Metformin inhibits proliferation and enhances chemosensitivity of intrahepatic cholangiocarcinoma cell lines

Ling,Sunbin; Feng,Tingting; Ke,Qinghong; Fan,Ning; Li,Lei; Li,Zhongxing; Dong,Chengyong; Wang,Cong; Xu,Fei; Li,Yan; Wang,Liming

doi:10.3892/or.2014.3151

Metformin inhibits proliferation and enhances chemosensitivity of intrahepatic cholangiocarcinoma cell lines

Authors:
- Sunbin Ling
- Tingting Feng
- Qinghong Ke
- Ning Fan
- Lei Li
- Zhongxing Li
- Chengyong Dong
- Cong Wang
- Fei Xu
- Yan Li
- Liming Wang
View Affiliations

Affiliations: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, P.R. China, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, P.R. China, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, P.R. China, College of Basic Medical Sciences, Dalian Medical University, Dalian, P.R. China
Published online on: April 23, 2014 https://doi.org/10.3892/or.2014.3151
Pages: 2611-2618

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Metformin is an oral anti-hyperglycemic agent of the biguanide family, which is used first-line for type II diabetes with few side-effects. A recent epidemiological study that included 1,828 potential intrahepatic cholangiocarcinoma (ICC) patients showed that metformin use was significantly associated with a 60% reduction in ICC risk in diabetic patients, demonstrating the potential value of metformin in ICC management. In the present study, we firstly showed that metformin exhibited a dose- and time-dependent anti-proliferation effect on ICC cell lines, by mechanisms including apoptosis induction and cell cycle arrest. Metformin targeted the AMPK/mTORC1 pathway in ICC cells. Furthermore, metformin sensitized ICC cells to certain chemotherapeutic agents, such as sorafenib, 5-fluorouracil and As2O3 by targeting the AMPK/mTOR/HIF-1α/MRP1 pathway and ERK. As it is an inexpensive and widely used antidiabetic drug without severe adverse effects, metformin may be a prospective chemotherapeutic agent or a chemosensitizer in future ICC treatment.

