Abstract
The genetic mechanisms underlying cisplatin (DDP) resistance in yeast were investigated by examining the cytotoxicity of DDP toSchizosaccharomyces pombe mutants that were either hypersensitive or resistant to Cd. Despite reports that have linked glutathione (GSH) to DDP resistance in human cancer cells, we found that a mutant of S. pombe that was hypersensitive to Cd by virtue of a 15-fold reduction in GSH level and lack of phytochelatin production was as tolerant as the wild-type strain to DDP. A mutant that harbored a mutation in hmt1, the gene encoding an ATP-binding cassette-type transporter for vacuolar sequestration of a phytochelatin/Cd complex, exhibited only mild hypersensitivity to DDP even though it was 100-fold more sensitive to Cd. Overexpression ofhmt1 in wild-type or mutant cells conferred tolerance to Cd but failed to do the same for DDP. However, a strain that produced 6-fold more sulfide than wild-type cells was found to be 6-fold more resistant to DDP and twice as resistant to Cd; an association between DDP resistance and sulfide production was observed in three other strains that were examined, and overproduction of sulfide was accompanied by reduced platination of DNA. These results indicate that GSH and the GSH-derived phytochelatin peptides do not play critical roles in determining sensitivity to DDP in S. pombe but rather identify increased production of sulfide as a possible new mechanism of DDP resistance that may also be relevant to human cells.
Footnotes
- Received July 8, 1996.
- Accepted October 14, 1996.
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Send reprint requests to: Paola Perego, Ph.D., Experimental Oncology B, Istituto Nazionale Tumori, via Venezian 1, 20133 Milano, Italy. E-mail: perego{at}icil64.cilea.it
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This work was supported in part by the Associazione Italiana per la Ricerca sul Cancro (P.P.) and the United States Department of Agriculture Agricultural Research Service Project 5335–21000-009-00D (D.W.O.). This work was conducted in part by the Clayton Foundation for Research, California Division. S.B.H. is a Clayton Foundation Investigator.
- The American Society for Pharmacology and Experimental Therapeutics
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