Response by Dhingra et al to Letter Regarding Article, "Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy".
Response by Dhingra et al to Letter Regarding Article, "Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy".
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Dhingra 等人对有关文章“TRAF2 的蛋白酶体降解介导多柔比星心肌病中的线粒体功能障碍”的信件的回应。
DOI：
10.1161/circulationaha.123.063546
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发表时间：
2023
期刊：
影响因子：
37.8
通讯作者：
Kirshenbaum,LorrieA
中科院分区：
文献类型：
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作者：
Dhingra,Rimpy;Javaheri,Ali;Diwan,Abhinav;Kirshenbaum,LorrieA
我们感谢施博士等人对我们文章的兴趣。1我们感谢他们的评论和讨论。蒽环类药物如阿霉素被广泛用于治疗人类癌症;它们诱导心力衰竭的倾向是一种公认但知之甚少的现象。肿瘤坏死因子受体相关因子2（TRAF 2）是NF-κB（活化B细胞的核因子κ轻链增强子）活化的平台，在癌症患者以及小鼠和人诱导多能干细胞衍生的心肌细胞的心脏组织中，阿霉素治疗后TRAF 2降解，导致广泛的细胞死亡和心功能障碍。相反，TRAF 2功能的获得抑制了阿霉素在体外和体内的心脏毒性作用。1尽管如此，本研究并未研究TRAF 2对阿霉素抗肿瘤特性的净影响，值得进一步在荷瘤小鼠模型中进行研究。多柔比星心脏毒性的最佳疗法不会影响或会增强多柔比星的疗效。尽管一些关于TRAF 2的研究表明其致癌潜力，但在其他情况下，TRAF 2可以作为肿瘤抑制因子。2因此，TRAF 2的作用可能具有肿瘤特异性。关于阿霉素的体外和体内给药，在重述癌症患者体内经历的阿霉素治疗的确切剂量和持续时间方面存在一些挑战（根据肿瘤类型而异）。在细胞培养中，由于与持续数周的慢性体内研究或可能需要数年时间才能形成的临床表现相比，维持原代心肌细胞在培养中存活的急性性质，其变得更具挑战性。其他问题包括与患者体内分布容积和药代动力学相关的假设，以及临床使用的药物本身稳定性的差异
We thank Drs Shi et al for their interest in our article. 1 We appreciate their comments and discussion. Anthracyclines such as doxorubicin are used widely for treating human cancers; their propensity for inducing heart failure is a well-established but poorly understood phenomenon. TRAF2 (tumor necrosis factor receptorassociated factor 2), which serves as a platform for NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation, was degraded in cardiac tissue of patients with cancer and mouse and human induced pluripotent stem cell–derived cardiac myocytes after doxorubicin treatment, resulting in widespread cell death and cardiac dysfunction. Conversely, gain of function of TRAF2 suppressed the cardiotoxic effects of doxorubicin in vitro and in vivo. 1 Nevertheless, the net effect of TRAF2 on the antineoplastic properties of doxorubicin was not investigated in this study and warrants future investigation in tumor-bearing mouse models. Optimal therapies for doxorubicin cardiotoxicity either would not affect or would enhance doxorubicin antineoplastic efficacy. Whereas some studies on TRAF2 suggest its oncogenic potential, in other contexts TRAF2 can act as a tumor suppressor. 2 Hence, the effect of TRAF2 may be tumor-specific.With respect to in vitro and in vivo dosing of doxorubicin, there are several challenges in recapitulating the exact dose and duration of doxorubicin treatment that patients with cancer experience in vivo (which varies with tumor type). In cell culture, it becomes even more challenging because of the acute nature of maintaining primary cardiac myocytes viable in culture, as compared with chronic in vivo studies lasting weeks, or the clinical manifestations that can take years to develop. Other issues include assumptions related to volume of distribution and pharmacokinetics in patients and differences in the stability of the drug itself as used clinically