View Figures

View References

1	Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR and Morris AD: Metformin and reduced risk of cancer in diabetic patients. BMJ. 330:1304–1305. 2005. View Article : Google Scholar : PubMed/NCBI
2	Lee MS, Hsu CC, Wahlqvist ML, Tsai HN, Chang YH and Huang YC: Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer. 11:202011. View Article : Google Scholar
3	Dowling RJ, Niraula S, Stambolic V and Goodwin PJ: Metformin in cancer: translational challenges. J Mol Endocrinol. 48:R31–R43. 2012. View Article : Google Scholar : PubMed/NCBI
4	Nair V, Pathi S, Jutooru I, et al: Metformin inhibits pancreatic cancer cell and tumor growth and downregulates Sp transcription factors. Carcinogenesis. 34:2870–2879. 2013. View Article : Google Scholar : PubMed/NCBI
5	Akinyeke T, Matsumura S, Wang X, et al: Metformin targets c-MYC oncogene to prevent prostate cancer. Carcinogenesis. 34:2823–2832. 2013. View Article : Google Scholar : PubMed/NCBI
6	Alimova IN, Liu B, Fan Z, et al: Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle. 8:909–915. 2009. View Article : Google Scholar : PubMed/NCBI
7	Kato K, Gong J, Iwama H, et al: The antidiabetic drug metformin inhibits gastric cancer cell proliferation in vitro and in vivo. Mol Cancer Ther. 11:549–560. 2012. View Article : Google Scholar : PubMed/NCBI
8	Petrushev B, Tomuleasa C, Soritau O, et al: Metformin plus PIAF combination chemotherapy for hepatocellular carcinoma. Exp Oncol. 34:17–24. 2012.PubMed/NCBI
9	Ashinuma H, Takiguchi Y, Kitazono S, et al: Antiproliferative action of metformin in human lung cancer cell lines. Oncol Rep. 28:8–14. 2012.
10	Chen G, Xu S, Renko K and Derwahl M: Metformin inhibits growth of thyroid carcinoma cells, suppresses self-renewal of derived cancer stem cells, and potentiates the effect of chemotherapeutic agents. J Clin Endocrinol Metab. 97:E510–E520. 2012. View Article : Google Scholar : PubMed/NCBI
11	Chaiteerakij R, Yang JD, Harmsen WS, et al: Risk factors for intrahepatic cholangiocarcinoma: association between metformin use and reduced cancer risk. Hepatology. 57:648–655. 2013. View Article : Google Scholar : PubMed/NCBI
12	Patel T: Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology. 33:1353–1357. 2001. View Article : Google Scholar : PubMed/NCBI
13	Tyson GL and El-Serag HB: Risk factors for cholangiocarcinoma. Hepatology. 54:173–184. 2011. View Article : Google Scholar
14	Khan SA, Thomas HC, Davidson BR and Taylor-Robinson SD: Cholangiocarcinoma. Lancet. 366:1303–1314. 2005. View Article : Google Scholar : PubMed/NCBI
15	Shaib YH, Davila JA, McGlynn K and El-Serag HB: Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatol. 40:472–477. 2004. View Article : Google Scholar : PubMed/NCBI
16	Chaudhary SC, Kurundkar D, Elmets CA, Kopelovich L and Athar M: Metformin, an antidiabetic agent reduces growth of cutaneous squamous cell carcinoma by targeting mTOR signaling pathway. Photochem Photobiol. 88:1149–1156. 2012. View Article : Google Scholar : PubMed/NCBI
17	Luo Q, Hu D, Hu S, Yan M, Sun Z and Chen F: In vitro and in vivo anti-tumor effect of metformin as a novel therapeutic agent in human oral squamous cell carcinoma. BMC Cancer. 12:5172012. View Article : Google Scholar : PubMed/NCBI
18	Lin B, Kolluri SK, Lin F, et al: Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell. 116:527–540. 2004. View Article : Google Scholar : PubMed/NCBI
19	Lee D, Do IG, Choi K, et al: The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas. Mod Pathol. 25:131–139. 2012. View Article : Google Scholar : PubMed/NCBI
20	Chung JY, Hong SM, Choi BY, Cho H, Yu E and Hewitt SM: The expression of phospho-AKT, phospho-mTOR, and PTEN in extrahepatic cholangiocarcinoma. Clin Cancer Res. 15:660–667. 2009. View Article : Google Scholar : PubMed/NCBI
21	Liu B, Fan Z, Edgerton SM, et al: Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle. 8:2031–2040. 2009. View Article : Google Scholar : PubMed/NCBI
22	McCubrey JA, Steelman LS, Chappell WH, et al: Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 1773:1263–1284. 2007. View Article : Google Scholar : PubMed/NCBI
23	McCubrey JA, Steelman LS, Chappell WH, et al: Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance. Oncotarget. 3:1068–1111. 2012.PubMed/NCBI
24	McCubrey JA, Steelman LS, Chappell WH, et al: Mutations and deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades which alter therapy response. Oncotarget. 3:954–987. 2012.PubMed/NCBI
25	Takiyama Y, Harumi T, Watanabe J, et al: Tubular injury in a rat model of type 2 diabetes is prevented by metformin: a possible role of HIF-1alpha expression and oxygen metabolism. Diabetes. 60:981–992. 2011. View Article : Google Scholar : PubMed/NCBI
26	Ece H, Cigdem E, Yuksel K, Ahmet D, Hakan E and Oktay TM: Use of oral antidiabetic drugs (metformin and pioglitazone) in diabetic patients with breast cancer: how does it affect serum Hif-1 alpha and 8Ohdg levels? Asian Pac J Cancer Prev. 13:5143–5148. 2012. View Article : Google Scholar : PubMed/NCBI
27	Zannella VE, Pra AD, Muaddi H, et al: Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response. Clin Cancer Res. 19:6741–6750. 2013. View Article : Google Scholar : PubMed/NCBI
28	Sheng B, Liu J and Li GH: Metformin preconditioning protects Daphnia pulex from lethal hypoxic insult involving AMPK, HIF and mTOR signaling. Comp Biochem Physiol B Biochem Mol Biol. 163:51–58. 2012.PubMed/NCBI
29	Li Y and Ye D: Cancer therapy by targeting hypoxia-inducible factor-1. Curr Cancer Drug Targets. 10:782–796. 2010. View Article : Google Scholar : PubMed/NCBI
30	Rho JK, Choi YJ, Lee JK, et al: Gefitinib circumvents hypoxia-induced drug resistance by the modulation of HIF-1α. Oncol Rep. 21:801–807. 2009.PubMed/NCBI
31	Huang C, Xu D, Xia Q, Wang P, Rong C and Su Y: Reversal of P-glycoprotein-mediated multidrug resistance of human hepatic cancer cells by Astragaloside II. J Pharm Pharmacol. 64:1741–1750. 2012. View Article : Google Scholar : PubMed/NCBI
32	Zhu H, Luo SF, Wang J, et al: Effect of environmental factors on chemoresistance of HepG2 cells by regulating hypoxia-inducible factor-1alpha. Chin Med J (Engl). 125:1095–1103. 2012.PubMed/NCBI
33	Ding Z, Yang L, Xie X, et al: Expression and significance of hypoxia-inducible factor-1 alpha and MDR1/P-glycoprotein in human colon carcinoma tissue and cells. J Cancer Res Clin Oncol. 136:1697–1707. 2010. View Article : Google Scholar : PubMed/NCBI
34	Li DW, Dong P, Wang F, Chen XW, Xu CZ and Zhou L: Hypoxia induced multidrug resistance of laryngeal cancer cells via hypoxia-inducible factor-1alpha. Asian Pac J Cancer Prev. 14:4853–4858. 2013. View Article : Google Scholar : PubMed/NCBI
35	Chen M, Huang SL, Zhang XQ, et al: Reversal effects of pantoprazole on multidrug resistance in human gastric adenocarcinoma cells by down-regulating the V-ATPases/mTOR/HIF-1alpha/P-gp and MRP1 signaling pathway in vitro and in vivo. J Cell Biochem. 113:2474–2487. 2012. View Article : Google Scholar : PubMed/NCBI
36	Woo HY and Heo J: Sorafenib in liver cancer. Expert Opin Pharmacother. 13:1059–1067. 2012. View Article : Google Scholar : PubMed/NCBI
37	Eguchi R, Fujimori Y, Takeda H, et al: Arsenic trioxide induces apoptosis through JNK and ERK in human mesothelioma cells. J Cell Physiol. 226:762–768. 2011. View Article : Google Scholar : PubMed/NCBI
38	Petit A, Delaune A, Falluel-Morel A, et al: Importance of ERK activation in As₂O₃-induced differentiation and promyelocytic leukemia nuclear bodies formation in neuroblastoma cells. Pharmacol Res. 77:11–21. 2013.