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

  • Amal Alzahrani
    Affiliations
    Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, 3321, College Ave, Fort Lauderdale, Florida 33314, United States

    Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia

    College of Pharmacy, Nova Southeastern University, Fort Lauderdale, Florida, United States
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  • Umamaheswari Natarajan
    Affiliations
    Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, 3321, College Ave, Fort Lauderdale, Florida 33314, United States
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  • Appu Rathinavelu
    Correspondence
    Corresponding author at: Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, 3321, College Ave, Fort Lauderdale, Florida 33314, United States.
    Affiliations
    Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, 3321, College Ave, Fort Lauderdale, Florida 33314, United States

    College of Pharmacy, Nova Southeastern University, Fort Lauderdale, Florida, United States
    Search for articles by this author

      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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