminoimidazole carboxamide ribonucleotide (AICAR) synergistically activated AMPK. CrT1-induced AMPK activation regulated cell viability and apoptosis. These results suggest that CrT1 is a novel AMPK activator and that AMPK activation in SK-HEP1 cells is responsible for CrT1-induced anticancer activity including apoptosis.Key words hepatocellular carcinoma; AMP-activated protein kinase; ent-kaurane diterpenoid Hepatocellular carcinoma (HCC) is the most common type of liver cancer with high mortality and causes 662000 deaths worldwide each year. To date, HCC has a life-threatening and unsatisfactory prognosis. Once the diagnosis is confirmed, most patients are already at the advanced stage and have lost the opportunity for surgical intervention. Further characterization of underlying molecular mechanisms in HCC would bring new insights into HCC research and clinical treatment.

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Section: )mentioning

confidence: 99%

An ent-Kaurane Diterpenoid from Croton tonkinensis Induces Apoptosis by Regulating AMP-Activated Protein Kinase in SK-HEP1 Human Hepatocellular Carcinoma Cells

Sul

Lee

Young

et al. 2013

Biological & Pharmaceutical Bulletin

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“…Metformin (1,1-dimethylbiguanide hydrochloride), a biguanide derivative, has emerged as potential anti-neoplastic agent in the prevention and treatment of HCC (9). Moreover, several studies have demonstrated that metformin has an inhibitory effect on hepatoma cell growth both in vitro and in vivo (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Low concentration of metformin induces a p53-dependent senescence in hepatoma cells via activation of the AMPK pathway

Gao

Zhou

et al. 2013

International Journal of Oncology

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The induction of senescence for cancer treatment has provoked considerable interest recently. Metformin, a first-line drug for diabetes mellitus type 2, appears to be associated with a lower risk and improved outcomes in hepatocellular carcinoma (HCC). The mechanism involved in function of metformin in HCC is poorly understood. We show that low doses of metformin induced hepatoma cell senescence characterized by accumulation of senescence-associated β-galactosidase activity (SA-β-gal) and the senescence marker Dec1, whereas the higher doses initiated apoptotic cell death. Metformin-induced senescence was accompanied by enhanced phosphorylation levels of AMP-activated protein kinase (AMPK) and its downstream target acetyl-CoA carboxylase (ACC). The expression of acetylated p53 at Lys382 (Ac-p53) and p21 was also increased, while phosphorylation of p53 at Ser15 (p-p53), p53, p16 and pRB was rarely altered after metformin treatment. Moreover, inhibition of AMPK decreased p-AMPK, p-ACC, Ac-p53 and p21 expression, diminished SA-β-gal staining and restored hepatoma cell proliferation. In addition, p53 siRNA transfection attenuated metformin-induced SA-β-gal staining. Intriguingly, co-expression of SIRT1 and p53 dramatically reduced the levels of Ac-p53, however, low doses of metformin treatment partially reversed the effect of SIRT1 on p53 acetylation and elevated SA-β-gal activity. These observations indicate that activation of the AMPK pathway promotes senescence in hepatoma cells exposed to low concentrations of metformin in a p53-dependent manner. Further, low doses of metformin may have the potential to be used as an adjuvant to HCC therapy.

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“…Cancer Bladder [74,75]; colorectal [76]; endometrial [77]; liver [78]; lung [79]; pancreatic [80]; prostate [81];…”

Section: Metforminmentioning

confidence: 99%

Using human experience to identify drug repurposing opportunities: theory and practice

Cavalla

2019

Brit J Clinical Pharma

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Retrospective evidence drawn from real-world experience of a medicine's use outside its labelled indication is one of a number of techniques used in drug repurposing (DRP). Relying as it does on large numbers of real incidences of human experience, rather than individual case reports with limited statistical support, preclinical experiments with poor translatability or in silico associations, which are early-stage hypotheses, it represents the best validated form of DRP. Cancer is the most frequent of such DRP examples (e.g. aspirin in pancreatic cancer, hazard ratio = 0.25). This approach can be combined with pathway analysis to provide first-in-class treatments for complex diseases. Alternatively, it can be combined with prospective preclinical studies to uncover a validated mechanism for a new indication, after which a repurposed molecule is chemically optimized. British Journal of Clinical PharmacologyBr J Clin Pharmacol (2019) 85 680-689 680 with cognitive dysfunction treated with metformin, to determine the relative benefit in situations involving vascular dementia relative to Alzheimer disease. Although case reports are often the bases for repurposing hypotheses, they lack statistical rigour and, for the purposes of this review, are not included in the definition of retrospective human evidence Retrospective data for drug repurposing Br J Clin Pharmacol (2019) 85 680-689 681 Retrospective data for drug repurposing Br J Clin Pharmacol (2019) 85 680-689 683 Retrospective data for drug repurposing Br J Clin Pharmacol (2019) 85 680-689 689

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Metformin and Hepatic Carcinogenesis

Cited by 8 publications

References 23 publications

An <i>ent</i>-Kaurane Diterpenoid from <i>Croton tonkinensis</i> Induces Apoptosis by Regulating AMP-Activated Protein Kinase in SK-HEP1 Human Hepatocellular Carcinoma Cells

An <i>ent</i>-Kaurane Diterpenoid from <i>Croton tonkinensis</i> Induces Apoptosis by Regulating AMP-Activated Protein Kinase in SK-HEP1 Human Hepatocellular Carcinoma Cells

Low concentration of metformin induces a p53-dependent senescence in hepatoma cells via activation of the AMPK pathway

Using human experience to identify drug repurposing opportunities: theory and practice

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