Fatima Sabiha, Suhail Nida, Alrashed May, Wasi Samina, Aljaser Feda S, AlSubki Roua A, Alsharidah Ashwag S, Banu Naheed
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.
Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Northern Border University, Arar, Saudi Arabia.
J Biochem Mol Toxicol. 2021 Apr;35(4):e22701. doi: 10.1002/jbt.22701. Epub 2021 Jan 4.
Despite the extensive use of cisplatin (CP) as a chemotherapeutic agent, its clinical use is often restricted by undesirable side effects, such as toxicity to normal tissues. The aim of this study was to probe the effect of a combinatorial treatment of low multiple doses of antioxidants on CP-induced toxicity and the mitochondrial apoptotic pathway in hepatocytes. Animals received a single toxic dose of CP (7.5 mg/kg body weight) with or without combined multiple doses of epigallocatechin gallate (EGCG) and coenzyme Q10 (CoQ10) (15 and 5 mg/kg body weight, respectively). CP-treated animals showed altered biochemical parameters, denoting hepatotoxicity, which was markedly improved by the multidose treatment with EGCG + CoQ10. The increased levels of oxidants found in the cytosolic and mitochondrial fractions isolated from the liver of CP-administered rats were significantly attenuated by the combinatorial doses of antioxidants. EGCG + CoQ10 ameliorated the CP-induced compromised antioxidant defenses, oxidative modification of macromolecules, decreased activities of respiratory chain enzymes, altered membrane depolarization, and swelling of liver mitochondria. Furthermore, EGCG + CoQ10 treatment inhibited CP-induced apoptosis by suppressing the activation and mitochondrial accumulation of proapoptotic proteins and preventing the inhibition of antiapoptotic protein expression, cytochrome c efflux, caspase-3 activation, and DNA fragmentation. Histological findings further confirmed the protective effects of EGCG + CoQ10 against CP-induced cellular injury. Our findings revealed that the combination of EGCG and CoQ10, owing to their individual antioxidant properties, can be an effective remedy, which by maintaining redox hemostasis attenuate the mitochondrial stress-mediated molecular and cellular processes involved in CP-induced liver toxicity and cell death.
尽管顺铂（CP）作为一种化疗药物被广泛使用，但其临床应用常常受到诸如对正常组织有毒性等不良副作用的限制。本研究的目的是探究低多次剂量抗氧化剂联合治疗对CP诱导的肝细胞毒性和线粒体凋亡途径的影响。动物接受单次毒性剂量的CP（7.5毫克/千克体重），同时或不联合多次剂量的表没食子儿茶素没食子酸酯（EGCG）和辅酶Q10（CoQ10）（分别为15和5毫克/千克体重）。接受CP治疗的动物表现出生化参数改变，表明存在肝毒性，而EGCG + CoQ10的多剂量治疗显著改善了这种情况。从给予CP的大鼠肝脏中分离出的胞质和线粒体部分中发现的氧化剂水平升高，被抗氧化剂的联合剂量显著减弱。EGCG + CoQ10改善了CP诱导的抗氧化防御受损、大分子的氧化修饰、呼吸链酶活性降低、膜去极化改变以及肝线粒体肿胀。此外，EGCG + CoQ10治疗通过抑制促凋亡蛋白的激活和线粒体积累，并防止抗凋亡蛋白表达的抑制、细胞色素c外流、半胱天冬酶-3激活和DNA片段化，从而抑制了CP诱导的细胞凋亡。组织学结果进一步证实了EGCG + CoQ10对CP诱导的细胞损伤的保护作用。我们的研究结果表明，由于EGCG和CoQ10各自的抗氧化特性，它们的组合可以成为一种有效的治疗方法，通过维持氧化还原稳态来减轻参与CP诱导的肝毒性和细胞死亡的线粒体应激介导的分子和细胞过程。
