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Antitumor Activity of UCN-01 in Carcinomas of the Head and Neck Is Associated with Altered Expression of Cyclin D3 and p27^KIP1

Oral & Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research [V. P., T. L., C. L., J. S. G., A. M. S.], Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute [E. A. S.], National Institutes of Health, Bethesda, Maryland 20892; Institute of Pathology, GSF-National Research Center for Environment and Health, Neuherberg, Germany [M. K., L. Q-M.]; and Division of Hematology-Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201 [J. F. E.]

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

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