MP52-14 SYNERGISTIC EFFECTS OF COMBINATION OF DOCETAXEL AND SAHA ON AR SIGNALING IN PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2014MP52-14 SYNERGISTIC EFFECTS OF COMBINATION OF DOCETAXEL AND SAHA ON AR SIGNALING IN PROSTATE CANCER Kyung-Sik Han, Taekmin Kwon, In Gab Jeong, Dalsan You, Bumjin Lim, Donghyun Lee, Chunwoo Lee, Sungwoo Hong, Ha-Gyeong Kim, Jung Jin Hwang, Jun Hyuk Hong, Myung-Soo Choo, Tai Young Ahn, and Choung-Soo Kim Kyung-Sik HanKyung-Sik Han More articles by this author , Taekmin KwonTaekmin Kwon More articles by this author , In Gab JeongIn Gab Jeong More articles by this author , Dalsan YouDalsan You More articles by this author , Bumjin LimBumjin Lim More articles by this author , Donghyun LeeDonghyun Lee More articles by this author , Chunwoo LeeChunwoo Lee More articles by this author , Sungwoo HongSungwoo Hong More articles by this author , Ha-Gyeong KimHa-Gyeong Kim More articles by this author , Jung Jin HwangJung Jin Hwang More articles by this author , Jun Hyuk HongJun Hyuk Hong More articles by this author , Myung-Soo ChooMyung-Soo Choo More articles by this author , Tai Young AhnTai Young Ahn More articles by this author , and Choung-Soo KimChoung-Soo Kim More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1624AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives Globally it is the sixth leading cause of cancer-related death in men, and it is now the first in the United Kingdom and second in the United States. At the early stage, androgen is required for cell growth and progression of prostate cancer. Therefore, androgen-deprivation therapy (ADT) is effective to patient with prostate cancer by inhibition of androgen synthesis. With time, however, most patients with prostate cancer eventually lose sensitivity to androgen withdrawal and progress to the development of hormone-refractory prostate cancer (HRPC) or castration-resistant prostate cancer (CRPC). Since the treatment for patient with CRPC is very limited, the novel therapeutic strategies and combination therapy are needed to overcome this resistance. Therefore, we examined whether histone deacetylase inhibitor (HDACI) might enhance the effects of docetaxel in CRPCs. Methods Hormone-independent CWR22Rv1 cells harboring androgen receptor (AR) were treated with docetaxel and/or HDACI, suberoylanilide hydroxamic acid (SAHA). Cell viability was measured with CellTiter-Glo¢ç reagent. AR signaling was analyzed by immunocytochemistry and Western blot of total cell lysates and nuclear fractionated proteins. Results The growth inhibitory effect of sequential treatment with docetaxel and SAHA was synergistic in CWR22Rv1 cells. Combination treatment decreased the levels of androgen receptor (AR), prostate specific antigen (PSA), and anti-apoptotic Bcl-2 proteins (Mcl-1, Bcl-xl) more efficiently, compared with docetaxel or SAHA alone. And combination treatment increased activation of caspase-3 remarkably, while docetaxel or SAHA alone increased it slightly. Moreover, combination treatment induced acetylation and bundling of tubulin, inhibiting nuclear accumulation of AR significantly. These synergistic effects of combination treatment were also observed in hormone-dependent LNCaP cells. Conclusions Docetaxel in combination with SAHA inhibited cell growth efficiently and induced apoptosis by repressing AR expression and translocation to nucleus, resulting in down regulation of AR signaling in hormone-independent CWR22Rv1 cells. These results suggest that combination treatment with docetaxel and SAHA can be a useful therapeutics for the treatment of CRPC patients. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e585 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Kyung-Sik Han More articles by this author Taekmin Kwon More articles by this author In Gab Jeong More articles by this author Dalsan You More articles by this author Bumjin Lim More articles by this author Donghyun Lee More articles by this author Chunwoo Lee More articles by this author Sungwoo Hong More articles by this author Ha-Gyeong Kim More articles by this author Jung Jin Hwang More articles by this author Jun Hyuk Hong More articles by this author Myung-Soo Choo More articles by this author Tai Young Ahn More articles by this author Choung-Soo Kim More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...