Abstract
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. 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. 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. 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.
Highlights
An important research goal in head and neck oncology is to optimize tumor control while preserving function and maximizing quality of life
We observed dose-dependent growth inhibition of 10 head and neck squamous cell carcinoma (HNSCC) cell lines at biologically achievable doses (2.5–10 mol/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
Summary
An important research goal in head and neck oncology is to optimize tumor control while preserving function and maximizing quality of life. The treatment of locally advanced head and neck cancer with chemotherapy and radiation allows organ preservation, but it is limited by the emergence of resistant cancer cells. Overexpression of Bcl-2 or Bcl-xL has been shown by several groups to confer resistance to various therapeutic agents, presumably by their ability to inhibit chemotherapy-induced apoptosis [3,4,5]. We hypothesized that overexpression of Bcl-2 and/or Bcl-xL plays a role in the resistance of HNSCC to chemotherapeutic agents, and that inhibition of antiapoptotic function should be a promising strategy for treatment
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