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 (NER), translesion synthesis (TLS), and recombination each play a role in drug tolerance. These data are consistent with published work showing that
KP1019 causes interstrand cross-links 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.