RT Journal Article SR Electronic T1 The Anticancer Ruthenium Complex KP1019 Induces DNA Damage, Leading to Cell Cycle Delay and Cell Death in Saccharomyces cerevisiae JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.112.079657 DO 10.1124/mol.112.079657 A1 Shannon K. Stevens A1 Amy P. Strehle A1 Rebecca L. Miller A1 Sarah H. Gammons A1 Kyle J. Hoffman A1 John T. McCarty A1 Mary E. Miller A1 Laura K. Stultz A1 Pamela K. Hanson YR 2012 UL http://molpharm.aspetjournals.org/content/early/2012/10/22/mol.112.079657.abstract AB The anticancer ruthenium complex trans-[tetrachlorobis(1H-indazole)ruthenate(III)], otherwise known as KP1019, has previously been shown to inhibit proliferation of ovarian tumor cells, induce DNA damage and apoptosis in colon carcinoma cells, and reduce tumor size in animal models. Notably, no dose-limiting toxicity was observed in a Phase I clinical trial. Despite these successes, KP1019's precise mechanism of action remains poorly understood. To determine whether Saccharomyces cerevisiae might serve as an effective model for characterizing the cellular response to KP1019, we first confirmed that this drug is internalized by yeast and induces mutations, cell cycle delay, and cell death. We next examined KP1019 sensitivity of strains defective in DNA repair, ultimately showing that rad1Δ, rev3Δ, and rad52Δ yeast are hypersensitive to KP1019, suggesting that nucleotide excision repair, translesion synthesis, and recombination each play a role in drug tolerance. These data are consistent with published work showing that KP1019 causes interstrand crosslinks and bulky DNA adducts in mammalian cell lines. Published research also showed that mammalian cell lines resistant to other chemotherapeutic agents exhibit only modest resistance, and sometimes hypersensitivity, to KP1019. Here we report similar findings for S. cerevisiae. Whereas gain-of-function mutations in the transcription activator-encoding gene PDR1 are known to increase expression of drug pumps, causing resistance to structurally diverse toxins, we now demonstrate that KP1019 retains its potency against yeast carrying the hypermorphic alleles PDR1-11 or PDR1-3. Combined, these data suggest that S. cerevisiae could serve as an effective model system for identifying evolutionarily conserved modulators of KP1019 sensitivity.