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The sGC-cGMP Signaling Pathway as a Potential Therapeutic Target in Doxorubicin-Induced Heart Failure: A Narrative Review

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Abstract

The anti-cancer agent doxorubicin (DOX) has high cardiotoxicity that is linked to DOX-mediated increase in oxidative stress, mitochondrial iron overload, DNA damage, autophagy, necrosis, and apoptosis, all of which are also associated with secondary tumorigenicity. This limits the clinical application of DOX therapies. Previous studies have attributed DOX-mediated cardiotoxicity to mitochondrial iron accumulation and the production of reactive oxygen species (ROS), which seem to be independent of its anti-tumor DNA damaging effects. Chemo-sensitization of soluble guanylate cyclase (sGC) in the cyclic guanosine monophosphate (cGMP) pathway induces tumor cell death despite the cardiotoxicity associated with DOX treatment. However, sGC–cGMP signaling must be activated during heart failure to facilitate myocardial cell survival. The sGC pathway is dependent on nitric oxide and signal transduction via the nitric oxide–sGC–cGMP pathway and is attenuated in various cardiovascular diseases. Additionally, cGMP signaling is regulated by the action of certain phosphodiesterases (PDEs) that protect the heart by inhibiting PDE, an enzyme that hydrolyses cGMP to GMP activity. In this review, we discuss the studies describing the interactions between cGMP regulation and DOX-mediated cardiotoxicity and their application in improving DOX therapeutic outcomes. The results provide novel avenues for the reduction of DOX-induced secondary tumorigenicity and improve cellular autonomy during DOX-mediated cardiotoxicity.

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Acknowledgements

We would like to acknowledge the contributions of each of our team members, as without their individual contributions, this article would not have reached fruition.

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Authors and Affiliations

  1. Division of Cardiology, Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University, 23, Kyung Hee Dae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea

    Haneul Cho, Sora Lee, Jong Shin Woo, Min-Young Song & Weon Kim

  2. Division of Cardiology, Department of Intensive Medical, Taizhou Hospital, Taizhou, Zhejiang Province, China

    Xiao-Xiao Zhao

  3. Department of Cardiology and Hypertension, Yanbian University Hospital, Yanji, China

    Xian Wu Cheng

  4. Department of Biotechnology, Cha University, Pocheon, Republic of Korea

    Kyung Hye Lee

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  1. Haneul Cho
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  4. Jong Shin Woo
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Correspondence to Weon Kim.

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Funding

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and Future Planning (2017R1C1B5075748) with additional funding from the Ministry of Education (2020R1F1A1076495).

Competing interests

Haneul Cho, Xiao–Xiao Zhao, Sora Lee, Jong Shin Woo, Min-Young Song, Xian Wu Cheng, Kyung Hye Lee, and Weon Kim declare no relationship with industry or other relevant entities that might pose a conflict of interest in connection with this article.

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HC and XXZ participated in drafting the manuscript. SL participated in acquisition of data and table creation. JSW supported research funding. MYS and KHL participated in concept design and analysis. XWC participated in critical revision of the manuscript for important intellectual content. WK participated in analysis as a supervisor. All authors read and approved the final manuscript.

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Cho, H., Zhao, XX., Lee, S. et al. The sGC-cGMP Signaling Pathway as a Potential Therapeutic Target in Doxorubicin-Induced Heart Failure: A Narrative Review. Am J Cardiovasc Drugs 22, 117–125 (2022). https://doi.org/10.1007/s40256-021-00487-5

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