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Sensitivity to the non-COX inhibiting celecoxib derivative, OSU03012, is p21(WAF1/CIP1) dependent

Haiming Ding1, Chunhua Han, Dongmei Guo

  • 1Department of Radiology, College of Medicine, The Ohio State University, Columbus, OH 43210, USA. ding.29@osu.edu

International Journal of Cancer
|September 18, 2008
PubMed

Insights

OSU03012, a celecoxib derivative, inhibits cancer cell growth and induces apoptosis. Its effectiveness is linked to p21(WAF1/CIP1) levels, with lower levels enhancing sensitivity to OSU03012

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Cycle Regulation

Background:

  • OSU03012 is a novel celecoxib derivative demonstrating significant anticancer properties, including growth inhibition and apoptosis induction across various cancer cell lines.
  • Understanding the molecular mechanisms underlying OSU03012's effects is crucial for its therapeutic development.
  • The cell cycle regulatory proteins p53 and p21(WAF1/CIP1) are frequently implicated in cancer progression and drug response.

Purpose of the Study:

  • To elucidate the role of cell cycle proteins, specifically p53 and p21(WAF1/CIP1), in mediating the growth inhibitory and apoptotic effects of OSU03012.
  • To investigate the differential sensitivity of cancer cells with varying p53 and p21(WAF1/CIP1) statuses to OSU03012 treatment.

Main Methods:

  • Human oral epithelial cell lines (TE1177) were engineered to express HPV16 E6 (TE/E6), HPV16 E7 (TE/E7), or an empty vector (TE/V) to create distinct p53 and p21(WAF1/CIP1) expression profiles.
  • Cell cycle progression was analyzed using flow cytometry, and protein levels of cyclin A and Cdk2 were assessed via Western blotting.
  • Apoptosis was evaluated by examining PARP and caspase 3 cleavage in both engineered cell lines and p21(WAF1/CIP1)-deficient mouse embryo fibroblasts.

Main Results:

  • TE/E6 cells, characterized by low p53 and undetectable p21(WAF1/CIP1), showed increased sensitivity to OSU03012-induced growth inhibition and apoptosis.
  • TE/E7 cells, with intact p53-p21(WAF1/CIP1) checkpoints, exhibited resistance to OSU03012, which reduced S-phase cells and cyclin A/Cdk2 levels.
  • p21(WAF1/CIP1)-/- mouse embryo fibroblasts demonstrated heightened sensitivity to OSU03012-induced apoptosis, confirming the protective role of p21(WAF1/CIP1).

Conclusions:

  • The study identifies p21(WAF1/CIP1) as a critical determinant of cellular sensitivity to the anticancer effects of OSU03012.
  • Deficiency in p21(WAF1/CIP1) function enhances OSU03012-induced apoptosis and growth inhibition, suggesting its potential as a predictive biomarker.
  • These findings provide valuable insights into the mechanism of action of OSU03012 and its potential application in cancer therapy.

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