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To understand the molecular mechanisms regulating chemotherapeutic responses to doxorubicin, we previously carried out a genomewide search of doxorubicin\u2010resistance genes in <jats:italic>Schizosaccharomyces pombe<\/jats:italic> 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\u2010resistance 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\u2010gated 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\u2010<jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>ase assembly; this suggests potential modulation of the calcium\u2013doxorubicin 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.<\/jats:p>","DOI":"10.1111\/gtc.12346","type":"journal-article","created":{"date-parts":[[2016,2,20]],"date-time":"2016-02-20T11:53:10Z","timestamp":1455969190000},"page":"226-240","source":"Crossref","is-referenced-by-count":17,"title":["Calcium modulation of doxorubicin cytotoxicity in yeast and human cells"],"prefix":"10.1111","volume":"21","author":[{"given":"Thi Thuy Trang","family":"Nguyen","sequence":"first","affiliation":[{"name":"Department of Biochemistry Yong Loo Lin School of Medicine National University of Singapore Singapore"},{"name":"National University Health System Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying Jun","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Yong Loo Lin School of Medicine National University of Singapore Singapore"},{"name":"National University 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