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Celecoxib Toxicity Is Cell Cycle Phase Specific

Departments of ¹ Otolaryngology-Head and Neck Surgery and ² Radiation Oncology, University of Iowa Hospital and Clinics, Iowa City, Iowa

Requests for reprints: Douglas K. Trask, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Hospitals & Clinics, 200 Hawkins Drive, Iowa City, IA 52242. Phone: 319-356-1616; Fax: 319-356-4547; E-mail: douglas-trask{at}uiowa.edu.

Celecoxib inhibits proliferation and induces apoptosis in human tumors, but the molecular mechanisms for these processes are poorly understood. In this study, we evaluated the ability of celecoxib to induce toxicity in head and neck squamous cell carcinomas (HNSCC) and explored the relationships between celecoxib-induced cell cycle inhibition and toxicity in HNSCC. Celecoxib inhibited the proliferation of UM-SCC-1 and UM-SCC-17B cells both in vitro and in vivo, accompanied by G₁ phase cell cycle arrest and apoptosis. Celecoxib induced p21^waf1/cip1 at the transcriptional level independent of wild-type p53 function, leading to decreased expression of cyclin D1 and hypophosphorylation of Rb, with subsequent marked downstream decreases in nuclear E2F-1 protein expression and E2F transactivating activity by luciferase reporter assay. Cell cycle phase–specific cytometric sorting showed that celecoxib induced clonogenic toxicity preferentially to cells within the S phase greater than G₁ and G₂ phases. Levels of p21^waf1/cip1 and cyclin D1 protein were reduced in the S phase compared with the G₁ and G₂ phases, suggesting a possible protective role for p21^waf1/cip1 expression in celecoxib toxicity. In conclusion, we show that celecoxib has marked antiproliferative activity against head and neck cancer cells through transcriptional induction of p21^waf1/cip1 and G₁ phase accumulation leading to S phase–specific clonogenic toxicity. We additionally show that a profound inhibition of nuclear E2F function provides a possible mechanism for this S phase–specific toxicity. [Cancer Res 2007;67(8):3801–8]

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