title: Catalytic inhibitors of DNA topoisomerase II suppress the androgen receptor signaling and prostate cancer progression.
abstract: Although the new generation of androgen receptor (AR) antagonists like enzalutamide (ENZ) prolong survival of metastatic castration-resistant prostate cancer (CRPC), AR-driven tumors eventually recur indicating that additional therapies are required to fully block AR function. 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 block AR signaling and suppress ENZ-resistant CRPC growth. Using multiple prostate cancer cell lines, we showed that catalytic Topo II inhibitors, ICRF187 and ICRF193 inhibited transcription activities of the wild-type AR, mutant ARs (F876L and W741C) and the AR-V7 splice variant. ICRF187 and ICRF193 decreased AR recruitment to target promoters and reduced AR nuclear localization. Both ICRF187 and ICRF193 also inhibited cell proliferation and delayed cell cycling at the G2/M phase. ICRF187 inhibited tumor growth of castration-resistant LNCaP and 22RV1 xenografts as well as ENZ-resistant MR49F xenografts. We conclude that catalytic Topo II inhibitors can block AR signaling and inhibit tumor growth of CRPC xenografts, identifying a potential co-targeting approach using these inhibitors in combination with AR pathway inhibitors in CRPC.
authors.affiliation: The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Haolong
authors.initials: H
authors.lastname: Li
authors.affiliation: The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Ning
authors.initials: N
authors.lastname: Xie
authors.affiliation: The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.affiliation: The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Xuesen
authors.initials: X
authors.lastname: Dong
mesh_terms: D059002:Androgen Receptor Antagonists / Q000627:therapeutic use*; D000818:Animals; D049109:Cell Proliferation; D004250:DNA Topoisomerases, Type II / Q000235:genetics* / Q000378:metabolism*; D018450:Disease Progression; D006801:Humans; D008297:Male; D051379:Mice; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D059002:Androgen Receptor Antagonists; D011944:Receptors, Androgen; D004250:DNA Topoisomerases, Type II
keywords: androgen receptor; castration resistant prostate cancer; catalytic inhibitor; prostate cancer; topoisomerase II