Induced growth inhibition, cell cycle arrest and apoptosis in CD133+/CD44+ prostate cancer stem cells by flavopiridol

被引:41
作者
Soner, Burak Cem [1 ]
Aktug, Huseyin [2 ]
Acikgoz, Eda [2 ]
Duzagac, Fahriye [3 ]
Guven, Ummu [3 ]
Ayla, Sule [4 ]
Cal, Cag [5 ]
Oktem, Gulperi [2 ]
机构
[1] Necmettin Erbakan Univ, Meram Fac Med, Dept Med Pharmacol, TR-42100 Meram, Konya, Turkey
[2] Ege Univ, Fac Med, Dept Histol & Embryol, TR-35100 Izmir, Turkey
[3] Ege Univ, Hlth Sci Inst, Dept Stem Cell, TR-35100 Izmir, Turkey
[4] Zeynep Kamil Gynecol & Matern Training & Res Hosp, Dept Obstet & Gynecol, TR-34668 Istanbul, Turkey
[5] Izmir Univ Econ, Fac Hlth Sci, TR-35330 Izmir, Turkey
关键词
flavopiridol; prostate cancer; apoptosis; stem cell; DEPENDENT KINASE INHIBITOR; IN-VITRO; P-TEFB; EXPRESSION; RESISTANCE; MECHANISM; BLOCKS; BCL-2; D1;
D O I
10.3892/ijmm.2014.1930
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Flavopiridol is a flavone that inhibits several cyclin-dependent kinases and exhibits potent growth-inhibitory activity, apoptosis and G(1)-phase arrest in a number of human tumor cell lines. Flavopiridol is currently undergoing investigation in human clinical trials. The present study focused on the effect of flavopiridol in cell proliferation, cell cycle progression and apoptosis in prostate cancer stem cells (CSCs). Therefore, cluster of differentiation 133 (CD133)(+high)/CD44(+high) prostate CSCs were isolated from the DU145 human prostate cancer cell line. The cells were treated with flavopiridol in a dose- and time-dependent manner to determine the inhibitory effect. Cell viability and proliferation were analyzed and the efficiency of flavopiridol was assessed using the sphere-forming assay. Flavopiridol was applied to monolayer cultures of CD133(high)/CD44(high) human prostate CSCs at the following final concentrations: 100, 300, 500 and 1000 nM. The cultures were incubated for 24, 48 and 72 h. The half maximal inhibitory concentration (IC50) value of the drug was determined as 500 nM for monolayer cells. Dead cells were analyzed prior and subsequent to exposure to increasing flavopiridol doses. Annexin-V and immunofluorescence analyses were performed for the evaluation of apoptotic pathways. According to the results, flavopiridol treatment caused significant growth inhibition at 500 and 1000 nM when compared to the control at 24 h. G(0)/G(1), analysis showed a statistically significant difference between 100 and 500 nM (P<0.005), 100 and 1000 nM (P<0.001), 300 and 1000 nM (P<0.001), and 500 and 1000 nM (P<0.001). Flavopiridol also significantly influenced the cells in the G(2)/M phase, particularly at highldose treatments. Flavopiridol induced growth inhibition and apoptosis at the IC50 dose (500 nM), resulting in a significant increase in immunofluorescence staining of caspase-3, caspase-8 and p53. In conclusion, the present results indicated that flavopiridol could be a useful therapeutic agent for prostate CSCs by inhibiting tumor growth and malignant progression, and inducing apoptosis.
引用
收藏
页码:1249 / 1256
页数:8
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