Abstract:

Objective: Ovarian cancer (OC) is the deadliest gynecologic malignancy and has a poor survival rate due to late diagnosis and chemoresistance development. In the standard treatment of OC, platinum-based chemotherapeutics are used. However, following several rounds of chemotherapy, these drugs’ efficacy eventually becomes limited due to the chemoresistance in most patients who previously responded to this treatment. Therefore, overcoming chemoresistance in the treatment of OC is of high importance. In this study, we investigated the effect of combinatorial inhibition of poly(ADP-ribose)polymerase (PARP) and proteasome by olaparib and bortezomib on chemosensitive and chemoresistant OC cell lines. Materials and Methods: We used sulphorhodamine B assay to screen cell viability following drug treatments alone or in combination, and used the cytotoxicity data to model the effect of drugs on cell death in R programming environment. In addition to olaparib and bortezomib, we performed cytotoxicity screenings where we applied cisplatin to OC cells. We also carried out flow cytometry analysis to quantify apoptotic cells following treatments. Results: We showed that combination treatment was more effective on chemosensitive OC cell lines when cisplatin was not used. In the presence of cisplatin, olaparib and bortezomib combination treatment resulted in higher cytotoxicity in chemoresistant OC lines compared to chemosensitive OC cell lines. Combinatorial inhibition of PARP and proteasome led to a higher number of apoptotic cells in OV2008 chemosensitive cell line compared to drugs alone. Conclusion: Our data shows that olaparib and bortezomib combination treatment might show promise in vivo in the treatment of OC. Also, the efficacy of this combination treatment might be dependent on OC cells’ chemosensitivity profiles.

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