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Published on: June 9, 2021
Calcium modulation of doxorubicin cytotoxicity in yeast and human cells
Thi Thuy Trang Nguyen1,2, Ying Jun Lim1,2, Melanie Hui Min Fan1,2
1Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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.
Insights
Calcium can reduce the toxic effects of doxorubicin chemotherapy. This study found that calcium suppresses doxorubicin cytotoxicity, offering potential new therapeutic strategies for cancer treatment.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Doxorubicin is a vital chemotherapy drug, but its effectiveness is hindered by drug resistance and side effects.
- Understanding the molecular basis of doxorubicin resistance is crucial for improving cancer therapy.
Purpose of the Study:
- To identify genes involved in doxorubicin resistance in Schizosaccharomyces pombe.
- To investigate the unexpected interaction between calcium and doxorubicin cytotoxicity.
Main Methods:
- Genome-wide screening in fission yeast (Schizosaccharomyces pombe) to identify doxorubicin-resistance genes.
- Assessing cell survival under various treatment conditions (doxorubicin, calcium, channel inhibitors).
- Epistasis analysis to determine genetic interactions.
Main Results:
- A subset of doxorubicin-resistance genes, when disrupted, caused sensitivity to calcium.
- Calcium significantly suppressed doxorubicin cytotoxicity in both yeast and human breast cancer cells.
- The calcium-mediated suppression of doxorubicin toxicity involved vacuolar-ATPase assembly regulators (Rav1 and Vph2).
Conclusions:
- Calcium concentration can modulate doxorubicin efficacy, potentially offering a protective effect against its toxicity.
- The interplay between calcium, proton gradients, and doxorubicin response warrants further investigation.
- Clinical and dietary modulation of calcium levels may impact doxorubicin treatment outcomes.
