Induced growth inhibition, cell cycle arrest and apoptosis in CD133+/CD44+ prostate cancer stem cells by flavopiridol.
Int J Mol Med
; 34(5): 1249-56, 2014 Nov.
Article
en En
| MEDLINE
| ID: mdl-25216351
ABSTRACT
Flavopiridol is a flavone that inhibits several cyclindependent kinases and exhibits potent growthinhibitory activity, apoptosis and G1phase 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 timedependent manner to determine the inhibitory effect. Cell viability and proliferation were analyzed and the efficiency of flavopiridol was assessed using the sphereforming 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 (IC(50)) 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. AnnexinV 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 highdose treatments. Flavopiridol induced growth inhibition and apoptosis at the IC(50) dose (500 nM), resulting in a significant increase in immunofluorescence staining of caspase3, caspase8 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.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Piperidinas
/
Próstata
/
Células Madre Neoplásicas
/
Flavonoides
/
Apoptosis
/
Puntos de Control del Ciclo Celular
Idioma:
En
Revista:
Int J Mol Med
Asunto de la revista:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Año:
2014
Tipo del documento:
Article