Enhancement of MDM2 inhibitory effects through blocking nuclear export mechanisms in ovarian cancer cells.

Over 90% of ovarian cancer cells exhibit p53 mutations or inactivation. In addition, p53 is exported outside of the nucleus by exportin-1 (XPO1), a protein that mediates the nuclear export of several cancer suppressor proteins. Overexpression of XPO1 is associated with resistance to chemotherapy, leading to poor prognosis in various cancers. The MDM2 inhibitor, RG-7388, is a known reactivator of p53 and has been tested with high interest as a therapeutic agent for cancer treatment. In addition, Selinexor, which is a second-generation selective inhibitor of nuclear export (SINE), is known to cause an accumulation of p53 in the nucleus and is also being explored as a therapy potentiating agent in combination treatments. This study was conducted to assess the efficacy of RG-7388 in combination with Selinexor for treating ovarian cancer. A combination of Selinexor and RG-7388 treatments was able to reduce the cell viability compared to individual treatments. In addition, the combination treatment revealed significant up-regulation of several cancer suppressor proteins in the whole lysate, cytoplasm, and nucleus. Finally, our results confirm that the combination of Selinexor with RG-7388 can induce a caspase-mediated apoptotic mechanism via up-regulation of p53 and p21.