Hofmann Polly A, Israel Mervyn, Koseki Yoshihiro, Laskin Jeffrey, Gray Joshua, Janik Aleksandra, Sweatman Trevor W, Lothstein Leonard
Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
J Pharmacol Exp Ther. 2007 Nov;323(2):658-64. doi: 10.1124/jpet.107.126110. Epub 2007 Aug 10.
N-Benzyladriamycin-14-valerate (AD 198) is one of several novel anthracycline protein kinase C (PKC)-activating agents developed in our laboratories that demonstrates cytotoxic superiority over doxorubicin (Adriamycin; DOX) through its circumvention of multiple mechanisms of drug resistance. This characteristic is attributed at least partly to the principal cellular action of AD 198: PKC activation through binding to the C1b (diacylglycerol binding) regulatory domain. A significant dose-limiting effect of DOX is chronic, dose-dependent, and often irreversible cardiotoxicity ascribed to the generation of reactive oxygen species (ROS) from the semiquinone ring structure of DOX. Despite the incorporation of the same ring structure in AD 198, we hypothesized that AD 198 might also be cardioprotective through its ability to activate PKC-epsilon, a key component of protective ischemic preconditioning in cardiomyocytes. Chronic administration of fractional LD(50) doses of DOX and AD 198 to mice results in histological evidence of dose-dependent ventricular damage by DOX but is largely absent from AD 198-treated mice. The absence of significant cardiotoxicity with AD 198 occurs despite the equal ability of DOX and AD 198 to generate ROS in primary mouse cardiomyocytes. Excised rodent hearts perfused with AD 198 prior to hypoxia induced by vascular occlusion are protected from functional impairment to an extent comparable to preconditioning ischemia. AD 198-mediated cardioprotection correlates with increased PKC-epsilon activation and is inhibited in hearts from PKC-epsilon knockout mice. These results suggest that, despite ROS production, the net cardiac effect of AD 198 is protection through activation of PKC-epsilon.
N-苄基阿霉素-14-戊酸酯（AD 198）是我们实验室研发的几种新型蒽环类蛋白激酶C（PKC）激活剂之一，它通过规避多种耐药机制，显示出比阿霉素（多柔比星；DOX）更强的细胞毒性。这一特性至少部分归因于AD 198的主要细胞作用：通过与C1b（二酰基甘油结合）调节域结合来激活PKC。DOX的一个显著剂量限制效应是慢性、剂量依赖性且通常不可逆的心脏毒性，这归因于DOX半醌环结构产生的活性氧（ROS）。尽管AD 198中含有相同的环结构，但我们推测AD 198可能也具有心脏保护作用，因为它能够激活PKC-ε，而PKC-ε是心肌细胞保护性缺血预处理的关键组成部分。对小鼠长期给予分次LD(50)剂量的DOX和AD 198，结果显示DOX导致了剂量依赖性的心室损伤组织学证据，但在接受AD 198治疗的小鼠中基本没有出现。尽管DOX和AD 198在原代小鼠心肌细胞中产生ROS的能力相同，但AD 198并未出现明显的心脏毒性。在血管闭塞诱导缺氧之前用AD 198灌注的离体啮齿动物心脏，其功能损伤得到了一定程度的保护，保护程度与预处理缺血相当。AD 198介导的心脏保护作用与PKC-ε激活增加相关，并且在PKC-ε基因敲除小鼠的心脏中受到抑制。这些结果表明，尽管会产生ROS，但AD 198对心脏的总体作用是通过激活PKC-ε来实现保护。
