Evaluation Of Recombinational Dna Damage Response In Castration-Resistant Prostate Cancer And Investigation Of The Combined Effect Of Rad51 And Wee1 Inhibitors On Radiosensitivity

Abstract

Castration-resistant prostate cancer (mCRPC) is a disease with a poor prognosis. Recently, DNA repair mechanisms have been targeted in new treatment regimens, in particular inpatients carrying mutations in the genes of DNA repair proteins. Rad51 recombinase is the key protein of recombinational repair process. It is one of the proteins targeted in cancer research in recent years. Wee1 is a protein kinase in nuclei, which is a negative regulator of mitosis by inactivating Cdc2-cyclinB1 complex. So it is an important regulatory protein in the G2/M phase of cell cycle. In vitro studies on Wee1 inhibition have intensified in the last decade. The aim of this study was to determine the effectiveness of Rad51 and Wee1 inhibition on radiosensitivity in mCRPC. For this aim, PC-3 cells were expose to ionizing radiation with or without pre-treatment with Rad51 and Wee1 inhibitors. Cell survival was determined by MTT and colony formation assays. The apoptotic rate was measured by flow cytometry method following Annexin V-FITC/PI staining. The synergism between AZD1775 and B02 was investigated by the median-effect method of Chou and Talalay. AZD1775 and B02 are promising radiosensitizing agents for prostate cancer cells both single treatment and in combination. AZD1775 and B02 increases radiosensitivity of PC-3 cells as a single treatment. In this study, it’s observed that combination of AZD1775 and B02 also increased radiosensitivity in PC-3 cells. Combined treatment of AZD1775 and B02’s decreased cell viability more than single treatment. In conclusion, as a single or combined therapy of Rad51 recombinase inhibitor and Wee1 kinase inhibitor may be a novel strategy to improve the clinical outcome in CRPC.