Melatonin promoted the therapeutic potential of cisplatin in a rat model of hepatocellular carcinoma: COX-2 and MDM2/p53/miR-155 modulation associated with cytoprotection and tumour regression

Globally, hepatocellular carcinoma (HCC) presents a clinical and financial burden, as it is often diagnosed at a later stage. Cisplatin is one of the most commonly used chemotherapeutics for treating various types of solid tumours; however, it is a double-edged sword due to its cytotoxic effects. Consequently, we hypothesized that combining cisplatin with melatonin could be effective in treating HCC. Additionally, melatonin may mitigate the severe adverse effects of cisplatin on normal cells through its cellular protection, immunomodulation, and antioxidant activities. Forty male adult Wistar rats were randomly divided into five groups: Group 1(n = 8), negative control group. HCC was induced in 32 rats with diethyl nitrosamine and carbon tetrachloride injection. Following induction, rats were divided into group 2 (HCC): diseased control; group 3 (HCC-Cis): HCC rats received cisplatin (2.5 mg/kg I.P. once every week for 3 weeks); group 4 (HCC-Melatonin): HCC rats received melatonin in drinking water (20 mg/L for 3 weeks); and group 5 (HCC-Cis-Melatonin; Combined therapy): the HCC rats received both cisplatin and melatonin. HCC group revealed significant elevation in ALT, AST, and AFP associated with increased TNF-α and MDA levels. Hepatic tissue exhibited a significant increase in VEGF, MDM2, COX-2, and miR-155, and a decrease in caspase-3 associated with hepatic damage, ballooning of hepatocytes, and increased BCL-2 and CD68 immunostaining. Although cisplatin was able to induce HCC apoptosis by COX-2 and MDM2/p53/ miR-155 modulation, it aggravated normal hepatocytic damage that was improved by the antioxidant and anti-inflammatory effects of melatonin. In conclusion, melatonin and cisplatin co-administration may be a viable strategy to preserve liver function by shielding healthy hepatocytes from the cytotoxic effects of cisplatin.