Reversal of cisplatin resistance with a BH3 mimetic, (-)-gossypol, in head and neck cancer cells: role of wild-type p53 and Bcl-xL
Authors: Shaomeng Wang
Jason Castro
Gerrit Los
Thomas E Carey
Joshua A Bauer
Jianyong Chen
Douglas K Trask
Bhavna Kumar
Julia Shin-Jung Lee
Carol R Bradford
Journal: Molecular Cancer Therapeutics (2005)
Discipline: CLINICAL MEDICINE
Keywords: Head and neck squamous cell carcinoma; p53 overexpression; cisplatin resistance; cell lines; Bcl-x(L) expression
Affiliations: Department of Pharmacology, University of Michigan, Ann Arbor, 48109-0506, USA.

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-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. 

Retracted: No

PubPeer comments:
 Subsequent STR profiling of some of the cell lines in this paper... However, more recent studies of the purported UMSCC5PT* and 10BPT* cell lines revealed that these lines, but not the parental lines contained HPV68. This suggested that a cell line mixup had occurred at some point in the cisplatin selection and a different cell line had been selected for resistance. A search of the literature showed that there was one known HPV68 positive cell line and that line was called ME180, a cervical carcinoma cell line (M. Longuet 1996). To test this, we genotyped the original ME180 cell line (also HPV68 positive), that we had in our bank, and the resistant lines (so called 5PT* and 10BPT*) and found that the resistant lines had identical genotypes to one another and this genotype did not match the genotypes of the original UMSCC5 or UMSCC10B cells, but did match the genotype of ME180 from our bank. Thus, we concluded that the cells selected for cisplatin resistance were ME180; these were designated ME180R. https: deepblue.lib.umich.edu bitstream handle 2027.42 63988 saun?sequence=1 ,