Abstract
Anthracyclines such as doxorubicin (Dox) are widely used to treat a variety of adult and childhood cancers, however, a major limitation to many of these compounds is their propensity for inducing heart failure. A naturally occurring polyphenolic compound such as Ellagic acid (EA) has been shown by our laboratory to mitigate the cardiotoxic effects of Dox, however, the effects of EA on cancer cell viability have not been established. In this study, we explored the effects of EA alone and in combination with Dox on cancer cell viability and tumorigenesis. Herein, we show that EA induces cell cycle exit and reduces proliferation in colorectal cancer (HCT116) and breast adenocarcinoma cells (MCF7). We show that EA promotes cell cycle exit by a mechanism that inhibits mitochondrial dynamics protein Drp-1. EA treatment of HCT116 and MCF7 cells resulted in a hyperfused mitochondrial morphology that coincided with mitochondrial perturbations including loss of mitochondrial membrane potential, impaired respiratory capacity. Moreover, impaired mitochondrial function was accompanied by a reduction in cell cycle and proliferation markers, CDK1, Ki67, and Cyclin B. This resulted in a reduction in proliferation and widespread death of cancer cells. Furthermore, while Dox treatment alone promoted cell death in both HCT116 and MCF7 cancer cell lines, EA treatment lowered the effective dose of Dox to promote cell death. Hence, the findings of the present study reveal a previously unreported anti-tumor property of EA that impinges on mitochondrial dynamics protein, Drp-1 which is crucial for cell division and tumorigenesis. The ability of EA to lower the therapeutic threshold of Dox for inhibiting cancer cell growth may prove beneficial in reducing cardiotoxicity in cancer patients undergoing anthracycline therapy.
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Acknowledgements
We thank Ben Margulets and Floribeth Aguilar for technical assistance.
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This work was supported by a Foundation grant (Grant No. FRN-42402) to L.A.K from the Canadian Institute for Health Research (CIHR), L.A.K. holds a Canada Research Chair in Molecular Cardiology. S.Y received B.Sc. Med studentship award from Max Rady College of Medicine.
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SY, RD, VM, AD, and LAK: conceived and wrote the paper. SY, RD, VM, AD, and MC: designed, performed, and analyzed the experiments. All the authors reviewed and approved the final version of the manuscript.
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Yakobov, S., Dhingra, R., Margulets, V. et al. Ellagic acid inhibits mitochondrial fission protein Drp-1 and cell proliferation in cancer. Mol Cell Biochem 478, 2029–2040 (2023). https://doi.org/10.1007/s11010-022-04627-6
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DOI: https://doi.org/10.1007/s11010-022-04627-6