Alterations in the mitochondrial responses to PENAO (ovarian cancer cell lines)

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

Highlights

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PENAO has promising anti-proliferative activity on cells established from four histological subtypes of ovarian cancer.

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SKOV-3 endometrioid ovarian carcinoma resistance towards PENAO results from a strong heme oxygenase induction and a shift towards glycolytic metabolism.

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PENAO and mTOR pathway inhibition synergizes to reverse SKOV-3 endometrioid ovarian carcinoma drug resistance.

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Objective

The purpose of this study was to test PENAO, a promising new organoarsenical that is in phase 1 testing in patients with solid tumors, 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-tumor efficacy in a murine model of SKOV-3 and OVCAR-3 tumors, 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.

 Organoarsenic chemistry is the chemistry of compounds containing a chemical bond between arsenic and carbon. A few organoarsenic compounds, also called "organoarsenicals," are produced industrially with uses as insecticides, herbicides, and fungicides. In general these applications are declining in step with growing concerns about their impact on the environment and human health. The parent compounds are arsine and arsenic acid. Despite their toxicity, organoarsenic biomolecules are well known.