Metformin and Dichloroacetate Suppress Proliferation of Liver Cancer Cells by Inhibiting mTOR Complex 1.

Tae Suk Kim,Minji Park,Sae Yun Kim,Yuri Cho,Minjong Lee,Min Suk Shim,Chea Yeon Lee,Dae Hee Choi

doi:10.3390/ijms221810027

Abstract

The Warburg effect is important for cancer cell proliferation. This phenomenon can be flexible by interaction between glycolysis and mitochondrial oxidation for energy production. We aimed to investigate the anticancer effects of the pyruvate dehydrogenase kinase inhibitor, dichloroacetate (DCA) and the mitochondrial respiratory complex I inhibitor metformin in liver cancer cells. The anticancer effect of DCA and/or metformin on HepG2, PLC/PRF5 human liver cancer cell lines, MH-134 murine hepatoma cell lines, and primary normal hepatocytes using MTT assay. Inhibition of lactate/ATP production and intracellular reactive oxygen species generation by DCA and metformin was investigated. Inhibition of PI3K/Akt/mTOR complex I was evaluated to see whether it occurred through AMPK signaling. Anticancer effects of a combination treatment of DCA and metformin were evaluated in HCC murine model. The results showed that metformin and DCA effectively induced apoptosis in liver cancer cells. A combination treatment of metformin and DCA did not affect viability of primary normal hepatocytes. Metformin upregulated glycolysis in liver cancer cells, thereby increasing sensitivity to the DCA treatment. Metformin and DCA inhibited mTOR complex I signaling through upregulated AMPK-independent REDD1. In addition, metformin and DCA increased reactive oxygen species levels in liver cancer cells, which induced apoptosis. A combination treatment of metformin and DCA significantly suppressed the tumor growth of liver cancer cells using in vivo xenograft model. Taken together, the combined treatment of metformin and DCA suppressed the growth of liver cancer cells. This strategy may be effective for patients with advanced liver cancer.

Highlights

In early stage of hepatocellular carcinoma (HCC), various treatment options can be considered such as radiofrequency ablation, resection, radiotherapy, and transplantation [1,2].in advanced stage of HCC, target therapy is only recommended: current antiangiogenic drugs, such as sorafenib, regorafenib, lenvatinib, and cabozantinib, significantly prolong survival of patients with advanced HCC [3].Recently, it was emphasized that magnetic resonance imaging (MRI) can be helpful to detect HCC within early stages [4,5,6,7,8,9]
It is well-known that most tumors are characterized by the “Warburg effect”, whereby glycolysis is used for energy production even though oxygen levels are sufficient
Energy metabolism of cancer cells is mainly dependent on the Warburg effect, some conditions can modulate the Warburg effect, such as inhibited mitochondrial oxidation or reactive oxygen species (ROS)

Summary

Introduction

In early stage of hepatocellular carcinoma (HCC), various treatment options can be considered such as radiofrequency ablation, resection, radiotherapy, and transplantation [1,2].in advanced stage of HCC, target therapy is only recommended: current antiangiogenic drugs, such as sorafenib, regorafenib, lenvatinib, and cabozantinib, significantly prolong survival of patients with advanced HCC [3].Recently, it was emphasized that magnetic resonance imaging (MRI) can be helpful to detect HCC within early stages [4,5,6,7,8,9]. In early stage of hepatocellular carcinoma (HCC), various treatment options can be considered such as radiofrequency ablation, resection, radiotherapy, and transplantation [1,2]. In advanced stage of HCC, target therapy is only recommended: current antiangiogenic drugs, such as sorafenib, regorafenib, lenvatinib, and cabozantinib, significantly prolong survival of patients with advanced HCC [3]. It was emphasized that magnetic resonance imaging (MRI) can be helpful to detect HCC within early stages [4,5,6,7,8,9]. In HCC patients with advanced stage, the long-term survival benefit from currently used anticancer treatments is a modest improvement of three months, which is far from satisfactory [6,7,16,17]. There are critical limitations to treat HCC patients: (1) a lack of available drugs after failure of tyrosine kinase inhibitors [18,19]; (2) increasing need of target therapy agents in patients with intermediate stage who showed refractoriness for transarterial chemoembolization or inadequate safety margin of embolized area after TACE [12,17,20,21,22,23,24]; (3) substantial risk of HCC recurrence even after five years in patients who underwent curative resection [25,26,27];

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