HXR9 AND PARP INHIBITION -A NOVEL THERAPEUTIC IN OVARIAN CANCER

ABSTRACT Background Ovarian cancer is the leading cause of cancer death among all gynaecological cancers. The majority of patients present with advanced stage disease having a median survival rate of only 3 years. A major obstacle in the treatment of ovarian cancers is the development of resistance to platinum-based therapies. It is therefore essential to introduce new therapeutic approaches. HOX genes are known to be deregulated in many solid tumours and in ovarian cancer. We have previously showed that HXR9, which inhibits the interaction between HOX and its down-stream cofactor-PBX induces apoptosis in the SKOV-3 epithelial ovarian cell line. HOXB7 is also known to have a role in DNA double strand break repair (DSBR). Another mechanism of cell death regulation through DNA DSBR is through inhibition of poly(ADP-ribose) polymerase (PARP). We have therefore tested the potential synergy between HXR9 and PARP-inhibitors. The objective of this study was to assess the cytotoxicity of HXR9 in cisplatin sensitive and resistant epithelial ovarian cancer cell lines, and to assess potential synergy with the PARP inhibitor, 3-aminobenzamide. Methods The MTS cell viability assay was used to show cytotoxicity in the ovarian cancer cell lines SKOV-3, COV-318, TOV-112D, PEO1, PEO4 and TOV-21G after treatment with HXR9, and in combination with presence PARP inhibitor 3-aminobenzamide. Flow cytometric analysis and the caspase-3 assay was used to evaluate mode of cell death. Results HXR9 induced apoptosis in all ovarian cancer cell lines treated compared to untreated cells with P values  Conclusion The combination of HXR9 with PARP inhibitor is synergistic and leads to enhancement of the apoptotic effect in the cisplatin-resistant ovarian cancer cell line SKOV-3. This strategy could potentially lead to a new therapeutic approach for patients with platinum-resistant ovarian cancer in the clinical setting. Disclosure All authors have declared no conflicts of interest.