title: The anticancer ruthenium complex KP1019 induces DNA damage, leading to cell cycle delay and cell death in Saccharomyces cerevisiae.
abstract: 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.
authors.affiliation: Department of Biology, Birmingham-Southern College, 900 Arkadelphia Rd. Birmingham, AL 35254, USA.
authors.forename: Shannon K
authors.initials: SK
authors.lastname: Stevens
authors.forename: Amy P
authors.initials: AP
authors.lastname: Strehle
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Miller
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Gammons
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Hoffman
authors.forename: John T
authors.initials: JT
authors.lastname: McCarty
authors.forename: Mary E
authors.initials: ME
authors.lastname: Miller
authors.forename: Laura K
authors.initials: LK
authors.lastname: Stultz
authors.forename: Pamela K
authors.initials: PK
authors.lastname: Hanson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D025141:Drug Resistance, Fungal; D007191:Indazoles / Q000494:pharmacology*; D009942:Organometallic Compounds / Q000494:pharmacology*; D017975:Ruthenium Compounds; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology; D051758:Transcription Factor TFIIH / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D007191:Indazoles; D009942:Organometallic Compounds; C085480:PDR1 protein, S cerevisiae; D017975:Ruthenium Compounds; C489575:SSL2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors; C499292:indazolium trans-(tetrachlorobis(1H-indazole)ruthenate (III)); D051758:Transcription Factor TFIIH; D004265:DNA Helicases; D004250:DNA Topoisomerases, Type II