The anti-diabetic drug metformin inhibits pancreatic cancer cell proliferation in vitro and in vivo: Study of the microRNAs associated with the antitumor effect of metformin

Kato, Kiyohito; Iwama, Hisakazu; Yamashita, Takuma; Kobayashi, Kiyoyuki; Fujihara, Shintaro; Fujimori, Takahiro; Kamada, Hideki; Kobara, Hideki; Masaki, Tsutomu

doi:10.3892/or.2015.4496

Cited by 37 publications

(31 citation statements)

References 42 publications

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“…A previous report has indicated that metformin may improve treatment resistance in hypoxic cell lines (27). Metformin is widely used worldwide as a therapeutic agent for type 2 diabetes, but also has antitumor effects in some types of cancer cell lines, including cholangiocarcinoma, ovarian cancer, pancreatic cancer, and epidermoid carcinoma (28)(29)(30)(31). Metformin exhibits its antitumor effects via inhibition of mTOR by activation of AMPK (32).…”

Section: Discussionmentioning

confidence: 99%

Metformin attenuates hypoxia‑induced resistance to cisplatin in the HepG2 cell line

et al. 2018

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Hepatoblastoma is the most commonly occurring liver tumor in children. Preoperative chemotherapy and surgery have improved treatment outcomes; however, further improvements are required in the treatment of advanced cases. Recently, the efficacy of transarterial chemoembolization (TACE) has garnered attention. TACE increases the local concentration of drugs by transcatheterically administering antitumor agents, and induces necrosis in the tumor by embolizing the feeding artery. However, studies have revealed that tumors exhibit resistance to anticancer drugs in hypoxic environments. Metformin is a drug used to treat type 2 diabetes; however, recent reports have indicated that it may also exhibit antitumor effects in various cancer cell lines. These effects are hypothesized to be mediated by the activation of adenosine monophosphate-activated protein kinase and reduction of mammalian target of rapamycin signaling, but these effects occur at high concentrations that are not suitable for use in a clinical setting. The potential efficacy of metformin at increased physiological concentrations has not been evaluated. The present study investigated the therapeutic effect of low concentrations of metformin in combination with cisplatin on liver cancer HepG2 cells in hypoxic conditions. HepG2 cells were treated with cisplatin alone, metformin alone, or a combination of these two drugs and cultured in normoxia or hypoxia. Treatment with either 5 µM cisplatin or 1 mM metformin alone did not significantly affect cell proliferation or apoptosis in hypoxic conditions. However, when 5 µM cisplatin was combined with 1 mM metformin, a significant inhibition of cell proliferation and induction of apoptosis was observed in hypoxic HepG2 cells. In conclusion, a low concentration of metformin attenuates hypoxia-induced resistance to cisplatin in HepG2 cells. Selective delivery of an effective dose of metformin to a hepatoblastoma tumor may be achievable and clinically useful with TACE.

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Section: Discussionmentioning

confidence: 99%

Metformin attenuates hypoxia‑induced resistance to cisplatin in the HepG2 cell line

et al. 2018

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“…However, in several previous studies, it has been shown that the inactivation of AMPK by siRNA or the pharmacological inhibitor did not totally abolish the anti-cancer effects of metformin in prostate and hepatic cancer cells [8,9], suggesting that the inhibitory effect of metformin in cancers can be independent of AMPK activation. Moreover, the alteration of the microRNA (miRNA) profiles in vivo and in vitro has been shown to be associated with the anti-tumor effect of metformin [10,11]. …”

