PP242 synergizes with suberoylanilide hydroxamic acid to inhibit growth of ovarian cancer cells.

Abstract

Overexpression of histone deacetylases and activation of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway are common aberrations in ovarian cancer. For this reason, simultaneous inhibition of such targets is a rational therapeutic strategy to treat patients with ovarian cancer. This study aimed to investigate the biological effect of the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), in combination with the dual mTOR complex 1 and mTOR complex 2 inhibitor, PP242, against ovarian cancer cells. The effects of SAHA and PP242 on the growth of SKOV3 and A2780 cells were examined using Cell Counting Kit-8. The apoptosis was analyzed through flow cytometry, and the expression of apoptosis-related proteins was investigated through Western blotting. Induction of autophagy was determined through fluorescence microscopy using a stably transfected green fluorescent protein/microtubule-associated protein light chain 3 construct to visualize autophagosome formation. The expression of autophagy-related proteins was determined through Western blot analysis. The effect of SAHA and PP242 on the growth of ovarian cancer was also examined in an orthotopic ovarian cancer model. The combination of SAHA and PP242 significantly inhibited cell proliferation and synergistically increased apoptosis and autophagy compared with each agent alone in vitro. In vivo, this combination exhibited greater inhibition on tumor growth than monotreatments did and it significantly prolonged the survival time of the mice. These results suggest that the combination of SAHA and PP242 may lead to a novel strategy in treating patients with ovarian cancer.