Nakamura Yoshihide, Yamamoto Takeshi, Kobayashi Shigeki, Suetomi Takeshi, Uchinoumi Hitoshi, Oda Tetsuro, Sano Motoaki, Yano Masafumi
Department of Therapeutic Science for Heart Failure in the Elderly, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Faculty of Health Sciences, Yamaguchi University Graduate School of Medicine, Ube, Japan.
JACC CardioOncol. 2024 Dec 10;7(1):38-52. doi: 10.1016/j.jaccao.2024.10.011. eCollection 2025 Jan.
Doxorubicin (DOX), a commonly used anticancer agent, can result in cardiac dysfunction, presenting a significant clinical challenge. DOX has been shown to induces Ca leakage via the ryanodine receptor 2 (RYR2) of the sarcoplasmic reticulum, increasing Ca levels in the cytoplasm.
This study investigated whether stabilizing RYR2 could suppress DOX-induced cardiomyopathy (DIC) and identified the optimal duration of dantrolene treatment as a pharmacological method.
We investigated the effects of RYR2 stabilization on DOX cardiotoxicity using in vivo and in vitro experiments.
DOX administration caused calmodulin dissociation, marked Ca leakage from RYR2, and increased oxidative stress in isolated cardiomyocytes. Stabilizing the RYR2 tetramer-either pharmacologically with dantrolene or genetically via RYR2 V3599K mutation, which enhances calmodulin binding affinity-suppressed these effects. In DIC mice models, DOX impaired cardiac function, increased fibrosis and TUNEL-positive cells, reduced GRP78, and elevated lipid peroxide levels, leading to endoplasmic reticulum stress and ferroptosis. Both continuous dantrolene treatment and RYR2 V3599K mutation improved cardiac function. Interestingly, dantrolene administration provided myocardial protection even when terminated 7 days after DOX.
Short-term concomitant use of dantrolene offers a promising and clinically feasible strategy to prevent DIC. Given dantrolene's established clinical safety as a treatment for malignant hyperthermia, these findings suggest potential for repositioning dantrolene in DIC prevention.
阿霉素（DOX）是一种常用的抗癌药物，可导致心脏功能障碍，这是一个重大的临床挑战。已表明DOX可通过肌浆网的兰尼碱受体2（RYR2）诱导钙泄漏，增加细胞质中的钙水平。
本研究调查稳定RYR2是否能抑制DOX诱导的心肌病（DIC），并确定丹曲林治疗作为一种药理学方法的最佳持续时间。
我们使用体内和体外实验研究RYR2稳定对DOX心脏毒性的影响。
给予DOX导致钙调蛋白解离、显著的RYR2钙泄漏以及分离的心肌细胞中氧化应激增加。稳定RYR2四聚体——无论是通过丹曲林进行药理学稳定还是通过RYR2 V3599K突变进行基因稳定，后者可增强钙调蛋白结合亲和力——均可抑制这些效应。在DIC小鼠模型中，DOX损害心脏功能，增加纤维化和TUNEL阳性细胞，降低GRP78，并提高脂质过氧化物水平，导致内质网应激和铁死亡。持续的丹曲林治疗和RYR2 V3599K突变均改善了心脏功能。有趣的是，即使在DOX给药7天后终止丹曲林给药，仍能提供心肌保护。
短期联合使用丹曲林为预防DIC提供了一种有前景且临床可行的策略。鉴于丹曲林作为恶性高热治疗药物已确立的临床安全性，这些发现表明丹曲林在预防DIC方面重新定位具有潜力。
