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Experimental Therapeutics, Preclinical Pharmacology |
1 Department of Otolaryngology–Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan; 2 Department of Community and Preventive Medicine, University of Rochester, Rochester, New York; and 3 Departments of Internal Medicine and Medicinal Chemistry, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan
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 µmol/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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