In vitro Effects of the BH3 Mimetic, (−)-Gossypol, on Head and Neck Squamous Cell Carcinoma Cells

• Published in: Clinical cancer research 2004-11, Vol.10 (22), p.7757-7763
• Main Authors: Oliver, Christopher L, Bauer, Joshua A, Wolter, Keith G, Ubell, Mathew L, Narayan, Ajita, O'Connell, Kathleen M, Fisher, Susan G, Wang, Shaomeng, Wu, Xihan, Ji, Min, Carey, Thomas E, Bradford, Carol R
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Apoptosis; bcl-X Protein; Biological and medical sciences; Blotting, Western; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dimerization; Dose-Response Relationship, Drug; Drug Resistance; Fibroblasts - metabolism; Gossypol - chemistry; Gossypol - pharmacology; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - pathology; Humans; In Situ Nick-End Labeling; Inhibitory Concentration 50; Medical sciences; Otorhinolaryngology (head neck, general aspects and miscellaneous); Otorhinolaryngology. Stomatology; Peptide Fragments - chemistry; Pharmacology. Drug treatments; Protein Structure, Tertiary; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins c-bcl-2 - chemistry; Proto-Oncogene Proteins c-bcl-2 - metabolism; Proto-Oncogene Proteins c-bcl-2 - pharmacology; Tetrazolium Salts - pharmacology; Thiazoles - pharmacology; Time Factors; Tumor Suppressor Protein p53 - metabolism; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-04-0551

Purpose: Bcl-x L 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-x L 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-x L 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-x L -to-Bcl-x S 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.