Abstract
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-xL 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-xL expression in these cells. We tested a small-molecule BH3 mimetic, (−)-gossypol, which binds to the BH3 domain of Bcl-2 and Bcl-xL, 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-xL for survival and BH3 mimetic agents, such as (−)-gossypol, may be useful adjuncts to overcome cisplatin resistance in HNSCC.
- cisplatin
- drug resistance
- p53
- Bcl-xL
- apoptosis
Footnotes
↵7 Unpublished observations.
Grant support: NIH through University of Michigan Head and Neck Cancer Specialized Programs of Research Excellence grant P50 CA97248, University of Michigan Comprehensive Cancer Center National Cancer Institute core grant P30 CA46592, NIH National Institute on Deafness and Other Communication Disorders grant P30 DC05188, and National Institute of Dental and Craniofacial Research DE13346 (T.E. Carey), NIH National Cancer Institute grant CA83087 (C.R. Bradford), Department of Defense grant BC000914 (S. Wang), NIH/National Institute of General Medical Sciences GM07767 (J.A. Bauer), and 5 T32 DC00011 (J.A. Bauer).
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.
- Accepted May 4, 2005.
- Received March 21, 2005.
- Revision received April 27, 2005.
- American Association for Cancer Research
Volume 4, Issue 7
