1. Academic Validation
  2. In vitro effects of the BH3 mimetic, (-)-gossypol, on head and neck squamous cell carcinoma cells

In vitro effects of the BH3 mimetic, (-)-gossypol, on head and neck squamous cell carcinoma cells

  • Clin Cancer Res. 2004 Nov 15;10(22):7757-63. doi: 10.1158/1078-0432.CCR-04-0551.
Christopher L Oliver 1 Joshua A Bauer Keith G Wolter Mathew L Ubell Ajita Narayan Kathleen M O'Connell Susan G Fisher Shaomeng Wang Xihan Wu Min Ji Thomas E Carey Carol R Bradford
Affiliations

Affiliation

  • 1 Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan 48109-0312, USA.
Abstract

Purpose: Bcl-xL overexpression is common in head and neck squamous cell carcinomas (HNSCC) and correlates with resistance to chemotherapy. Thus, a nonpeptidic, cell-permeable small molecule that mimics the BH3 domain of proapoptotic proteins may inhibit Bcl-xL function and have therapeutic potential for HNSCC by overcoming drug-resistance. (-)-Gossypol, the levorotatory isomer of a natural product isolated from cottonseeds and roots, was recently discovered to bind to the BH3 binding groove of Bcl-xL and Bcl-2.

Experimental design: We investigated the in vitro effects of (-)-gossypol on HNSCC cell lines as well as on fibroblast and keratinocyte cultures by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell survival assays and assessed the results with respect to Bcl-2 Family protein expression.

Results: We observed dose-dependent growth inhibition of 10 HNSCC cell lines at biologically achievable doses (2.5-10 micromol/L). (-)-Gossypol doses required to inhibit the growth of human fibroblast cell lines by 50% were 2- to 10-fold higher than for HNSCC cell lines. To inhibit human oral keratinocyte growth by 50%, (-)-gossypol concentrations were 2-to 3-fold higher than for HNSCC cell lines.

Conclusions: There is a direct correlation between Bcl-xL-to-Bcl-xS ratios and sensitivity to (-)-gossypol. This agent induced Apoptosis in a much higher proportion of cells with wild-type p53. Importantly, cell lines resistant to cisplatin were very sensitive to (-)-gossypol. These results demonstrate that (-)-gossypol has potent antitumor activity in HNSCC in vitro. This agent may be developed as a novel therapeutic agent for HNSCC, either alone or in combination with existing chemotherapeutic agents.

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