M V Blagosklonny1, S C Dixon, W D Figg. 1. Medicine Branch, Division of Clinical Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Abstract
PURPOSE: Once a relapse occurs following primary endocrine treatment, metastatic prostate cancer is one of the most therapy-resistant human neoplasms. Ketoconazole is used for complete androgen deprivation, and recent data suggest it has direct activity against prostate cancer cells. MATERIALS AND METHODS: LNCaP, DU145, and PC3 cells, human prostate cancer cell lines, and HL60, a human leukemia cell line, were lysed and soluble proteins were harvested. Cells were plated in 96-well flat bottom plates and then exposed to the pharmacological agents, ketoconazole, vinblastine and paclitaxel. DNA synthesis was monitored by 3H-thymidine incorporation. RESULTS: We demonstrate that ketoconazole exerts a cytostatic effect on a panel of human prostate cancer cell lines, with IC50 of 4 to 5 microg./ml., 12 microg./ml., and 25 microg./ml. for LNCaP, PC3/PC3M, and DU145 cells, respectively. On the other hand, using microtubule-active drugs, vinblastine and paclitaxel, we found that PC3M and PC3 cells were more resistant than either DU145 or LNCaP cells. This resistance was associated with a lesser degree of Raf-1 and Bcl-2 phosphorylation following exposure to microtubule-active drugs. Combinations of microtubule-active drugs with ketoconazole were a beneficial treatment in DU145 cancer cells. Furthermore, ketoconazole blocked recovery of all the prostate cancer cell lines following 24 hours-pulse treatment with vinblastine. CONCLUSION: Pulse-administration of vinblastine followed by continuous administration of ketoconazole warrants investigation in the treatment of hormone-independent metastatic prostate cancer.
PURPOSE: Once a relapse occurs following primary endocrine treatment, metastatic prostate cancer is one of the most therapy-resistant humanneoplasms. Ketoconazole is used for complete androgen deprivation, and recent data suggest it has direct activity against prostate cancer cells. MATERIALS AND METHODS: LNCaP, DU145, and PC3 cells, humanprostate cancer cell lines, and HL60, a humanleukemia cell line, were lysed and soluble proteins were harvested. Cells were plated in 96-well flat bottom plates and then exposed to the pharmacological agents, ketoconazole, vinblastine and paclitaxel. DNA synthesis was monitored by 3H-thymidine incorporation. RESULTS: We demonstrate that ketoconazole exerts a cytostatic effect on a panel of humanprostate cancer cell lines, with IC50 of 4 to 5 microg./ml., 12 microg./ml., and 25 microg./ml. for LNCaP, PC3/PC3M, and DU145 cells, respectively. On the other hand, using microtubule-active drugs, vinblastine and paclitaxel, we found that PC3M and PC3 cells were more resistant than either DU145 or LNCaP cells. This resistance was associated with a lesser degree of Raf-1 and Bcl-2 phosphorylation following exposure to microtubule-active drugs. Combinations of microtubule-active drugs with ketoconazole were a beneficial treatment in DU145 cancer cells. Furthermore, ketoconazole blocked recovery of all the prostate cancer cell lines following 24 hours-pulse treatment with vinblastine. CONCLUSION: Pulse-administration of vinblastine followed by continuous administration of ketoconazole warrants investigation in the treatment of hormone-independent metastatic prostate cancer.
Authors: William D Figg; Sukyung Woo; Wenhui Zhu; Xiaohong Chen; A Seun Ajiboye; Seth M Steinberg; Douglas K Price; John J Wright; Howard L Parnes; Philip M Arlen; James L Gulley; William L Dahut Journal: J Urol Date: 2010-06 Impact factor: 7.450
Authors: Nicholas Toupin; Sean J Steinke; Sandeep Nadella; Ao Li; Thomas N Rohrabaugh; Eric R Samuels; Claudia Turro; Irina F Sevrioukova; Jeremy J Kodanko Journal: J Am Chem Soc Date: 2021-06-10 Impact factor: 16.383
Authors: Eun Jin Seo; Il Ho Jang; Eun Kyoung Do; Hyo Cheon Cheon; Soon Chul Heo; Yang Woo Kwon; Geun Ok Jeong; Ba Reun Kim; Jae Ho Kim Journal: PLoS One Date: 2013-09-30 Impact factor: 3.240