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

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.

Disturbance of the Warburg effect by dichloroacetate and niclosamide suppresses the growth of different sub-types of malignant pleural mesothelioma in vitro and in vivo

“…Synergism has been reported when DCA is combined with different drugs for anti-cancer research: DCA/cisplatin or gefitnib or elotinib ( Al-Azawi et al, 2021 ), DCA/metformin ( Kim et al, 2021 ; Klose et al, 2021 ; Korsakova et al, 2021 ), DCA/3-bromopyruvate ( Nikravesh et al, 2021 ), DCA/sorafenib ( Sun et al, 2021 ), DCA/PX-478 ( Parczyk et al, 2021 ) and DCA/erlotinib ( Dyrstad et al, 2021 ). Said synergistic effect has also been observed when Nic is combined with other agents: Nic/gemcitabine ( Guo et al, 2022b ), Nic/metformin ( Kang et al, 2021 ) and Nic/doxorubicin ( Lohiya and Katti, 2021 ).…”

“…DCA has been shown to decrease serum pyruvate and lactate in a phase II clinical trial ( Lam et al, 2016 ). DCA decreases lactate level ( Michelakis et al, 2008 ), glucose consumption ( Kolesnik et al, 2020 ; Guo et al, 2022a ), lactate production ( Dyrstad et al, 2021 ; Kim et al, 2021 ) and lactate excretion ( Dyrstad et al, 2021 ), intracellular ATP ( Kim et al, 2021 ) and citrate ( El Sayed et al, 2019 ) but elevates succinate ( Zhang et al, 2018 ).…”

Transarterial chemoembolization combined with metformin improves the prognosis of hepatocellular carcinoma patients with type 2 diabetes

“…The upregulation of mTOR is associated with lower tumor differentiation, worse prognosis, and early recurrence ( 22 ). Metformin can effectively inhibit HCC growth by inhibiting mTOR through the phosphatidylinositol-3-kinase (PI3K)/protein kinase B(AKT)/mTOR signal pathway ( 14 ). Metformin also has antitumor effects by reducing mitochondrial complex I in the respiratory chain to activate AMPK ( 23 ).…”

“…It is vital to prevent recurrence after TACE in improving the long-term survival of patients. Metformin has recently attracted increasing attention due to its effects on inhibiting tumor cell proliferation and promoting tumor cell apoptosis ( 14 ). Some studies reported controversial data on its antitumor effects in non-surgical treatment ( 15 , 16 ).…”

Metformin Protects against Spinal Cord Injury and Cell Pyroptosis via AMPK/NLRP3 Inflammasome Pathway

“…MET activates AMPK through STK11 (also experienced as LKB1), which has to do with multiple signaling pathways and affects cell growth, development, apoptosis, and other biological functions [ 13 , 23 , 24 ]. AMPK is the main regulator of cellular energy producing and the interaction between metabolism and tumors [ 25 , 26 ].…”