Mechanistic insights into the role of melatonin in cancer cell chemoresistance

Abstract

Cells become more highly functionally pleiotropic when they transition into a cancer phenotype. Many cancer cells reorganize the glucose processing pathway such that the end product of glucose metabolism, pyruvate, is not transported into the mitochondria for conversion to acetyl coenzyme A. Rather, pyruvate undergoes fermentation to lactic acid which is released into the extracellular microenvironment where it acidifies the associated interstitial fluid. This acidification aids in angiogenesis, invasion and metastasis of the cancerous cell. This adopted metabolism of eukaryotic cells is referred to as Warburg metabolism, was discovered more than 100 years ago, and is sufficiently common to where it is classified as a “Hallmark of Cancer”. Although contributing to cancer cell chemoresistance, it is per se not the cause of the failure of cancer cells to respond to drugs that normally kill them. immune escape.Normal cells typically rely on mitochondrial respiration (oxidative phosphorylation; OXPHOS) for energy production (ATP); in contrast, cancer cells primarily derive energy from cytosolic glycolysis (Warburg metabolism). Cancer cells can switch their metabolic phenotype via tumor cell autonomous means or as a result of drug administration. Drugs that force cancer cells to adopt mitochondrial OXPHOS over cytosolic glycolysis for ATP synthesis are referred to as glycolytics; these drugs are classified as oncostatic agents because they rewire glucose back to that of the non-cancer cell and rendering the cell more sensitive to procedures that normally kill the tumor cell, i.e., chemotherapy of radiotherapy. Some of the best known glycolytic agents include synthetic chemicals, e.g., dichloroacetate and oxamic acid, and plant derived flavanoids, e.g., quercertin, as well as plant non-flavonoid polyphenols, e.g., resveratrol.