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.
机构:
Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USA
Budak-Alpdogan, Tulin
Chen, Bobin
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Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USA
Fudan Univ, Dept Hematol, Huashan Hosp, Shanghai Med Coll, Shanghai 200433, Peoples R ChinaUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USA
Chen, Bobin
Warrier, Aniali
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Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USA
Warrier, Aniali
Medina, Daniel J.
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Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USA
Medina, Daniel J.
Moore, Dirk
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Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Biometr, New Brunswick, NJ 08903 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USA
Moore, Dirk
Bertino, Joseph R.
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Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USA
Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pharmacol, New Brunswick, NJ 08903 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USA
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Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USAAlbert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA
Cimica, Velasco
Smith, Melissa E.
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Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USAAlbert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA
Smith, Melissa E.
Zhang, Zhikai
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Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USAAlbert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA
Zhang, Zhikai
Mathur, Deepti
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Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USAAlbert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA
Mathur, Deepti
Mani, Sridhar
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Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA
Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA
Albert Einstein Coll Med, Albert Einstein Canc Ctr, Bronx, NY 10461 USAAlbert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA
Mani, Sridhar
Kalpana, Ganjam V.
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Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA
Albert Einstein Coll Med, Albert Einstein Canc Ctr, Bronx, NY 10461 USAAlbert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA
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Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USA
Budak-Alpdogan, Tulin
Chen, Bobin
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机构:
Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USA
Fudan Univ, Dept Hematol, Huashan Hosp, Shanghai Med Coll, Shanghai 200433, Peoples R ChinaUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USA
Chen, Bobin
Warrier, Aniali
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Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USA
Warrier, Aniali
Medina, Daniel J.
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Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USA
Medina, Daniel J.
Moore, Dirk
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Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Biometr, New Brunswick, NJ 08903 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USA
Moore, Dirk
Bertino, Joseph R.
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Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USA
Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pharmacol, New Brunswick, NJ 08903 USAUniv Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USA
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Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USAAlbert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA
Cimica, Velasco
Smith, Melissa E.
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Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USAAlbert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA
Smith, Melissa E.
Zhang, Zhikai
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Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USAAlbert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA
Zhang, Zhikai
Mathur, Deepti
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Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USAAlbert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA
Mathur, Deepti
Mani, Sridhar
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Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA
Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA
Albert Einstein Coll Med, Albert Einstein Canc Ctr, Bronx, NY 10461 USAAlbert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA
Mani, Sridhar
Kalpana, Ganjam V.
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Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA
Albert Einstein Coll Med, Albert Einstein Canc Ctr, Bronx, NY 10461 USAAlbert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA