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Thioredoxin Decreases Anthracycline Cardiotoxicity, But Sensitizes Cancer Cell Apoptosis

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Abstract

Cardiotoxicity is a major limitation for anthracycline chemotherapy although anthracyclines are potent antitumor agents. The precise mechanism underlying clinical heart failure due to anthracycline treatment is not fully understood, but is believed to be due, in part, to lipid peroxidation and the generation of free radicals by anthracycline-iron complexes. Thioredoxin (Trx) is a small redox-active antioxidant protein with potent disulfide reductase properties. Here, we present evidence that cancer cells overexpressing Trx undergo enhanced apoptosis in response to daunomycin. In contrast, cells overexpressing redox-inactive mutant Trx were not effectively killed. However, rat embryonic cardiomyocytes (H9c2 cells) overexpressing Trx were protected against daunomycin-mediated apoptosis, but H9c2 cells with decreased levels of active Trx showed enhanced apoptosis in response to daunomycin. We further demonstrate that increased level of Trx is specifically effective in anthracycline toxicity, but not with other topoisomerase II inhibitors such as etoposide. Collectively these data demonstrate that whereas high levels of Trx protect cardiomyocytes against anthracycline toxicity, it potentiates toxicity of anthracyclines in cancer cells.

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Funding

The study was funded by National Institutes of Health Grant Number HL107885, HL109397, HL132953.

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Authors and Affiliations

  1. Department of Internal Medicine, Texas Tech University Health Sciences Center, 3601 4th Street, MS 6598, Lubbock, TX 79430, USA

    Kumuda C. Das, Harish Muniyappa, Venkatesh Kundumani-Sridharan & Jaganathan Subramani

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  1. Kumuda C. Das
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  2. Harish Muniyappa
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  3. Venkatesh Kundumani-Sridharan
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  4. Jaganathan Subramani
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Contributions

KD conceptualized the idea, designed the study, wrote manuscript, performed experiments; HM performed experiments; VK-S performed experiments; JS performed experiments.

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Correspondence to Kumuda C. Das.

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All authors declare that they have no conflicts of interest.

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Handling editor: Vittorio Fineschi.

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Das, K.C., Muniyappa, H., Kundumani-Sridharan, V. et al. Thioredoxin Decreases Anthracycline Cardiotoxicity, But Sensitizes Cancer Cell Apoptosis. Cardiovasc Toxicol 21, 142–151 (2021). https://doi.org/10.1007/s12012-020-09605-2

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  • DOI: https://doi.org/10.1007/s12012-020-09605-2

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