Epothilone B confers radiation dose enhancement in DAB2IP gene knock-down radioresistant prostate cancer cells.
OBJECTIVE
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
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 IC(50) 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 G(2)/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 G(2) block, and increased apoptosis in cells entering the cell cycle after G(2)/M arrest.
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9187, USA.
Zhaolu
Z
Kong
Pavithra
P
Raghavan
Daxing
D
Xie
Thomas
T
Boike
Sandeep
S
Burma
David
D
Chen
Arup
A
Chakraborty
Jer-Tsong
JT
Hsieh
Debabrata
D
Saha
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D034261:Epothilones / Q000627:therapeutic use*; D016195:G2 Phase; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000532:radiotherapy*; D011836:Radiation Tolerance / Q000187:drug effects* / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D020703:ras GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics*
D000970:Antineoplastic Agents; C462952:DAB2IP protein, human; D034261:Epothilones; D009363:Neoplasm Proteins; D011838:Radiation-Sensitizing Agents; D020703:ras GTPase-Activating Proteins; C093788:epothilone B