About the molecular mechanisms of celecoxib's anticancer effects

Bock JM, Menon SG, Sinclair LL, Bedford NS, Goswami PC, Domann FE,
Trask DK.
Celecoxib toxicity is cell cycle phase specific.
Cancer Res. 2007 Apr 15;67(8):3801-8.
PMID: 17440094 [PubMed - in process]
<http://cancerres.aacrjournals.org/cgi/content/short/67/8/3801?rss=1>

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

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 G(1) 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 G(1) and G(2) phases. Levels of p21(waf1/cip1) and
cyclin D1 protein were reduced in the S phase compared with
the G(1) and G(2) 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 G(1)
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].


--
Matti Narkia
.