Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA.
Division of Applied Mathematical Sciences, Korea University, Sejong, South Korea.
J Appl Toxicol. 2022 May;42(5):778-792. doi: 10.1002/jat.4256. Epub 2021 Oct 20.
Subclinical cardiotoxicity at low total cumulative doxorubicin (DOX) doses can manifest into cardiomyopathy in long-term cancer survivors. However, the underlying mechanisms are poorly understood. In male B6C3F mice, assessment of cardiac function by echocardiography was performed at 1, 4, 10, 17, and 24 weeks after exposure to 6, 9, 12, and 24 mg/kg total cumulative DOX doses or saline (SAL) to monitor development of delayed-onset cardiotoxicity. The 6- or 9-mg/kg total cumulative doses resulted in a significant time-dependent decline in systolic function (left ventricular ejection fraction (LVEF) and fractional shortening (FS)) during the 24-week recovery although there was not a significant alteration in % LVEF or % FS at any specific time point during the recovery. A significant decline in systolic function was elicited by the cardiotoxic cumulative DOX dose (24 mg/kg) during the 4- to 24-week period after treatment compared to SAL-treated counterparts. At 24 weeks after DOX treatment, a significant dose-related decrease in the expression of genes and proteins involved in sarcoplasmic reticulum (SR) calcium homeostasis (Ryr2 and Serca2) was associated with a dose-related increase in the transcript level of Casp12 (SR-specific apoptosis) in hearts. These mice also showed enhanced apoptotic activity in hearts indicated by a significant dose-related elevation in the number of apoptotic cardiomyocytes compared to SAL-treated counterparts. These findings collectively suggest that a steady decline in SR calcium handling and apoptosis might be involved in the development of subclinical cardiotoxicity that can evolve into irreversible cardiomyopathy later in life.
低累积总多柔比星 (DOX) 剂量下的亚临床心脏毒性可在长期癌症幸存者中表现为心肌病。然而，其潜在机制尚不清楚。在雄性 B6C3F 小鼠中，通过超声心动图评估心脏功能，在暴露于 6、9、12 和 24mg/kg 总累积 DOX 剂量或生理盐水 (SAL) 后 1、4、10、17 和 24 周进行，以监测迟发性心脏毒性的发展。尽管在恢复过程中的任何特定时间点，% LVEF 或 % FS 均未发生显著改变，但 6 或 9mg/kg 的总累积剂量导致收缩功能（左心室射血分数 (LVEF) 和分数缩短 (FS)）在 24 周的恢复期间呈现出显著的时间依赖性下降。与 SAL 处理的对应物相比，在治疗后 4 至 24 周期间，心脏毒性累积 DOX 剂量（24mg/kg）引起的收缩功能显著下降。在 DOX 治疗后 24 周，与 SAL 处理的对应物相比，与肌浆网 (SR) 钙稳态（Ryr2 和 Serca2）相关的基因和蛋白表达显著减少，与 Casp12（SR 特异性凋亡）的转录水平呈剂量相关性增加相关。这些小鼠的心脏还表现出凋亡活性增强，与 SAL 处理的对应物相比，凋亡性心肌细胞的数量呈剂量相关性增加。这些发现共同表明，SR 钙处理和细胞凋亡的稳定下降可能与亚临床心脏毒性的发展有关，这种毒性可能在以后的生活中发展为不可逆的心肌病。
