Efficacy of microtubule-active drugs followed by ketoconazole in human metastatic prostate cancer cell lines

Mikhail V. Blagosklonny, Shannon C. Dixon, William D. Figg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


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 fiat 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 μg./ml., 12 μg./ml., and 25 μg./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 microtubuleactive 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.

Original languageEnglish
Pages (from-to)1022-1026
Number of pages5
JournalJournal of Urology
Issue number3
StatePublished - Mar 2000
Externally publishedYes


  • Ketoconazole
  • Paclitaxel
  • Prostate cancer
  • Vinblastine


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