Melatonin inhibits cholangiocarcinoma and reduces liver injury in Opisthorchis viverrini‐infected and N‐nitrosodimethylamine‐treated hamsters

Abstract

The human liver fluke Opisthorchis viverrini infection and N-nitrosodimethylamine (NDMA) administration induce cholangiocarcinoma (CCA) and liver injury in hamsters. Melatonin protects against liver injury and reduces the alteration of mitochondrial structure, mitochondrial membrane potential, and mitochondrial pro- and anti-apoptotic pathways in various cancer types. To investigate the chemopreventive effect of melatonin on CCA genesis and liver injury, hamsters were treated with a combination of O. viverrini infection and NDMA concurrently administered with melatonin (10 mg/kg and 50 mg/kg) for 120 days. Melatonin treatment at 50 mg/kg caused a significant reduction in liver/body weight ratios and decreased tumor volumes leading to an increase in the survival of animals. In the tumorous tissues, the high-dose melatonin reduced DNA fragmentation and mitochondrial apoptosis by inducing anti-apoptotic protein (Bcl-2) in the mitochondrial fraction and down-regulating cytochrome c, pro-apoptotic protein (Bax), and caspase-3 in tumor cytosol. Moreover, a high-dose melatonin treatment significantly increased mitochondrial antioxidant enzymes and prevented mitochondrial ultrastructure changes in the tumor. Overall, melatonin has potent chemopreventive effects in inhibiting CCA genesis and also reduces liver injury in hamster CCA, which, in part, might involve in the suppression of CCA by reducing tumor mitochondria alteration.

Action of Melatonin on Severe Acute Liver Failure in Rats

“…Similar results were previously reported in the literature using MLT in the treatment of different induced pathological conditions in animal models, such as sepsis [30][31], Alzheimer [32], and liver injury caused by cholangiocarcinoma [33]. Table 2 shows the result for enzyme concentrations associated with liver damage in the 24-hour experiment.…”

Human liver flukes

“…Likewise inhibition of NFκB with cepharanthine has been shown to have anti-tumour activity against cholangiocarcinoma in mice (57) , and may represent a potential future treatment. Use of ciclosporin to suppress the raised levels of cyclophilin A seen in O. viverrini has been shown reduce cholangiocarcinoma cell proliferation and tumour growth in a mouse model (43) .…”

Melatonin-Induced Oncostasis, Mechanisms and Clinical Relevance

“…Table 1 summarizes relevant data on this subject. Melatonin decreases growth in most tumor cell lines by increasing necrosis, decreasing proliferation, and increasing apoptosis [14,141,166]. Taken together, the different pathways involved in carcinogenesis, including cell proliferation and metastasis, are important targets of melatonin, which represents a unique molecule able to interact with these different pathways, reducing oncogenesis.…”

“…Mitochondrial impairment produces ROS and reactive nitrogen species (RNS) that in turn reduce mitochondrial bioenergetics, favoring cell damage and death [142,143]. Effectively, melatonin treatment significantly inhibits cholangiocarcinoma development [141]. Melatonin is a special class of antioxidant because when scavenging free radicals, it is processed in a series of metabolites that are also free radical scavengers [144].…”

“…The oxidative damage of mitochondria is also strongly involved in carcinogenesis [140]; e.g., it is hypothesized that mitochondrial changes can be associated with cholangiocarcinoma development [141]. Mitochondrial impairment produces ROS and reactive nitrogen species (RNS) that in turn reduce mitochondrial bioenergetics, favoring cell damage and death [142,143].…”