Search

Clinicopathological correlation of ERK3 expression in 73 ICC patients. (DOCX 14 kb)

The multi‑kinase inhibitor sorafenib is the only drug for which randomized control trials have shown improved patient survival in advanced hepatocellular carcinoma (HCC). However, life expectancy is extended in these cases by only a few months. The anti‑type II diabetes agent metformin was used in this study in an effort to find a more efficient approach to HCC treatment. Sorafenib effectively reversed the activation status of mTORC2 induced by metformin and enhanced the suppression of the mTORC1 and MAPK pathway by metformin in HCC cells, which may be responsible for reduced proliferation upon combined treatment. The metformin and sorafenib combination led to increased impaired proliferation and tumor inhibition of HCC in vitro and in vivo compared to single agent, which was partially bridged by disrupting the mTORC1/mTORC2 feedback loop. Metformin and sorafenib cooperated to promote apoptosis and autophagy in HCC cells. Pharmacological inhibition of autophagy sensitized HCC cells to metformin and sorefenib‑induced apoptotic cell death. Therefore, the anti‑autophagy treatment should be considered in metformin and sorafenib-based treatments in HCC cells.

Metformin is a first-line used agent for type II diabetes with few side effects. The antineoplastic effect of metformin was widely explored recently. Metformin may also be a prospective chemosensitizer or radiosensitizer in cancer treatment. In the present study, we firstly showed that metformin could effectively enhance the anti-proliferation effect of ionizing radiation (IR) on esophageal cancer (EC) cells ECa109. More potent DNA damage was observed by detection of γH2AX foci. Metformin synergistically induce apoptosis and cell cycle arrest in ECa109 cells with IR. Furthermore, the mechanisms how metformin sensitized ECa109 cells to IR may be targeting the ATM and AMPK/mTOR/HIF-1α pathways. Metformin may be a valuable agent in comprehensive treatment of EC.

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.

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.

Inflammatory responses are known to be correlated with cancer initiation and progression, and exploration of the route from inflammation to cancer makes a great contribution in elucidating the mechanisms underlying cancer development. Pancreatic cancer (PC) is a lethal disease with a low radical-resection rate and a poor prognosis. As chronic pancreatitis is considered to be a significant etiological factor for PC development, the current review aims to describe the molecular pathways from inflammation to pancreatic carcinogenesis, in support of the strategies for the prevention, diagnosis and treatment of PC.