Metformin inhibits proliferation and enhances chemosensitivity of intrahepatic cholangiocarcinoma cell lines

Abstract

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 As 2 O 3 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. IntroductionMetformin, a first-line oral anti-type II diabetes agent used worldwide, displays an antitumorigenesis effect, according to recent epidemic studies (1-3). As compared to insulin or sulfonylureas administration, metformin use may markedly reduce the cancer risk in patients with type II diabetes. Recent studies have confirmed the anti-proliferation effect on various human cancer cell types, such as pancreas (4), prostate (5), breast (6), stomach (7) and liver (8). Metformin inhibits the pro-proliferation effect of insulin receptor-and IGF receptor-dependent signaling by reducing insulin resistance. Furthermore, metformin activates AMP-activated protein kinase (AMPK) and subsequently inhibits activation of mammalian target of rapamycin (mTOR) to prevent proliferation of tumor cells, and activates p53 protein-inducing cell cycle arrest of tumor cells. Several studies have indicated that metformin can potentiate the effect of chemotherapeutic agents or reverse drug resistance in cancer cells (8-10). However, the mechanism of the anti-cancer effects of metformin remains unclear.A recent epidemiological study that included 1,828 potential intrahepatic cholangiocarcinoma (ICC) patients described that metformin use was significantly associated with a 60% reduction in ICC risk in diabetic patients (11). Cholangiocarcinoma (CC)categorized as intrahepatic and extrahepatic cholangiocarcinoma (ECC) is highly lethal. ICC is the second most common type of primary liver cancer and its incidence and mortality rates have been rising in recent decades (12-15). Less than 30% of patients with ICC have the opportunity to have radical operation at diagnostic presentation. Apart from radical operation, some treatment approaches such as systemic chemotherapy, transarterial chemoembolization and radiofrequency ablation may be applied at advanced stages of ICC; however, none of the approaches can significantly improve the prognosis of ICC. Thus, new treatment strategies are needed ...

Metformin Exerts Antiproliferative and Anti-metastatic Effects Against Cholangiocarcinoma Cells by Targeting STAT3 and NF-ĸB

“…In addition, the western blot analyses indicated an increase of p21 and suppression of cyclin D1 in metformin-treated cells. These observations were in agreement with those previously reported in many cancer cell types (13,20), including non-liver flukeassociated CCA cells (12,19). In addition to cell-cycle regulatory proteins, the alteration of microRNA expression in metformin treated CCA cells was also noted (12,21).…”

“…KKU-100, a chemoresistant cell line (17) and KKU-055, a radioresistant clone (18), responded to metformin in the same manner. These effective doses were in agreement with reports on non-liver fluke-associated CCA (12,19). Metformin also affected proliferation of CCA cells irrespectively of the glucose condition.…”

“…Apart from AMPK, metformin exerts anticancer effects via multiple pathways, e.g. inhibition of the mTOR pathway in CCA (19), a decrease of forkhead box protein M1 (FOXM1) in leukemia (23), suppression of STAT3 activation in lung adenocarcinoma (24)and in triple-negative breast cancer (25), and inactivation of STAT3 and NF-ĸB in several cancer cell lines (26,27).…”

WITHDRAWN: Metformin antagonizes MPS-1-mediated IL-6/Stat3 signaling in ovarian cancer cells: possible mechanisms of stemness and angiogenesis inhibition

“…The protective effects of metformin against ovarian cancer are thought to be due to inhibition of tumor cell proliferation, angiogenesis and metastatic spread of ovarian cancer [13]. Similar findings were also observed in intrahepatic cholangiocarcinoma (ICC) cells and demonstrated that metformin has showed to inhibit proliferation and facilitate apoptosis [14]. In our present study, metformin treatment showed potential …”

Metformin synergizes with rapamycin to inhibit the growth of pancreatic cancer in�vitro and in�vivo

“…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).…”