Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 18, Pages -Publisher
MDPI
DOI: 10.3390/ijms221810027
Keywords
liver cancer; Warburg effect; mTOR complex I; REDD1
Funding
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, South Korea [2017R1D1A1B03031499]
- National Research Foundation of Korea (NRF) - Korea government (Ministry of Science and ICT) [2020R1C1C1004112]
- Hanmi Pharmaceutical Co., Ltd.
- 2020 Kangwon National University Hospital Grant
- National Research Foundation of Korea (NRF) - Korea government (MSIT) [2021R1A2C4001401]
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health & Welfare, Republic of Korea [HI21C0240]
- National Research Foundation of Korea [2021R1A2C4001401, 2020R1C1C1004112, 2017R1D1A1B03031499] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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This study demonstrates the anticancer effects of the combination treatment of metformin and DCA on liver cancer cells, including induction of apoptosis, inhibition of mTOR complex I signaling through upregulated AMPK-independent pathway, and increased reactive oxygen species levels in cancer cells. Moreover, the combination treatment did not affect the viability of normal hepatocytes, suggesting its broad applicability.
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.
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