Melatonin Prevents Mitochondrial Damage Induced by Doxorubicin in Mouse Fibroblasts Through Ampk-Ppar Gamma-Dependent Mechanisms

Abstract

BackgroundDoxorubicin (brand name: Adriamycin®) is used to treat solid tissue cancer but it also affects noncancerous tissues. Its mechanism of cytotoxicity is probably related to increased oxidation, mitochondrial dysfunction, and apoptosis. Melatonin is reported to have antiapoptotic and antioxidative effects. The aim of this study was to determine whether melatonin would counteract in vitro cytotoxicity of doxorubicin in mouse fibroblasts and determine the pathway of its action against doxorubicin-induced apoptosis.Material/MethodsWe measured markers of apoptosis (cytochrome-c, mitochondrial membrane potential, and apoptotic cell number) and oxidative stress (total oxidant and antioxidant status) and calculated oxidant stress index in 4 groups of fibroblasts: controls, melatonin-treated, doxorubicin-treated, and fibroblasts concomittantly treated with a combination of melatonin and doxorubicin.ResultsMelatonin given with doxorubicin succesfully countered apoptosis generated by doxorubicin alone, which points to its potential as a protective agent against cell death in doxorubicin chemotherapy. This also implies that patients should be receiving doxorubicin treatment when their physiological level of melatonin is at its highest, which is early in the morning.ConclusionsThis physiological level may not be high enough to overcome doxorubicin-induced oxidative stress, but adjuvant melatonin treatment may improve quality of life. Further research is needed to verify our findings.

Differentiated mitochondrial function in mouse 3T3 fibroblasts and human epithelial or endothelial cells in response to chemical exposure

“…An additional argument given in favour of using the 3T3 cell line is that it is a globally accepted cell line for use in the neutral red uptake assay (NRU), which is a standardized method for acute toxicity testing in rodents . Another reason for using the 3T3 fibroblasts by some researchers is their good responsiveness to external stimuli; however, this feature has been primarily ascribed to cardiac fibroblasts: the main cellular constituents of the heart . Fibroblasts are dispersed throughout the connective tissue of the body, and their morphology and physiology have been found to vary depending on the body part .…”

“…The utility of the 3T3 cell line has been shown in many other biological and toxicological studies, using various experimental approaches. For example, 3T3 fibroblasts have been selected for the following purposes: 1/investigating the activity of bacterial toxins, antioxidants and cytokines, 2/evaluating the toxicity of drugs, e‐waste leachate, nanomaterials and nanoparticles or 3/studying the beneficial effects of electromagnetic radiation in living cells . These cells can also serve as a tool for the verification and validation of techniques assessing mitochondrial toxicity .…”

The Anticancer Activity of Cetraria Islandica (L.) Ach in Breast Cancer Cells Through Crosstalk of Ampk-α1 and Erk1/2 Signalling

“…One of a recent study was indicated that AMPK gave rise to decline P38 MAPK, resulting in inhibition of inflammatory pathway . Interestingly, there was reported a positive correlation between AMPK-α and ERK½ in a recent study (Guven et al, 2016). ERK½ is related to attenuate apoptosis in some cell line.…”

Circadian rhythms, Neuroinflammation and Oxidative Stress in the Story of Parkinson’s Disease

“…Melatonin presents some effects, such as anti-inflammatory, anti-oxidant, and neuroprotective effects [128,[132][133][134][135][136]. Melatonin increases the potential of mitochondrial membrane, activates mitochondrial biogenesis [137], and increases the mitochondrial function [138].…”