Epothilone B confers radiation dose enhancement in DAB2IP gene knock-down radioresistant prostate cancer cells

Zhaolu Kong, Pavithra Raghavan, Daxing Xie, Thomas Boike, Sandeep Burma, David Chen, Arup Chakraborty, Jer Tsong Hsieh, Debabrata Saha

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Purpose: In metastatic prostate cancer, DOC-2/DAB2 interactive protein (DAB2IP) is often downregulated and has been reported as a possible prognostic marker to predict the risk of aggressive prostate cancer (PCa). Our preliminary results show that DAB2IP-deficient PCa cells are radioresistant. In this study, we investigated the anticancer drug Epothilone B (EpoB) for the modulation of radiosensitivity in DAB2IP-deficient human PCa cells. Methods and Materials: We used a stable DAB2IP-knock down human PCa cell line, PC3 shDAB2IP, treated with EpoB, ionizing radiation (IR), or the combined treatment of EpoB and IR. The modulation of radiosensitivity was determined by surviving fraction, cell cycle distribution, apoptosis, and DNA double-strand break (DSB) repair. For in vivo studies, the PC3shDAB2IP xenograft model was used in athymic nude mice. Results: Treatment with EpoB at IC50 dose (33.3 nM) increased cellular radiosensitivity in the DAB2IP-deficient cell line with a dose enhancement ratio of 2.36. EpoB delayed the DSB repair kinetics after IR and augmented the induction of apoptosis in irradiated cells after G2/M arrest. Combined treatment of EpoB and radiation enhanced tumor growth delay with an enhancement factor of 1.2. Conclusions: We have demonstrated a significant radiation dose enhancement using EpoB in DAB2IP-deficient prostate cancer cells. This radiosensitization can be attributed to delayed DSB repair, prolonged G2 block, and increased apoptosis in cells entering the cell cycle after G2/M arrest.

Original languageEnglish (US)
Pages (from-to)1210-1218
Number of pages9
JournalInternational Journal of Radiation Oncology Biology Physics
Volume78
Issue number4
DOIs
StatePublished - Nov 4 2010

Keywords

  • Apoptosis
  • Cell cycle check points
  • DNA Repair
  • Prostate cancer
  • Radiosensitization

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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