Abstract 1846: Catalytic topoisomerase II inhibitors suppress the androgen receptor signaling and prostate cancer progression

Abstract

Abstract Background: Although the new generation of anti-androgens (e.g. MDV) improves survival of metastatic prostate cancer patients, tumors eventually recur indicating that additional therapeutic means is required to fully block the functions of the androgen receptor (AR). Since DNA topoisomerase II (Topo II) was demonstrated to be essential for AR to initiate gene transcription, this study tested whether catalytic inhibitors of Topo II can suppress the AR signaling and block prostate tumor growth. Methods and Results: Androgen-dependent and MDV-resistant prostate cancer cells were treated with increasing doses of catalytic Topo II inhibitors, ICRF187 and ICRF193. Luciferase reporter assays showed that both inhibitors suppressed the transcriptional activities of wild-type AR, mutant AR (F876L and W741C), and AR-V7 splice variant. ICRF187 and ICRF193 decreased AR recruitment to its target promoters and reduced AR nuclear localization. Both ICRF187 and ICRF193 inhibited androgen-dependent and MDV-resistant cancer cell proliferation and delayed cell cycling at the G2/M stages. In castration-resistant LNCaP tumors, ICRF187 inhibited tumor growth, PSA secretion and expressions of several other AR regulated genes. These repressive effects became stronger when tumors were co-treated with MDV. Additionally, ICRF187 effectively inhibited tumor growth of MDV-resistant MR49F as well as castration-resistant 22RV1 xenografts. Conclusions: Catalytic Topo II inhibitors can block the AR signaling and inhibit tumor growth of castration-resistant xenografts, suggesting their potential applications in treating castration-resistant cancers in patients. Citation Format: Haolong Li, Ning Xie, Martin Gleave, Xuesen Dong. Catalytic topoisomerase II inhibitors suppress the androgen receptor signaling and prostate cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1846. doi:10.1158/1538-7445.AM2015-1846