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Tumor Biology
Published in: Tumor Biology 4/2015

01-04-2015 | Research Article

Metformin sensitizes hepatocellular carcinoma to arsenic trioxide-induced apoptosis by downregulating Bcl2 expression

Authors: Xuejun Yang, Deguang Sun, Yu Tian, Sunbin Ling, Liming Wang

Published in: Tumor Biology | Issue 4/2015

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Abstract

Hepatocellular carcinoma (HCC) is a highly malignant tumor that can evolve rapidly to acquire resistance to conventional chemotherapies. Arsenic trioxide (ATO) is a traditional Asian medicine, and a phase II study has shown that treatment with ATO alone was not effective against HCC. Bcl2 is an antiapoptotic protein that regulates chemotherapy in HCC. Metformin is reported to decrease Bcl2 expression, and the purpose of this study was to verify whether metformin could potentiate the anti-HCC efficacy of ATO in vitro. In the present study, we used metformin and ATO alone or in combination and then tested proliferation, apoptosis, and Bcl2 level of HCC cells. The results showed that metformin enhanced both the proliferation-inhibiting and apoptosis-inducing effects of ATO on HCC cell lines HepG2 and BEL7402. Furthermore, this activity proceeded via a mechanism involving metformin-induced downregulation of Bcl2. A combination of ATO and metformin is therefore a potentially promising approach for HCC therapy.
Literature
1.
Zheng Y, Wang X, Wang H, Yan W, Zhang Q, Chang X. Bone morphogenetic protein 2 inhibits hepatocellular carcinoma growth and migration through downregulation of the PI3K/AKT pathway. Tumour Biol. 2014;35(6):5189–98.CrossRefPubMed
2.
Yao M, Wang L, Dong Z, Qian Q, Shi Y, Yu D, et al. Glypican-3 as an emerging molecular target for hepatocellular carcinoma gene therapy. Tumour Biol. 2014;35(6):5857–68.CrossRefPubMed
3.
Yao N, Yao D, Wang L, Dong Z, Wu W, Qiu L, et al. Inhibition of autocrine IGF-II on effect of human HepG2 cell proliferation and angiogenesis factor expression. Tumour Biol. 2012;33(5):1767–76.CrossRefPubMed
4.
Zheng L, Gong W, Liang P, Huang X, You N, Han KQ, et al. Effects of AFP-activated PI3K/Akt signaling pathway on cell proliferation of liver cancer. Tumour Biol. 2014;35(5):4095–9.CrossRefPubMed
5.
Liu ZM, Tseng JT, Hong DY, Huang HS. Suppression of TG-interacting factor sensitizes arsenic trioxide-induced apoptosis in human hepatocellular carcinoma cells. Biochem J. 2011;438(2):349–58.CrossRefPubMed
6.
Antman KH. Introduction: the history of arsenic trioxide in cancer therapy. Oncologist. 2001;6 Suppl 2:1–2.CrossRefPubMed
7.
Park MT, Kang YH, Park IC, Kim CH, Lee YS, Chung HY, et al. Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide-resistant cancer cells. Mol Cancer Ther. 2007;6(1):82–92.CrossRefPubMed
8.
Beauchamp EM, Ringer L, Bulut G, Sajwan KP, Hall MD, Lee YC, et al. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. J Clin Invest. 2011;121(1):148–60.CrossRefPubMed
9.
Ma Y, Wang J, Liu L, Zhu H, Chen X, Pan S, et al. Genistein potentiates the effect of arsenic trioxide against human hepatocellular carcinoma: role of Akt and nuclear factor-kappaB. Cancer Lett. 2011;301(1):75–84.CrossRefPubMed
10.
Lin CC, Hsu C, Hsu CH, Hsu WL, Cheng AL, Yang CH. Arsenic trioxide in patients with hepatocellular carcinoma: a phase II trial. Invest New Drugs. 2007;25(1):77–84.CrossRefPubMed
11.
Takahashi A, Kimura F, Yamanaka A, Takebayashi A, Kita N, Takahashi K, et al. Metformin impairs growth of endometrial cancer cells via cell cycle arrest and concomitant autophagy and apoptosis. Cancer Cell Int. 2014;14:53.CrossRefPubMedPubMedCentral
12.
Feng Y, Ke C, Tang Q, Dong H, Zheng X, Lin W, et al. Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling. Cell Death Dis. 2014;5:e1088.CrossRefPubMedPubMedCentral
13.
