PtIV-RG7388

While a number of p53-MDM2 inhibitors have progressed into clinical trials for the treatment of cancer, their progression has been hampered by a variety of problems, including acquired drug resistance, dose-dependent toxicity, and limited clinical efficiency. To make more progress, we integrated the advantages of MDM2 inhibitors and platinum drugs to construct novel Pt^IV-RG7388 (a selective MDM2 inhibitor) complexes. Most complexes, especially 5a and 5b, displayed greatly improved antiproliferative activity against both wild-type and mutated p53 cancer cells. Remarkably, 5a exhibited potent in vivo tumor growth inhibition in the A549 xenograft model (66.5%) without apparent toxicity. It arrested the cell cycle at both the S phase and the G2/M phase and efficiently induced apoptosis via the synergistic effects of RG7388 and cisplatin. Altogether, Pt^IV-RG7388 complex 5a exhibited excellent in vitro and in vivo antitumor activities, highlighting the therapeutic potential of Pt^IV-RG7388 complexes as antitumor agents.

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.