Identification of genetic factors modulating doxorubicin-associated cytotoxicity by calcium

OBJECTIVE To examine the effect of calcium on the response towards doxorubicin,a widely used chemotherapeutic agent in the clinic,using fission yeast(Schizosaccharomycespombe)and human cancer cells(MCF7)This project built on a previously performed genome-wide search of doxorubicin-resistance(DXR)genes in Schizosaccharomycespombefission yeast,which identified a host of genes that counteracted doxorubicin cytotoxicity.METHODS Growth fitness of Schizosaccharomycespombe knock-out mutants of doxorubicin-resistance genes were tested on varying concentrations of calcium,doxorubicin or calcium+doxorubicin.Similar growth fitness experiments were also performed on MCF7 breast cancer cells.RESULTS We found that a subset of null mutants of DXR genes show concurrent hypersensitivity to calcium and doxorubicin.Interestingly,their hypersensitivity towards doxorubicinwas suppressed by calcium.This phenotype was dependent on the integrity of the proton pump vacuolar-ATPase(V-ATPase)as the disruption of the V-ATPase-assembly factors(Rav1 and Vph2)abolished the suppressive effect of calcium.CONCLUSION Our findings uncovered an unexpected negative regulation of chemotherapeutic drug efficacy by dietary micronutrient that may caution against the concurrent consumption of calcium-rich dietary products alongside doxorubicin treatment.