Abstract:
Since its discovery in the 1960 s, doxorubicin (DOX) has constantly elicited the broadest spectrum of cancerocidal activity against human cancers. However, cardiotoxicity caused by DOX directly as well as its metabolites is a great source of concern over the continuous use of DOX in chemotherapy. While the exact mechanism of DOX-induced cardiotoxicity is yet to be completely understood, recent studies indicate oxidative stress, inflammation, and several forms of cell death as key pathogenic mechanisms that underpin the etiology of doxorubicin-induced cardiotoxicity (DIC). Notably, these key mechanistic events are believed to be negatively regulated by 3,4-dihydroxybenzoic acid or protocatechuic acid (PCA)-a plant-based phytochemical with proven anti-oxidant, anti-inflammatory, and anti-apoptotic properties. Here, we review the experimental findings detailing the potential ameliorative effects of PCA under exposure to DOX. We also discuss molecular insights into the pathophysiology of DIC, highlighting the potential intervention points where the use of PCA as a veritable chemoprotective agent may ameliorate DOX-induced cardiotoxicities as well as toxicities due to other anticancer drugs like cisplatin. While we acknowledge that controlled oral administration of PCA during chemotherapy may be insufficient to eliminate all toxicities due to DOX treatment, we propose that the ability of PCA to block oxidative stress, attenuate inflammation, and abrogate several forms of cardiomyocyte cell death underlines its great promise in the amelioration of DIC.
摘要:
自从它在1960年代被发现以来,多柔比星(DOX)不断引发最广泛的抗人类癌症活性。然而,直接由DOX及其代谢物引起的心脏毒性是在化疗中持续使用DOX引起关注的重大问题。虽然DOX诱导的心脏毒性的确切机制尚未完全了解,最近的研究表明氧化应激,炎症,和几种形式的细胞死亡是支撑多柔比星诱导的心脏毒性(DIC)病因的关键致病机制。值得注意的是,这些关键的机制事件被认为是由3,4-二羟基苯甲酸或原儿茶酸(PCA)负调控-一种基于植物的植物化学物质,具有经过验证的抗氧化剂,抗炎,和抗凋亡特性。这里,我们回顾了实验结果,详细说明了暴露于DOX下PCA的潜在改善作用。我们还讨论了DIC病理生理学的分子见解,强调了潜在的干预点,即使用PCA作为名副其实的化学保护剂可以改善DOX诱导的心脏毒性以及其他抗癌药物如顺铂引起的毒性.虽然我们承认在化疗期间控制口服PCA可能不足以消除由于DOX治疗引起的所有毒性,我们认为PCA阻断氧化应激的能力,减轻炎症,并废除几种形式的心肌细胞死亡,突显了其在改善DIC方面的巨大前景。