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The sGC-cGMP Signaling Pathway as a Potential Therapeutic Target in Doxorubicin-Induced Heart Failure: A Narrative Review
American Journal of Cardiovascular Drugs ( IF 2.8 ) Pub Date : 2021-06-21 , DOI: 10.1007/s40256-021-00487-5
Haneul Cho 1 , Xiao-Xiao Zhao 2 , Sora Lee 1 , Jong Shin Woo 1 , Min-Young Song 1 , Xian Wu Cheng 3 , Kyung Hye Lee 4 , Weon Kim 1
Affiliation  

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.



中文翻译:

sGC-cGMP 信号通路作为阿霉素诱导的心力衰竭的潜在治疗靶点:叙述性综述

抗癌剂多柔比星 (DOX) 具有高心脏毒性,这与 DOX 介导的氧化应激增加、线粒体铁过载、DNA 损伤、自噬、坏死和细胞凋亡有关,所有这些也与继发性致瘤性有关。这限制了 DOX 疗法的临床应用。先前的研究将 DOX 介导的心脏毒性归因于线粒体铁的积累和活性氧 (ROS) 的产生,这似乎与其抗肿瘤 DNA 损伤作用无关。尽管与 DOX 治疗相关的心脏毒性,环磷酸鸟苷 (cGMP) 途径中可溶性鸟苷酸环化酶 (sGC) 的化学增敏作用会诱导肿瘤细胞死亡。然而,在心力衰竭期间必须激活 sGC-cGMP 信号以促进心肌细胞存活。sGC 通路依赖于一氧化氮和通过一氧化氮-sGC-cGMP 通路的信号转导,并在各种心血管疾病中减弱。此外,cGMP 信号传导受某些磷酸二酯酶 (PDE) 的作用调节,这些磷酸二酯酶 (PDE) 通过抑制 PDE 来保护心脏,PDE 是一种将 cGMP 水解为 GMP 活性的酶。在这篇综述中,我们讨论了描述 cGMP 调节和 DOX 介导的心脏毒性之间相互作用的研究,以及它们在改善 DOX 治疗结果中的应用。该结果为减少 DOX 诱导的继发性致瘤性和改善 DOX 介导的心脏毒性过程中的细胞自主性提供了新途径。cGMP 信号传导受某些磷酸二酯酶 (PDE) 的作用调节,这些磷酸二酯酶 (PDE) 通过抑制 PDE 来保护心脏,PDE 是一种将 cGMP 水解为 GMP 活性的酶。在这篇综述中,我们讨论了描述 cGMP 调节和 DOX 介导的心脏毒性之间相互作用的研究,以及它们在改善 DOX 治疗结果中的应用。该结果为减少 DOX 诱导的继发性致瘤性和改善 DOX 介导的心脏毒性过程中的细胞自主性提供了新途径。cGMP 信号传导受某些磷酸二酯酶 (PDE) 的作用调节,这些磷酸二酯酶 (PDE) 通过抑制 PDE 来保护心脏,PDE 是一种将 cGMP 水解为 GMP 活性的酶。在这篇综述中,我们讨论了描述 cGMP 调节和 DOX 介导的心脏毒性之间相互作用的研究,以及它们在改善 DOX 治疗结果中的应用。该结果为减少 DOX 诱导的继发性致瘤性和改善 DOX 介导的心脏毒性过程中的细胞自主性提供了新途径。

更新日期:2021-06-21
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