Alterations in the mitochondrial responses to PENAO as a mechanism of resistance in ovarian cancer cells

作者：Decollogne Stephanie; Joshi Swapna; Chung Sylvia A; Luk Peter P; Yeo Reichelle X; Nixdorf Sheri; Fedier Andre; Heinzelmann Schwarz Viola; Hogg Philip J; Dilda Pierre J^*

来源：Gynecologic Oncology, 2015, 138(2): 363-371.

DOI：10.1016/j.ygyno.2015.06.018

• Ovarian cancer
• Mitochondria
• Arsenic-based cancer drugs
• PENAO
• Oxidative stress
• Drug resistance
• Metabolism
• mTOR signalling pathway

Objective. The purpose of this study was to test PENAO, a promising new organoarsenical that is in phase 1 testing in patients with solid tumours, on a range of ovarian cancer cell lines with different histotypes, and to understand the molecular basis of drug resistance exhibited by the endometrioid ovarian cancer cell line, SKOV-3.
Methods. Proliferation arrest and cell death induced by PENAO in serous (OVCAR-3), endometrioid (SKOV-3, TOV112D), clear cell (TOV21G) and mucinous (EFO27) ovarian cancer cells in culture, and anti-tumour efficacy in a murine model of SKOV-3 and OVCAR-3 tumours, were measured. Cells were analysed for cell cycle arrest, cell death mechanisms, reactive oxygen species production, mitochondrial depolarisation, oxygen consumption and acid production.
Results. PENAO demonstrated promising anti-proliferative activity on the most common (serous, endometrioid) as well as on rare (clear cell, mucinous) subtypes of ovarian cancer cell lines. No cross-resistance with platinum-based drugs was evident. Endometrioid SKOV-3 cells were, however, shown to be resistant to PENAO in vitro and in a xenograft mouse model. This resistance was due to an ability to cope with PENAO-induced oxidative stress, notably through heme oxygenase-1 induction, and a shift in metabolism towards glycolysis. The adaptive glycolytic shift in SKOV-3 was targeted using a mTORC1 inhibitor in combination with PENAO. This strategy was successful with the two drugs acting synergistically to inhibit cell proliferation and to induce cell death via apoptosis and autophagy.
Conclusion. Mitochondria/mTOR dual-targeting therapy may constitute a new approach for the treatment of recurrent/resistant forms of epithelial ovarian cancer.

• 出版日期2015-8