Modulation of Intrinsic and Extrinsic Apoptotic Pathways by Macrolide Antibiotics in Chemically‐Induced Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma(HCC) is one of the most common solid malignancies and a leading cause of cancer‐related deaths. Macrolide antibiotics demonstrated beneficial effects in several pathological conditions however; their therapeutic potential in cancer is not fully elucidated. The current study aimed to investigate the individual anti‐tumor effect of some macrolide antibiotics in chemically‐induced HCC. HCC was induced in rats by initiation‐selection‐promotion protocol using diethylnitrosamine (200 mg/kg, single i.p. injection)/2‐acetylaminofluorene (2‐AAF) (0.03%w/w supplemented diet for 2 weeks/carbon tetrachloride (2ml/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 from the beginning of the 3rd week until week 17 at a dose of 100mg/kg and study was terminated on week 32. Current data proved that clarithromycin suppresses HCC via induction of apoptosis through up‐regulation of both extrinsic and intrinsic apoptotic pathways proteins (TNF‐α, TNFR1, cytochrome‐c, caspase‐3, and Bax with increased Bax/Bcl2 ratio). Similarly azithromycin reduced the tumorgenic effect of the former carcinogenic agents, however to a lesser extent compared to clarithromycin. Surprisingly, erythromycin worsened the tumorgenic effect of the carcinogenic agents used in the current model with insignificant apoptotic outcome. It is concluded that the anticancer potential of some macrolide antibiotics is an individual effect rather than a group effect and the current detected anti‐tumor mechanism involved the activation of both intrinsic and extrinsic apoptotic pathways.