Reactive Oxygen Species, DNA Damage, and Carcinogenesis: Intervention with Melatonin

Abstract

A variety of cancer-inducing agents cause cancer by virtue of their ability to damage DNA via free radical mechanisms. Damaged DNA is a primary cause of cancer if it goes unrepaired and mutates. Free radicals, many of which are oxygen metabolites, indiscriminately attack both mitochondrial and nuclear DNA when they are generated in the vicinity of these molecules. Melatonin is a highly effective free radical scavenger which protects DNA from the damage inflicted by free radicals; the attack of molecules by reduced oxygen metabolites is referred to as oxidative stress. In order for any antioxidant to protect DNA from oxidative stress it must be essentially surrounding the genome, since most free radicals that destroy DNA are generated in the immediate vicinity (most often within 10 angstroms) of the DNA. Melatonin is known to get into the nucleus, and studies, using a variety of techniques, have shown the indole to reduce DNA damage due to a variety of carcinogens, e.g., safrole, ionizing radiation, chromium, etc. In this context melatonin is capable of reducing cancer initiation. Besides the primary damage to DNA which initiates a tumor, the progressive accumulation of oxidatively altered DNA is believed to be involved in the transition of benign to malignant tumor cells. Due to melatonin antioxidant activities, the indole may also reduce this process and thereby lower the degree of malignancy of tumor cells.