The effect of cell killing by ABT-737 synergized with docetaxel in human prostate cancer PC-3 cells.
- Author:
Jian-wei HAO
1
;
Xiao-peng MAO
;
De-gang DING
;
Guang-hui DU
;
Zhong-hua LIU
Author Information
- Publication Type:Journal Article
- MeSH: Apoptosis; drug effects; Biphenyl Compounds; pharmacology; Caspase 3; metabolism; Cell Cycle; drug effects; Cell Line, Tumor; Drug Synergism; Humans; Male; Myeloid Cell Leukemia Sequence 1 Protein; metabolism; Nitrophenols; pharmacology; Piperazines; pharmacology; Prostatic Neoplasms; metabolism; pathology; Proto-Oncogene Proteins c-bcl-2; metabolism; Sulfonamides; pharmacology; Taxoids; pharmacology; bcl-X Protein; metabolism
- From: Chinese Journal of Surgery 2012;50(2):161-165
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVETo investigate the synergistical killing effect of docetaxel combined with ABT-737 on human prostate cancer cell line PC-3 by inducing apoptosis and further to determine the mechanism underlying such effect.
METHODSPC-3 cells were treated with various concentrations of docetaxel or (and) ABT-737. Cell viability was determined using MTT assay. Apoptosis was assessed by fluorescence microscopy analysis of cells with condensed and segmented nuclei following staining with 4',6-diamidino-2-phenylindole (DAPI). Cellular DNA was stained with propidium iodide and flow cytometric analysis was performed to analyze the cell cycle distribution. Bcl-2, Bax, Bcl-xL and Mcl-1 protein changes were detected by Western blot. The activity of caspase-3 was measured using a colorimetric assay.
RESULTSDocetaxel (20 nmol/L) combination with ABT-737 (400 nmol/L) for 48 hours, the cell viability was decreased to 19.7% ± 3.2% to compare with 44.2% ± 4.4% (t = 4.45) of docetaxel and 93.2% ± 1.8% of ABT-737 separately and there was a synergistic effect between the two drugs (CI = 0.8). Apoptosis rate of the combination group was higher than other two drugs. Docetaxel increased the cell number arrested in G(2)/M phase compared with control group (P < 0.05), but the combination treatment resulted in a significant arrest in the G(0)/G(1) phase. The combination treatment could significantly reduced the Bcl-2, Bcl-xL and Mcl-1 expression (F = 369.53, 57.89 and 32.77, all P < 0.05) and enhanced the activity of caspase-3 (419.7% ± 15.6%) (F = 207.33, P < 0.05).
CONCLUSIONSThe combination of ABT-737 with docetaxel can synergistically inhibit the proliferation of PC-3 cells through inducing apoptosis, which may be associated with cell cycle arrest, down-regulation of Bcl-2, Bcl-xL and Mcl-1 expression and activation of caspase-3.