Details

Autor(en) / Beteiligte

• Nguyen, Thi Thuy Trang
• Lim, Ying Jun
• Fan, Melanie Hui Min
• Jackson, Rebecca A.
• Lim, Kim Kiat
• Ang, Wee Han
• Ban, Kenneth Hon Kim
• Chen, Ee Sin

Titel

Calcium modulation of doxorubicin cytotoxicity in yeast and human cells

Ist Teil von

• Genes to cells : devoted to molecular & cellular mechanisms, 2016-03, Vol.21 (3), p.226-240

Ort / Verlag

England: Wiley Subscription Services, Inc

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. Suppression of doxorubicin cytotoxicity by calcium in human breast cancer cells.