Section: Introductionmentioning

confidence: 99%

Metformin Induces Growth Inhibition and Cell Cycle Arrest by Upregulating MicroRNA34a in Renal Cancer Cells

et al. 2017

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BackgroundMetformin is a widely used biguanide drug for the treatment of type 2 diabetes. It has been revaluated as a potential anti-cancer drug with promising activity in various tumors. However, the precise mechanisms underlying the suppression of cancer cells by metformin remain not well understood.Material/MethodsIn this study, human renal cell carcinoma cell line ACHN was used to investigate the anti-proliferation effect of metformin. A cell counting kit-8 assay was used to detect the cell viability. The cell cycle distribution and apoptosis were analyzed by flow cytometry. The expression of cyclin D1 and p27KIP1 was detected by Western blot. The underlying mechanism involving miRNA34a was further investigated by quantitative RT-PCR and transfection with miRNA inhibitor specific for miRNA34a in ACHN, 769-P, and A498 cells.ResultsMetformin could significantly inhibit the proliferation of ACHN cells in a dose- and time-dependent manner. In addition, the results showed that metformin induced G0/G1 phase arrest and delayed entry into S phase in ACHN cells. It was shown that metformin downregulates the expression of cyclin D1 and increases the p27KIP1 level. Furthermore, metformin increased ACHN cell death. Lastly, miRNA34a was found to be upregulated by metformin in ACHN, 769-P, and A498 cells. Subsequently, it was demonstrated that inhibition of miRNA34a could partially attenuate the suppressive effect of metformin on renal cancer cell proliferation.ConclusionsThe study data revealed that metformin induced cell growth inhibition and cell cycle arrest partially by upregulating miRNA34a in renal cancer cells.

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“…Although AMPK-independent effects have been reported3132, Metformin acts through its effect on AMPK-dependent signaling have also been shown in several studies282930. Because of this, we next examined the relevant molecular mechanism by solamargine in the presence or absence of metformin.…”

Section: Resultsmentioning

confidence: 97%

“…Metformin, the most widely used drug in treatment of type 2 diabetes, has been shown to inhibit growth of different cancer types in several studies through AMPK-dependent and -independent signaling pathways2829303132. Herein, we also asked whether combination of known AMPK activator metformin and solamargine could have enhanced effect.…”

Section: Resultsmentioning

confidence: 99%

Activation of AMPKα mediates additive effects of solamargine and metformin on suppressing MUC1 expression in castration-resistant prostate cancer cells

Xiang

Zhang

Tang

et al. 2016

Sci Rep

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Prostate cancer is the second most common cause of cancer-related deaths worldwide. The mucin 1 (MUC1) oncoprotein is highly expressed in human prostate cancers with aggressive features. However, the role for MUC1 in occurrence and progression of castration-resistant prostate cancer (CRPC) remained elusive. In this study, we showed that solamargine, a major steroidal alkaloid glycoside, inhibited the growth of CRPC cells, which was enhanced in the presence of metformin. Furthermore, we found that solamargine increased phosphorylation of AMPKα, whereas reducing the protein expression and promoter activity of MUC1. A greater effect was observed in the presence of metformin. In addition, solamargine reduced NF-κB subunit p65 protein expression. Exogenously expressed p65 resisted solamargine-reduced MUC1 protein and promoter activity. Interestingly, exogenously expressed MUC1 attenuated solamargine-stimulated phosphorylation of AMPKα and, more importantly reversed solamargine-inhibited cell growth. Finally, solamargine increased phosphorylation of AMPKα, while inhibiting MUC1, p65 and tumor growth were observed in vivo. Overall, our results show that solamargine inhibits the growth of CRPC cells through AMPKα-mediated inhibition of p65, followed by reduction of MUC1 expression in vitro and in vivo. More importantly, metformin facilitates the antitumor effect of solamargine on CRPC cells.

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The anti-diabetic drug metformin inhibits pancreatic cancer cell proliferation in vitro and in vivo: Study of the microRNAs associated with the antitumor effect of metformin

Cited by 37 publications

References 42 publications

Metformin attenuates hypoxia‑induced resistance to cisplatin in the HepG2 cell line

Metformin attenuates hypoxia‑induced resistance to cisplatin in the HepG2 cell line

Metformin Induces Growth Inhibition and Cell Cycle Arrest by Upregulating MicroRNA34a in Renal Cancer Cells

Activation of AMPKα mediates additive effects of solamargine and metformin on suppressing MUC1 expression in castration-resistant prostate cancer cells

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