Antitumor activity of UCN-01 in carcinomas of the head and neck is associated with altered expression of cyclin D3 and p27KIP1

摘要: Altered and deregulated cyclin-dependent kinase (cdk) activity is now believed to play a major role in the pathogenesis of head neck squamous cell carcinomas (HNSCC), thus providing suitable cellular target for therapeutic intervention. UCN-01 (7-hydroxy-staurosporine), known protein C cdk modulator, demonstrates antiproliferative antitumor properties many experimental tumor models may represent potential candidate test HNSCC. In this study, displayed potent (IC50 approximately 17-80 nM) HNSCC cells. Cell cycle analysis revealed that treatment cells 24 h leads G1 block with concomitant loss S G2-M emerging sub-G1 population, confirmed be apoptotic by terminal deoxynucleotidyl transferase-mediated nick end labeling analysis. Additional vitro studies demonstrated arrest was preceded depletion cyclin D3, elevation p21(WAF1) p27(KIP1) leading cdks (cdk2, cdk4), reduction pRb phosphorylation. Antitumor were also assessed vivo treating HN12 xenografts (7.5 mg/kg/i.p./daily) 5 consecutive days. Total sustained abolition growth (P < 0.00001) obtained only one treatment. Terminal staining xenograft samples higher incidence apoptosis treated tissues when compared control. tissue elevated minimal increase reduced D3 levels readily detected those animals UCN-01, similar observed Thus, exhibits both models, these effects are associated decrease an levels, appropriate surrogate markers follow efficacy and, therefore, drug patients.