Melatonin Enhances Anti-tumoral Effects of Menadione on Colon Cancer Cells.

BACKGROUND: Colon cancer is one of the most important causes of death in the entire world. New pharmacological strategies are always needed, especially in resistant variants of this pathology. We have previously reported that drugs such as menadione (MEN), D, L-buthionine-S,R-sulfoximine or calcitriol, used in combination, enhanced cell sensibility of breast and colon tumour models, due to their ability to modify the oxidative status of the cells. Melatonin (MEL), a hormone regulating circadian rhythms, has anti-oxidant and anti-apoptotic properties at low concentrations, while at high doses, it has been shown to inhibit cancer cell growth. OBJECTIVE: The objective of this study is to determine the antitumoral action of the combination MEN and MEL on colon cancer cells. METHODS: Caco-2 cells were employed to evaluate the effects of both compounds, used alone or combined, on cellular growth/morphology, oxidative and nitrosative stress, and cell migration. RESULTS: MEN plus MEL dramatically reduced cell proliferation in a time and dose-dependent manner. The antiproliferative effects began at 48 h. At the same time, the combination modified the content of superoxide anion, induced the formation of reactive nitrogen species and enhanced catalase activity. Cell migration process was delayed. Also, changes in nuclear morphology consistent with cell death were observed. CONCLUSION: The enhanced effect of simultaneous use of MEN and MEL on Caco-2 cells suggests that this combined action may have therapeutic potential as an adjuvant on intestinal cancer acting in different oncogenic pathways.

Reactive oxygen species in cancer: a paradox between pro- and anti-tumour activities.

Cancer constitutes a group of heterogeneous diseases that share common features. They involve the existence of altered cellular pathways which result in uncontrolled cell proliferation. Deregulation of production and/or elimination of reactive oxygen species (ROS) appear to be a relevant issue in most of them. ROS have a dual role in cell metabolism: they are compromised in normal cellular homeostasis, but their overproduction has been reported to promote oxidative stress (OS), a process that may induce the damage of cell structures. ROS accumulation is implicated in the activation of signaling pathways that promote cell proliferation and metabolic adaptations to tumour growth. One characteristic of cancer cells is the sensitivity to OS, which often results from the combination of high anabolic needs and hypoxic growth conditions. However, there is still no clear evidence about the levels of oxidant species that promote cellular transformation or, otherwise, if OS induction could be adequate as an antitumour therapeutic tool. There is a need for novel therapeutic strategies based on the new knowledge of cancer biology. Targeting oncogenic molecular mechanisms with non-classical agents and/or natural compounds would be beneficial as chemoprevention or new adjuvant therapies. In addition, epigenetics and environment, and particularly dietary factors may influence the development and prevention of cancer. This article will present a revision of the current research about molecular aspects proposed to be involved in the anticancer features of oxidant and antioxidant-based therapies targeting cancer cells, and their participation in the balance of oxidative species and cancer cell death.