Abstract
Abstract Intra-tumoral hypoxia has been proposed to create a “mutator” phenotype through down-regulation of DNA repair, leading to increased genomic instability and drug resistance. There is increasing interest to target hypoxic cancer cells with DNA-damaging agents and inhibitors of DNA repair. Here, we showed that hypoxia did not sensitize castration-resistant prostate cancer cells to the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib or the DNA-damaging topoisomerase I inhibitor: Irinotecan or SN38. Although DNA repair proteins like Rad51 were decreased under hypoxia, up-regulation of Rad51 and Rad51 nuclear foci formation was observed soon after treatment with veliparib and SN-38 under hypoxia. This Rad51 up-regulation occurred at the transcription level and was mediated at least in part by E2F1. Inhibiting Rad51 expression with siRNA overcame prostate cancer cells’ resistance to SN-38 under hypoxia. Combining veliparib with Irinotecan significantly enhanced DNA damage and apoptosis under both hypoxic and normoxic culture conditions. Such enhanced DNA damage and anti-tumor activities were seen in the presence of Rad51 up-regulation and confirmed in vivo with PC3 mouse xenografts. These data illustrate a dynamic regulation of Rad51 by prostate cancer cells in response to hypoxia and DNA damage. The veliparib and Irinotecan combination can be further explored as a treatment for metastatic castration-resistant prostate cancer patients who have progressed through standard treatments. Citation Format: Minghui Wu, Jingsong Zhang, Xue Wang. Poly(ADP-Ribose) polymerase inhibitor overcomes Rad51- mediated prostate cancer cells’ resistance to Topoisomerase I inhibitor under hypoxia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 998. doi:10.1158/1538-7445.AM2013-998
Published Version
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