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Departments of ¹ Pharmacology, ² Otolaryngology-Head and Neck Surgery, and ³ Internal Medicine and Medicinal Chemistry; ⁴ Biostatistics Unit; and ⁵ University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan; and ⁶ Pfizer Global Research and Development, La Jolla, California

Requests for reprints: Thomas E. Carey, Department of Otolaryngology, University of Michigan, 6020 KHRI, 1301 East Ann Street, Ann Arbor, MI 48109-0506. Phone: 734-764-4371; Fax: 734-764-0014. E-mail: careyte{at}umich.edu

Organ preservation protocols in head and neck squamous cell carcinoma (HNSCC) are limited by tumors that fail to respond. We observed that larynx preservation and response to chemotherapy is significantly associated with p53 overexpression, and that most HNSCC cell lines with mutant p53 are more sensitive to cisplatin than those with wild-type p53. To investigate cisplatin resistance, we studied two HNSCC cell lines, UM-SCC-5 and UM-SCC-10B, and two resistant sublines developed by cultivation in gradually increasing concentrations of cisplatin. The cisplatin-selected cell lines, UM-SCC-5PT and UM-SCC-10BPT, are 8 and 1.5 times more resistant to cisplatin than the respective parental cell lines, respectively. The parental lines overexpress p53 and contain p53 mutations but the cisplatin-resistant cell lines do not, indicating that cells containing mutant p53 were eliminated during selection. Bcl-x_L expression increased in the cisplatin-resistant lines relative to the parental lines, whereas Bcl-2 expression was high in the parental lines and decreased in the cisplatin-resistant lines. Thus, cisplatin selected for wild-type p53 and high Bcl-x_L expression in these cells. We tested a small-molecule BH3 mimetic, (–)-gossypol, which binds to the BH3 domain of Bcl-2 and Bcl-x_L, for activity against the parental and cisplatin-resistant cell lines. At physiologically attainable levels, (–)-gossypol induces apoptosis in 70% to 80% of the cisplatin-resistant cells but only in 25% to 40% of the parental cells. Thus, cisplatin-resistant cells seem to depend on wild-type p53 and Bcl-x_L for survival and BH3 mimetic agents, such as (–)-gossypol, may be useful adjuncts to overcome cisplatin resistance in HNSCC.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: D.K. Trask is currently in the Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, Iowa.

⁷ Unpublished observations.

Received 3/21/05; revised 4/27/05; accepted 5/ 4/05.