Praeruptorin A screened by a ferrous ion probe inhibited DMT1 and ferroptosis to attenuate Doxorubicin-induced cardiomyopathy.

Autor: Li D; Wuxi School of Medicine & Wuxi Mental Health Center, Jiangnan University, Wuxi, 214122, China., Chen Y; Wuxi School of Medicine & Wuxi Mental Health Center, Jiangnan University, Wuxi, 214122, China., Zhang B; School of Pharmacy, Changzhou University, Changzhou, 213164, China., Heng X; Wuxi School of Medicine & Wuxi Mental Health Center, Jiangnan University, Wuxi, 214122, China., Yin J; Wuxi School of Medicine & Wuxi Mental Health Center, Jiangnan University, Wuxi, 214122, China., Zhao P; Wuxi School of Medicine & Wuxi Mental Health Center, Jiangnan University, Wuxi, 214122, China., Sun N; Wuxi School of Medicine & Wuxi Mental Health Center, Jiangnan University, Wuxi, 214122, China., Shao C; Wuxi School of Medicine & Wuxi Mental Health Center, Jiangnan University, Wuxi, 214122, China. Electronic address: shaochenwen@jiangnan.edu.cn.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Nov 26; Vol. 283, pp. 117108. Date of Electronic Publication: 2024 Nov 26.
DOI: 10.1016/j.ejmech.2024.117108
Abstrakt: Doxorubicin (DOX)-induced cardiomyopathy (DIC) greatly limits its clinical application of the anticancer drug. Therefore, there is an immediate necessity to undertake intervention studies to minimize DIC, encompassing the screening of regulatory compounds and delving into the underlying regulatory mechanisms. A growing body of research suggests that ferroptosis is an essential process in the development of DIC. Here, we demonstrated that DOX causes elevated iron levels in cardiomyocytes and mouse hearts, and leads to ferroptosis and cardiac insufficiency. Next, we performed high-throughput screening of a library of herbal small molecule compounds for novel compounds that inhibit ferroptosis, using Fe 2+ levels as a screening index for DIC prevention and treatment drugs. We found that Praeruptorin A (PA) was able to reduce Fe 2+ concentration in cardiomyocytes, inhibit ferroptosis, and alleviate DIC and cardiac dysfunction in mice. Concurrently, PA exhibits a synergistic effect with DOX in suppressing the proliferation of carcinoma of breast MCF-7 cell in nude mice. Mechanistically, we found that PA inhibited the expression of divalent metal transporter protein 1 (DMT1), suppressed Fe 2+ overload in cardiomyocytes, and inhibited ferroptosis, thereby alleviating DIC. Our study demonstrated the feasibility of high-throughput screening targeting the Fe 2+ concentration, and elucidated the role and mechanism of PA in alleviating DIC, which provides a new possibility.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Databáze: MEDLINE
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