Licorice Ameliorates Cisplatin-Induced Hepatotoxicity through Anti-apoptosis, Anti-oxidative Stress, Anti-inflammation, and Acceleration of Metabolism

Cisplatin (CP) is one of the most effective antitumor drugs in the clinic, but has serious adverse reactions, and its hepatotoxicity has not been fully investigated. Licorice (GC), a traditional herbal medicine, has been commonly used as a detoxifier for poisons and drugs, and may be an effective drug for CP-induced hepatotoxicity. However, its mechanism and the effector molecules remain ambiguous. Therefore, in this study, a network pharmacology and proteomics-based approach was established, and a panoramic view of the detoxification of GC on CP-induced hepatotoxicity was provided. The experimental results indicated that GC can recover functional indices and pathological liver injury, inhibit hepatocyte apoptosis, upregulate B-cell lymphoma/leukemia 2 (Bcl-2) and superoxide dismutase (SOD) levels, and downregulate cellular tumor antigen p53 (p53), caspase-3, malondialdehyde (MDA), high mobility group protein B1 (HMGB1), tumor necrosis factor alpha (TNF-α), and interleukin 1β (IL-1β) levels. Proteomics indicated that GC regulates phosphatidylcholine translocator ABCB1 (ABCB1B), canalicular multispecific organic anion transporter 1 (ABCC2), cytochrome P450 4A2 (CYP4A2), cytochrome P450 1A1 (CYP1A1), cytochrome P450 1A2 (CYP1A2), estrogen receptor (ESR1), and DNA topoisomerase 2-alpha (TOP2A), inhibits oxidative stress, apoptosis, and inflammatory responses, and accelerates drug metabolism. In this study, we provide the investigation of the efficacy of GC against CP-induced hepatotoxicity, and offers a promising alternative for the clinic.

顺铂（Cisplatin, CP）是临床最有效的抗肿瘤药物之一，但存在严重不良反应，其诱发的肝毒性尚未得到全面阐明。甘草（Licorice, GC）作为传统中药，常被用作毒物与药物的解毒剂，或可成为缓解顺铂诱导肝毒性的有效药物，但其具体作用机制与效应分子仍不明确。为此，本研究构建了基于网络药理学与蛋白质组学的研究策略，全面解析了甘草对抗顺铂诱导肝毒性的作用全景。实验结果表明，甘草可恢复肝功能指标、减轻肝脏病理性损伤，抑制肝细胞凋亡，上调B细胞淋巴瘤/白血病2（B-cell lymphoma/leukemia 2）与超氧化物歧化酶（superoxide dismutase）的表达水平，同时下调细胞肿瘤抗原p53（cellular tumor antigen p53）、半胱天冬氨酸蛋白酶3（caspase-3）、丙二醛（malondialdehyde）、高迁移率族蛋白B1（high mobility group protein B1）、肿瘤坏死因子α（tumor necrosis factor alpha）及白细胞介素1β（interleukin 1β）的表达水平。蛋白质组学分析显示，甘草可调控磷脂酰胆碱转运蛋白ABCB1B（phosphatidylcholine translocator ABCB1B）、小管多特异性有机阴离子转运蛋白1（canalicular multispecific organic anion transporter 1）、细胞色素P450 4A2（cytochrome P450 4A2）、细胞色素P450 1A1（cytochrome P450 1A1）、细胞色素P450 1A2（cytochrome P450 1A2）、雌激素受体（estrogen receptor）及DNA拓扑异构酶2-α（DNA topoisomerase 2-alpha）的表达，抑制氧化应激、细胞凋亡与炎症反应，并加速药物代谢。本研究阐明了甘草对抗顺铂诱导肝毒性的药效作用，为临床提供了极具潜力的治疗备选方案。