Abdel-Hamid Nagwa I, El-Azab Mona F, Moustafa Yasser M
Ministry of Health, Suez, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt.
Naunyn Schmiedebergs Arch Pharmacol. 2017 Apr;390(4):379-395. doi: 10.1007/s00210-016-1337-0. Epub 2017 Jan 9.
This study was designed to examine the potential antitumor effect of some macrolides: clarithromycin, azithromycin, and erythromycin on chemically induced hepatocellular carcinoma (HCC) in rats and on human hepatoma cells (HepG2) as well. The possible underlying antiapoptotic mechanisms were investigated. Antiproliferative activity was assessed in HepG2 using Sulforhodamine-B staining method. In vivo, HCC was induced in rats by initiation-selection-promotion protocol using diethylnitrosamine (200 mg/kg, single i.p. injection)/2-acetylaminofluorene (0.03% w/w supplemented-diet for 2 weeks)/carbon tetrachloride (2 ml/kg diluted in corn oil 1:1, single intra-gastric dose)/phenobarbitone sodium (0.05% w/w supplemented-diet for 28 weeks). Macrolides were administered once daily starting from the 3rd week until the 17th week at a dose of 100 mg/kg in the current 33-week study period. Clarithromycin showed a higher efficacy in the suppression of HepG2 proliferation with lower IC50 value than doxorubicin. In vivo, chemically-induced HCC rat model proved that clarithromycin suppressed HCC via induction of apoptosis through up-regulation of both extrinsic/intrinsic apoptotic pathways' proteins (TNFR1, cleaved caspase-3, and Bax with an increased Bax/Bcl-2 ratio) along with MMP-9 normalization. Similarly, azithromycin demonstrated antitumorigenic effect through both apoptotic pathways, however, to a lesser extent compared to clarithromycin. Moreover, azithromycin suppressed the proliferation of HepG2, however, at a higher IC50 than doxorubicin. Surprisingly, erythromycin increased HepG2 proliferation in vitro, along with worsened tumorigenic effect of the carcinogenic agents in the in vivo study with ineffective apoptotic outcome. Some macrolides represent potential antitumor agents; however, this evident anticancer activity is an individual effect rather than a group effect and involves modulation of both intrinsic and extrinsic apoptotic pathways.
克拉霉素、阿奇霉素和红霉素对化学诱导的大鼠肝细胞癌（HCC）以及人肝癌细胞（HepG2）的潜在抗肿瘤作用。同时研究了其可能的抗凋亡机制。采用磺酰罗丹明-B染色法评估HepG2细胞中的抗增殖活性。在体内，通过启动-选择-促进方案，使用二乙基亚硝胺（200mg/kg，单次腹腔注射）/2-乙酰氨基芴（0.03%w/w添加到饲料中，持续2周）/四氯化碳（2ml/kg，用玉米油1:1稀释，单次胃内给药）/苯巴比妥钠（0.05%w/w添加到饲料中，持续28周）诱导大鼠发生HCC。在当前为期33周的研究期间，从第3周开始至第17周，每天以100mg/kg的剂量给予大环内酯类药物。克拉霉素在抑制HepG2增殖方面表现出更高的疗效，其IC50值低于阿霉素。在体内，化学诱导的HCC大鼠模型证明，克拉霉素通过上调外源性/内源性凋亡途径的蛋白质（TNFR1、裂解的半胱天冬酶-3和Bax，同时Bax/Bcl-2比值增加）以及使MMP-9正常化来诱导凋亡，从而抑制HCC。同样，阿奇霉素通过两条凋亡途径均表现出抗肿瘤作用，然而，与克拉霉素相比程度较小。此外，阿奇霉素抑制HepG2的增殖，但其IC50高于阿霉素。令人惊讶的是，红霉素在体外增加了HepG2的增殖，并且在体内研究中使致癌剂的致瘤作用恶化，凋亡结果无效。一些大环内酯类药物代表潜在的抗肿瘤药物；然而，这种明显的抗癌活性是个体效应而非群体效应，并且涉及对内在和外在凋亡途径的调节。
