Transcriptional response pathways in a yeast strain sensitive to saframycin a and a more potent analog: evidence for a common basis of activity.
Saframycin A (SafA) is a natural product that inhibits human cancer cell proliferation. Its synthetic analog, QAD, is a more potent inhibitor of these cells. SafA does not affect wild-type yeast, but it does inhibit growth of the strain CCY333 (DeltaPDR1/PDR3/ERG6) (IC50 = 0.9 microM). QAD is also a more effective inhibitor of CCY333 growth (IC50 = 0.4 microM). Transcription profiling of SafA- and QAD-treated CCY333 cultures showed that both drugs generated nearly identical profiles, with altered expression levels (> or =2-fold) of more than 240 genes. Both agents induced the overexpression of genes involved in glycolysis, oxidative stress, and protein degradation and repressed genes encoding histones, biosynthetic enzymes, and the cellular import machinery. Significantly, neither drug affected the expression of known DNA-damage repair genes, as might have been expected if their primary mechanism of action involved the covalent modification of DNA.
Plowright
Alleyn T
AT
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
Schaus
Scott E
SE
Myers
Andrew G
AG
D000105:Acetyl Coenzyme A / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D004271:DNA, Fungal / Q000032:analysis / Q000235:genetics / Q000302:isolation & purification; D004149:Dioxoles / Q000494:pharmacology; D005227:Fatty Acids / Q000096:biosynthesis; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism*; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D016681:Genome, Fungal; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D011804:Quinolines / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D004271:DNA, Fungal; D004149:Dioxoles; D005227:Fatty Acids; D005656:Fungal Proteins; D007546:Isoquinolines; D011804:Quinolines; D044005:Tetrahydroisoquinolines; D000105:Acetyl Coenzyme A; D000077606:Trabectedin; C026925:saframycin A; C008898:quinaldic acid; D020123:Sirolimus