Combining metformin and nelfinavir exhibits synergistic effects against the growth of human cervical cancer cells and xenograft in nude mice

Chenglai Xia,Lanying Du,Yanbin Pan,Shibo Jiang,Qianqian Qi,Jinman Chen,Guohong Xiao,Ruihong Chen

doi:10.1038/srep43373

Abstract

Human cervical cancer is the fourth most common carcinoma in women worldwide. However, the emergence of drug resistance calls for continuously developing new anticancer drugs and combination chemotherapy regimens. The present study aimed to investigate the anti-cervical cancer effects of metformin, a first-line therapeutic drug for type 2 diabetes mellitus, and nelfinavir, an HIV protease inhibitor, when used alone or in combination. We found that both metformin and nelfinavir, when used alone, were moderately effective in inhibiting proliferation, inducing apoptosis and suppressing migration and invasion of human cervical cell lines HeLa, SiHa and CaSki. When used in combination, these two drugs acted synergistically to inhibit the growth of human cervical cancer cells in vitro and cervical cancer cell xenograft in vivo in nude mice, and suppress cervical cancer cell migration and invasion. The protein expression of phosphoinositide 3-kinase catalytic subunit PI3K(p110α), which can promote tumor growth, was remarkably downregulated, while the tumor suppressor proteins p53 and p21 were substantially upregulated following the combinational treatment in vitro and in vivo. These results suggest that clinical use of metformin and nelfinavir in combination is expected to have synergistic antitumor efficacy and significant potential for the treatment of human cervical cancer.

Highlights

Metformin, a first-line therapeutic drug for type 2 diabetes mellitus, has recently been identified as a potential and attractive anticancer drug[12]
Our previous studies have shown that nelfinavir, a HIV protease inhibitor, inhibits the growth of cervical cancer cell lines (SiHa, HeLa, and CaSki) by promoting apoptosis and arresting the cell cycle at G1 phase[11]
Since metformin and nelfinavir inhibit the growth of cervical cancer cells by different mechanisms of action, we hypothesized that combining metformin and nelfinavir could have synergistic effects against human cervical cancer cell growth

Summary

Introduction

A first-line therapeutic drug for type 2 diabetes mellitus, has recently been identified as a potential and attractive anticancer drug[12]. Metformin in combination with doxorubicin, a chemotherapeutic agent, could kill both cancer stem cells and cancer cells[13]. It acts as an anti-cancer agent for inhibiting growth of endometrial, ovarian, and cervical cancer cells through mechanism by directly activating AMP-dependent protein kinase (AMPK) and subsequent suppressing mammalian targets of rapamycin (mTOR), inhibiting global protein synthesis and proliferation in target cells[14,15]. Metformin is effective in inhibiting the growth of cervical cancer cell lines C33A and Me180 through the LKB1-AMPK-mTOR signaling pathway, it is less effective against CaSki and HeLa cells. We used an HPV-18-infected human cervical cell line (HeLa) and two HPV-16-infected human cervical cell lines (SiHa and CaSki) to investigate the potential synergistic anticancer effect of metformin and nelfinavir, as a combinational therapy, in addition to the mechanisms underlying such synergy

Methods

Results

Conclusion