title: Calcium modulation of doxorubicin cytotoxicity in yeast and human cells.
abstract: Doxorubicin is a widely used chemotherapeutic agent, but its utility is limited by cellular resistance and off-target effects. To understand the molecular mechanisms regulating chemotherapeutic responses to doxorubicin, we previously carried out a genomewide search of doxorubicin-resistance genes in Schizosaccharomyces pombe fission yeast and showed that these genes are organized into networks that counteract doxorubicin cytotoxicity. Here, we describe the identification of a subgroup of doxorubicin-resistance genes that, when disrupted, leads to reduced tolerance to exogenous calcium. Unexpectedly, we observed a suppressive effect of calcium on doxorubicin cytotoxicity, where concurrent calcium and doxorubicin treatment resulted in significantly higher cell survival compared with cells treated with doxorubicin alone. Conversely, inhibitors of voltage-gated calcium channels enhanced doxorubicin cytotoxicity in the mutants. Consistent with these observations in fission yeast, calcium also suppressed doxorubicin cytotoxicity in human breast cancer cells. Further epistasis analyses in yeast showed that this suppression of doxorubicin toxicity by calcium was synergistically dependent on Rav1 and Vph2, two regulators of vacuolar-ATPase assembly; this suggests potential modulation of the calcium-doxorubicin interaction by fluctuating proton concentrations within the cellular environment. Thus, the modulatory effects of drugs or diet on calcium concentrations should be considered in doxorubicin treatment regimes.
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|National University Health System, Singapore.
authors.forename: Thi Thuy Trang
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|National University Health System, Singapore.
authors.forename: Ying Jun
authors.initials: YJ
authors.lastname: Lim
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|National University Health System, Singapore.
authors.forename: Melanie Hui Min
authors.initials: MH
authors.lastname: Fan
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Jackson
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|National University Health System, Singapore.
authors.forename: Kim Kiat
authors.initials: KK
authors.lastname: Lim
authors.affiliation: Department of Chemistry, Faculty of Science, National University of Singapore, Singapore.
authors.forename: Wee Han
authors.initials: WH
authors.lastname: Ang
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|National University Health System, Singapore.
authors.forename: Kenneth Hon Kim
authors.initials: KH
authors.lastname: Ban
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|National University Health System, Singapore.|NUS Graduate School of Science & Engineering, National University of Singapore, Singapore.|NUS Synthetic Biology for Clinical and Technological Innovation (SynCTI), Life Sciences Institute, National University of Singapore, Singapore.
authors.forename: Ee Sin
authors.initials: ES
authors.lastname: Chen
mesh_terms: D002118:Calcium / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002470:Cell Survival; D004317:Doxorubicin / Q000633:toxicity*; D025141:Drug Resistance, Fungal / Q000235:genetics; D005800:Genes, Fungal; D006801:Humans; D061986:MCF-7 Cells; D012568:Schizosaccharomyces / Q000187:drug effects / Q000378:metabolism; D059005:Topoisomerase II Inhibitors / Q000633:toxicity*
chemical_list: D002121:Calcium Channel Blockers; D059005:Topoisomerase II Inhibitors; D004317:Doxorubicin; D002118:Calcium