Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) incidence, as well as related mortality, has been steadily increasing in the USA and across the globe, partly due to the lack of effective therapeutic options for advanced HCC. Though sorafenib is considered standard-of-care for advanced HCC, it only improves median survival by a few months when compared to placebo. Sorafenib is also associated with several unpleasant side effects that often lead to early abatement of therapy. Here, we investigate whether a combination regimen including low-dose sorafenib and a non-toxic dose of anti-diabetic drug metformin can achieve effective inhibition of HCC. Indeed, combining metformin with low-dose sorafenib inhibited growth, proliferation, migration, and invasion potential of HCC cells. We observed a 5.3- and 1.9-fold increase in sub-G1 population in the combination treatment compared to sorafenib alone. We found that the combination of metformin enhanced the efficacy of sorafenib and inhibited the MAPK/ERK/Stat3 axis. Our in vivo studies corroborated the in vitro findings, and mice harboring HepG2-derived tumors showed effective tumor reduction upon treatment with low-dose sorafenib and metformin combination. This work sheds light on a therapeutic strategy aiming to augment sorafenib efficacy or dose-de-escalation that may prove beneficial in circumventing sorafenib resistance as well as minimizing related side effects.

Metformin Improves Ovarian Cancer Sensitivity to Paclitaxel and Platinum-Based Drugs: A Review of In Vitro Findings

“…Ovarian cancer is among the most lethal gynecologic malignancies due to late diagnosis and the occurrence of chemoresistance, which significantly weakens the chemotherapeutic efficiency in these patients [ 1 , 2 , 3 , 4 ]. Although metformin is widely used as a hypoglycemic agent to treat patients with type 2 diabetes mellitus and non-alcoholic fatty liver disease, this drug showed important anti-tumor activity in many types of cancer, including ovarian, breast, and endometrial cancer and uterine myomas [ 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 ]. The most accepted hypothesis regarding the mechanism of action of metformin in cancer cells is that this compound is an important inhibitor of respiratory chain complex I, which oxidizes NADH generated through the Krebs cycle [ 7 , 108 ].…”

The Emerging Role of Metformin in the Treatment of Hepatocellular Carcinoma: Is There Any Value in Repurposing Metformin for HCC Immunotherapy?

“…The combination treatment also led to the downregulation of the CRAF/ERK and PI3K/AKT/mTOR pathways [ 100 ]. Siddharth et al further demonstrated that metformin and sorafenib led to a significant inhibition of HCC cell growth and induced apoptosis compared to either drug alone, suppressing the MAPK/ERK/Stat3 signaling pathway [ 101 ]. Another implicated pathway is the mTOR signaling pathway.…”

Targeting Tumor Microenvironment by Metal Peroxide Nanoparticles in Cancer Therapy

“…A key component of cancer therapy is combination therapy, a mode of care that combines two or more therapeutic drugs. Te combination of anticancer medications improves efcacy in comparison to monotherapy because it targets important pathways in a manner that is often additive or synergistic [192]. In addition to therapeutic anticancer efects including reducing tumor growth and metastatic potential, this strategy may also diminish drug resistance [79].…”