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Oncol Rep. 2018 Apr;39(4):1957-1965. doi: 10.3892/or.2018.6275. Epub 2018 Feb 20.

Metformin facilitates BG45‑induced apoptosis via an anti‑Warburg effect in cholangiocarcinoma cells.

Author information

1
Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing, Jiangsu 210008, P.R. China.
2
Department of Gastroenterology, Nanjing Medical University Affiliated Drum Tower Clinical Medical College, Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China.
3
Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
4
Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai 200040, P.R. China.
5
School of Life Sciences, Fudan University, Shanghai 200032, P.R. China.

Abstract

Cholangiocarcinoma (CCA) is a highly lethal malignancy with an often late diagnosis and consequent poor prognosis. Chemotherapy is the only therapeutic strategy for most patients. Compared to normal cells, tumor cells preferentially metabolize glucose to lactate, even in aerobic conditions. Such metabolic alterations not only support the growth and invasion of tumor cells, but also promote their chemoresistance. The purpose of our study was to explore the role of metformin in regulating the metabolism of CCA, as well as to investigate whether metformin could act as a chemosensitizer of the HDAC3 inhibitor BG45, and therefore have potential for the treatment of CCA. Through bioinformatic analysis, we found that aberrant metabolism contributed to the proliferation of CCA cells. Seahorse XF96 Extracellular Flux Analyzer analysis and lactate production analysis showed that metformin could act as a suppressor of the Warburg effect in CCA cells. Western blotting showed that metformin decreased the expression of LDHA, which plays a key role in the Warburg effect. However, suppression of the Warburg effect was not sufficient to induce CCA cellular apoptosis. According to our previous research, which showed that an HDAC3 inhibitor (MI192) was involved in CCA apoptosis, we observed that metformin combined with BG45 (a novel specific HDAC3 inhibitor) effectively induced the apoptosis of CCA cells in vitro. Furthermore, in vivo experiments revealed that the combined treatment with metformin and BG45 markedly reduced CCA growth in a CCA xenograft model. Our data revealed that reversing the Warburg effect with metformin sensitizes cells to the antitumor effects of HDAC3 inhibitors. This provides a rationale for using the combination of metformin and BG45 as a new therapeutic strategy in the treatment of CCA.

PMID:
29484415
DOI:
10.3892/or.2018.6275
[Indexed for MEDLINE]

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