Xiao Y, Zhang S, Hou G, Zhang X, Hao X, Zhang J. Clinical pathological characteristics and prognostic analysis of diabetic women with luminal subtype breast cancer. Tumour Biol. 2014;35(3):2035–45.CrossRefPubMed
14.
Rocha GZ, Dias MM, Ropelle ER, Osorio-Costa F, Rossato FA, Vercesi AE, et al. Metformin amplifies chemotherapy-induced AMPK activation and antitumoral growth. Clin Cancer Res. 2011;17(12):3993–4005.CrossRefPubMed
15.
Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, et al. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene. 2008;27(25):3576–86.CrossRefPubMed
16.
Isakovic A, Harhaji L, Stevanovic D, Markovic Z, Sumarac-Dumanovic M, Starcevic V, et al. Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis. Cell Mol Life Sci. 2007;64(10):1290–302.CrossRefPubMed
17.
Zakikhani M, Dowling RJ, Sonenberg N, Pollak MN. The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase. Cancer Prev Res (Phila). 2008;1(5):369–75.CrossRef
18.
Saito T, Chiba T, Yuki K, Zen Y, Oshima M, Koide S, et al. Metformin, a diabetes drug, eliminates tumor-initiating hepatocellular carcinoma cells. PLoS One. 2013;8(7):e70010.CrossRefPubMedPubMedCentral
19.
Do MT, Kim HG, Khanal T, Choi JH, Kim DH, Jeong TC, et al. Metformin inhibits heme oxygenase-1 expression in cancer cells through inactivation of Raf-ERK-Nrf2 signaling and AMPK-independent pathways. Toxicol Appl Pharmacol. 2013;271(2):229–38.CrossRefPubMed
20.
Bodmer M, Meier C, Krahenbuhl S, Jick SS, Meier CR. Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care. 2010;33(6):1304–8.CrossRefPubMedPubMedCentral
21.
Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 2009;27(20):3297–302.CrossRefPubMedPubMedCentral
22.
Zeng HZ, Qu YQ, Zhang WJ, Xiu B, Deng AM, Liang AB. Proteomic analysis identified DJ-1 as a cisplatin resistant marker in non-small cell lung cancer. Int J Mol Sci. 2011;12:3489–99.CrossRefPubMedPubMedCentral
23.
Han C, Gu H, Wang J, Lu W, Mei Y, Wu M. Regulation of L-threonine dehydrogenase in somatic cell reprogramming. Stem Cells. 2013;31(5):953–65.CrossRefPubMed
24.
Yang CL, Jiang FQ, Xu F, Jiang GX. ADAM10 overexpression confers resistance to doxorubicin-induced apoptosis in hepatocellular carcinoma. Tumour Biol. 2012;33(5):1535–41.CrossRefPubMed
25.
Davison K, Mann KK, Miller Jr WH. Arsenic trioxide: mechanisms of action. Semin Hematol. 2002;39(2 Suppl 1):3–7.CrossRefPubMed
26.
Chen GQ, Zhu J, Shi XG, Ni JH, Zhong HJ, Si GY, et al. In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia: As2O3 induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RAR alpha/PML proteins. Blood. 1996;88(3):1052–61.PubMed
27.
Oketani M, Kohara K, Tuvdendorj D, Ishitsuka K, Komorizono Y, Ishibashi K, et al. Inhibition by arsenic trioxide of human hepatoma cell growth. Cancer Lett. 2002;183(2):147–53.CrossRefPubMed
28.
Siu KP, Chan JY, Fung KP. Effect of arsenic trioxide on human hepatocellular carcinoma HepG2 cells: inhibition of proliferation and induction of apoptosis. Life Sci. 2002;71(3):275–85.CrossRefPubMed
29.
Chaudhary SC, Kurundkar D, Elmets CA, Kopelovich L, Athar M. Metformin, an antidiabetic agent reduces growth of cutaneous squamous cell carcinoma by targeting mTOR signaling pathway. Photochem Photobiol. 2012;88(5):1149–56.CrossRefPubMedPubMedCentral
30.
Carmignani M, Volpe AR, Aldea M, Soritau O, Irimie A, Florian IS, et al. Glioblastoma stem cells: a new target for metformin and arsenic trioxide. J Biol Regul Homeost Agents. 2014;28(1):1–15.PubMed
Metadata
Title
Metformin sensitizes hepatocellular carcinoma to arsenic trioxide-induced apoptosis by downregulating Bcl2 expression
Authors
Xuejun Yang
Deguang Sun
Yu Tian
Sunbin Ling
Liming Wang
Publication date
01-04-2015
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 4/2015
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-014-2926-5

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