Highlights
- •Individual treatments with RG-7388 and Selinexor are able to reduce the viability of ovarian cancer cells.
- •The ovarian cancer cells (A2780) treated with the drug combination produced higher levels of apoptosis.
- •The combination treatments with RG-7388 and Selinexor are involved in the induction of caspase-mediated apoptotic mechanism via up-regulation of MDM2, p53, phospho-p53, and p21.
- •The combination treatments enhanced the Inhibitory effects of MDM2 through blocking nuclear export mechanisms in A2780 Ovarian Cancer Cells.
Abstract
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.
Keywords
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Article info
Publication history
Published online: June 11, 2022
Accepted:
June 9,
2022
Received:
May 1,
2022
Identification
Copyright
© 2022 Published by Elsevier Inc.
