title: Sequential combination of flavopiridol and docetaxel reduces the levels of X-linked inhibitor of apoptosis and AKT proteins and stimulates apoptosis in human LNCaP prostate cancer cells.
abstract: Clinical trials have shown that chemotherapy with docetaxel combined with prednisone can improve survival of patients with androgen-independent prostate cancer. It is likely that the combination of docetaxel with other novel chemotherapeutic agents would also improve the survival of androgen-independent prostate cancer patients. We investigated whether the combination of docetaxel and flavopiridol, a broad cyclin-dependent kinase inhibitor, can increase apoptotic cell death in prostate cancer cells. Treatment of DU 145 prostate cancer cells with 500 nmol/L flavopiridol and 10 nmol/L docetaxel inhibited apoptosis probably because of their opposing effects on cyclin B1-dependent kinase activity. In contrast, when LNCaP prostate cancer cells were treated with flavopiridol for 24 hours followed by docetaxel for another 24 hours (FD), there was a maximal induction of apoptosis. However, there was greater induction of apoptosis in DU 145 cells when docetaxel was followed by flavopiridol or docetaxel. These findings indicate a heterogeneous response depending on the type of prostate cancer cell. Substantial decreases in X-linked inhibitor of apoptosis (XIAP) protein but not survivin, both being members of the IAP family, were required for FD enhanced apoptosis in LNCaP cells. Androgen ablation in androgen-independent LNCaP cells increased activated AKT and chemoresistance to apoptosis after treatment with FD. The proteasome inhibitor MG-132 blocked FD-mediated reduction of XIAP and AKT and antagonized apoptosis, suggesting that the activation of the proteasome pathway is one of the mechanisms involved. Overall, our data suggest that the docetaxel and flavopiridol combination requires a maximal effect on cyclin B1-dependent kinase activity and a reduction of XIAP and AKT prosurvival proteins for augmentation of apoptosis in LNCaP cells.
authors.affiliation: Geriatric Research, Education, and Clinical Center and Research Service, Veterans Affairs Medical Center, 11-GRC, 1201 Northwest 16 Street, Miami, FL 33125, USA.
authors.forename: Lourdes A
authors.initials: LA
authors.lastname: Gomez
authors.forename: Alicia
authors.initials: A
authors.lastname: de Las Pozas
authors.forename: Carlos
authors.initials: C
authors.lastname: Perez-Stable
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D000077143:Docetaxel; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D000077022:Survivin; D043823:Taxoids / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: C107489:BIRC5 protein, human; C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D005419:Flavonoids; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D010880:Piperidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000077022:Survivin; D043823:Taxoids; D051636:X-Linked Inhibitor of Apoptosis Protein; D000077143:Docetaxel; C077990:alvocidib; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex