Hydropersulfides (RSSH) attenuate doxorubicin-induced cardiotoxicity while boosting its anticancer action

Author:

Pharoah, Blaze M

Zhang, Chengximeng

Khodade, Vinayak S

Keceli, Gizem

McGinity,Chris

Paolocci, Nazareno

Toscano, John P
Author Address

Department of Chemistry, Johns Hopkins University, Baltimore, MD 21218, United States., Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States., Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, United States., Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States; Department of Biomedical Sciences, University of Padova, Padova, Italy. Electronic address: npaoloc1@jhmi.edu., Department of Chemistry, Johns Hopkins University, Baltimore, MD 21218, United States. Electronic address: jtoscano@jhu.edu.,

Abstract:

Cardiotoxicity is a frequent and often lethal complication of doxorubicin (DOX)-based chemotherapy. Here, we report that hydropersulfides (RSSH) are the most effective reactive sulfur species in conferring protection against DOX-induced toxicity in H9c2 cardiac cells. Mechanistically, RSSH supplementation alleviates the DOX-evoked surge in reactive oxygen species (ROS), activating nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent pathways, thus boosting endogenous antioxidant defenses. Simultaneously, RSSH turns on peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a), a master regulator of mitochondrial function, while decreasing caspase-3 activity to inhibit apoptosis. Of note, we find that RSSH potentiate anticancer DOX effects in three different cancer cell lines, with evidence that suggests this occurs via induction of reductive stress. Indeed, cancer cells already exhibit much higher basal hydrogen sulfide (H2S), sulfane sulfur, and reducing equivalents compared to cardiac cells. Thus, RSSH may represent a new promising avenue to fend off DOX-induced cardiotoxicity while boosting its anticancer effects. Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.

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