988P - Hxr9 and parp inhibition -a novel therapeutic in ovarian cancer

Date 29 September 2012
Event ESMO Congress 2012
Session Poster presentation I
Topics Ovarian Cancer
Translational Research
Presenter Zoe Kelly
Authors Z. Kelly1, H. Pandha2, R. Morgan2, A. Michael2
  • 1Department Of Microbial And Cellular Science, University of Surrey, GU27WG - Guildford/UK
  • 2Institute Of Bioscience And Medicine, Department Of Microbial And Cellular Science, University of Surrey, GU27WG - Guildford/UK

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 < 0.0001 for each of the cell lines tested, irrespective of cisplatin sensitivity status. The combination of HXR9 and 3-aminobenzamide induced enhanced cell death and showed clear synergy between the two drugs. The apoptosis rate in treated cells was confirmed by the capase-3 activity, which was increased for all cell lines (an average fold increases ranging from 1.3-3.4- compared to untreated controls).

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.