Metformin reverses multidrug resistance in human hepatocellular carcinoma Bel-7402/5-fluorouracil cells

Ling, Sunbin; Tian, Yu; Zhang, Haiquan; Jia, Kaiqi; Feng, Tingting; Sun, Da; Gao, Zhenming; Xu, Fei; Hou, Zhaoyuan; Li, Yan; Wang, Liming

doi:10.3892/mmr.2014.2614

Cited by 46 publications

(37 citation statements)

References 33 publications

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“…Metformin and salicylate may synergistically reduce the survival of cancer cells in vitro by inhibiting de novo lipogenesis and targeting pro-apoptotic and Bcl-2 family members (25,26). Metformin also synergizes with chemotherapy to reverse multi-drug resistance in cancers by targeting the AMPK/mTOR/hypoxia inducible factor-1α/P-glycoprotein/multidrug resistance-associated protein 1 signaling pathway (27,28). Metformin potentiates the anti-tumor effect of resveratrol on PC by targeting the VEGF-B signaling pathway (29).…”

Section: Discussionmentioning

confidence: 99%

Metformin synergizes with rapamycin to inhibit the growth of pancreatic cancer inï¿½vitro and inï¿½vivo

2017

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Abstract. Previous studies have suggested that metformin may improve the survival rate of patients with pancreatic cancer (PC) by regulating the adenosine monophosphate-activated protein kinase/mammalian target of rapamycin (mTOR) signaling pathway. Rapamycin specifically targets mTOR. In the present study, the efficacy of metformin and rapamycin in isolation and combination were investigated for the treatment of PC. The efficacy of metformin and rapamycin in reducing the proliferation of PC cell line SW1990 in vitro and in vivo was evaluated. It was revealed that metformin (10 mmol/l) + rapamycin (2 ng/ml), metformin (15 mmol/l) + rapamycin (20 ng/ml) and metformin (20 mmol/l) + rapamycin (200 ng/ml) significantly inhibited the viability of PC cells compared with untreated cells. Additionally, metformin (20 mmol/l) + rapamycin (200 ng/ml) significantly suppressed the expression of phosphorylated mTOR compared with metformin or rapamycin alone. Using a xenograft tumor model, it was revealed that combination treatment significantly inhibited the growth of PC cells compared with monotherapy. The present study revealed that a combination of metformin and rapamycin synergistically inhibited the growth of PC in vitro and in vivo and may be a potential treatment option for patients with PC.

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Section: Discussionmentioning

confidence: 99%

Metformin synergizes with rapamycin to inhibit the growth of pancreatic cancer inï¿½vitro and inï¿½vivo

2017

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“…57 In addition, metformin can reverse multidrug resistance in human hepatocellular carcinoma Bel-7402/5-fluorouracil cells. 58 These data indicate that metformin may potentiate the resensitization of therapeutic-resistant cancer cells to the anticancer drugs.…”

Section: ■ Antineoplastic Actions Of Metforminmentioning

confidence: 95%

Metformin: A Novel but Controversial Drug in Cancer Prevention and Treatment

Sui

Wang

et al. 2015

Mol. Pharmaceutics

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Metformin, a biguanide derivative that is widely used for treating type 2 diabetes mellitus, has recently been shown to exert potential anticancer effects. Many retrospective data and laboratory studies suggest the idea that metformin has antineoplastic activity, but some other studies reach conflicting conclusions. Although the precise molecular mechanisms by which metformin affects various cancers have not been fully elucidated, activation of AMPK-dependent and AMPK-independent pathways along with energy metabolism aberration, cell cycle arrest and apoptosis or autophagy induction have emerged as crucial regulators in this process. In this Review, we describe the role of metformin in the prevention and treatment of a variety of cancers and summarize the molecular mechanisms that are currently well documented in the ability of metformin as an anticancer agent. In addition, the scientific and clinical hurdles regarding the potential role of metformin in cancer will be discussed.

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“…cancer [37,38] may be circumvented, and metformin has anti-proliferative potential against cancer cells or reversing MDR in vitro and in vivo [39,40] . However, the precise molecular mechanisms whereby metformin works in cancer prevention remain multi-factorial and ill-defined.…”

Section: Discussionmentioning

confidence: 99%

Reversal of multidrug resistance of hepatocellular carcinoma cells by metformin through inhibitingNF-κBgene transcription

Yang

Wang

et al. 2016

WJH

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AIM:To interfere with the activation of nuclear factor-κB (NF-κB) with metformin and explore its effect in reversing multidrug resistance (MDR) of hepatocellular carcinoma (HCC) cells. METHODS:Expression of P-glycoprotein (P-gp) and NF-κB in human HepG2 or HepG2/adriamycin (ADM) cells RESULTS: P-gp overexpression in HepG2 and HepG2/ ADM cells was closely related to mdr1 mRNA (3.310 ± 0.154) and NF-κB mRNA (2.580 ± 0.040) expression. NF-κB gene transcription was inhibited by specific siRNA with significant down-regulation of P-gp and enhanced HCC cell chemosensitivity to doxorubicin. After pretreatment with metformin, HepG2/ADM cells were sensitized to doxorubicin and P-gp was decreased through the NF-κB signaling pathway. The synergistic effect of metformin and NF-κB siRNA were found in HepG2/ADM cells with regard to proliferation inhibition, cell cycle arrest and inducing cell apoptosis. Core tip: Metformin might target AMP-activated protein kinase mammalian target of rapamycin pathway, suppress hypoxia-inducible factor-1α and transcriptionally down-regulate P-glycoprotein (P-gp) and multidrug resistance (MDR)-associated protein 1, suggesting that metformin may reverse MDR by targeting the AMPactivated protein kinase/mammalian target of rapamycin/ hypoxia-inducible factor-1α/P-gp and MDR-associated protein 1 pathways. In the present study, HepG2/ADM cells pretreated with metformin were sensitized to doxorubicin and P-gp was decreased through the nuclear factor-κB (NF-κB) signaling pathway. The synergistic effects were found in the cells with regard to proliferation inhibition, cell cycle arrest and inducing apoptosis, and inhibiting P-gp expression via the NF-κB signaling pathway effectively reversed MDR by down-regulating MDR1/P-gp expression. CONCLUSION:

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Metformin reverses multidrug resistance in human hepatocellular carcinoma Bel-7402/5-fluorouracil cells

Cited by 46 publications

References 33 publications

Metformin synergizes with rapamycin to inhibit the growth of pancreatic cancer inï¿½vitro and inï¿½vivo

Metformin synergizes with rapamycin to inhibit the growth of pancreatic cancer inï¿½vitro and inï¿½vivo

Metformin: A Novel but Controversial Drug in Cancer Prevention and Treatment

Reversal of multidrug resistance of hepatocellular carcinoma cells by metformin through inhibitingNF-κBgene transcription

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