Melatonin has the ability to intervene in the initiation, progression and metastasis of some experimental cancers. A large variety of potential mechanisms have been advanced to describe the metabolic and molecular events associated with melatonin’s interactions with cancer cells. There is one metabolic perturbation that is common to a large number of solid tumors and accounts for the ability of cancer cells to actively proliferate, avoid apoptosis, and readily metastasize, i.e., they use cytosolic aerobic glycolysis (the Warburg effect) to rapidly generate the necessary ATP required for the high metabolic demands of the cancer cells. There are several drugs, referred to as glycolytic agents, that cause cancer cells to abandon aerobic glycolysis and shift to the more conventional mitochondrial oxidative phosphorylation for ATP synthesis as in normal cells. In doing so, glycolytic agents also inhibit cancer growth. Herein, we hypothesize that melatonin also functions as an inhibitor of cytosolic glycolysis in cancer cells using mechanisms, i.e., downregulation of the enzyme (pyruvate dehydrogenase kinase) that interferes with the conversion of pyruvate to acetyl CoA in the mitochondria, as do other glycolytic drugs. In doing so, melatonin halts the proliferative activity of cancer cells, reduces their metastatic potential and causes them to more readily undergo apoptosis. This hypothesis is discussed in relation to the previously published reports. Whereas melatonin is synthesized in the mitochondria of normal cells, we hypothesize that this synthetic capability is not present in cancer cell mitochondria because of the depressed acetyl CoA; acetyl CoA is necessary for the rate limiting enzyme in melatonin synthesis, arylalkylamine-N-acetyltransferase. Finally, the ability of melatonin to switch glucose oxidation from the cytosol to the mitochondria also explains how tumors that become resistant to conventional chemotherapies are re-sensitized to the same treatment when melatonin is applied.

褪黑素具有干预某些实验性癌症的发生，发展和转移的能力。已经提出了各种各样的潜在机制来描述与褪黑激素与癌细胞相互作用有关的代谢和分子事件。有一种代谢扰动是许多实体瘤所共有的，它解释了癌细胞活跃增殖，避免凋亡和易于转移的能力，即，它们利用胞质需氧糖酵解（Warburg效应）来快速产生肿瘤。癌细胞高代谢需求所需的必需ATP。有几种药物，称为糖酵解剂，导致癌细胞放弃有氧糖酵解，转而使用更常规的线粒体氧化磷酸化来合成ATP，就像正常细胞一样。这样，糖酵解剂也抑制癌症的生长。在本文中，我们假设褪黑素与其他糖酵解药物一样，通过机制（即下调干扰线粒体中丙酮酸转化为乙酰辅酶A的酶（丙酮酸脱氢酶激酶）的机制）在癌细胞中还充当了细胞溶质糖酵解的抑制剂。 。在这种情况下，褪黑素会阻止癌细胞的增殖活性，降低其转移潜力，并使它们更容易发生凋亡。相对于先前发表的报告讨论了该假设。褪黑激素是在正常细胞的线粒体中合成的，我们假设由于乙酰辅酶A降低，癌细胞线粒体中不存在这种合成能力。乙酰辅酶A对褪黑激素合成中的限速酶，芳基烷基胺-N-乙酰基转移酶。最后，褪黑激素将葡萄糖氧化从胞质溶胶转换为线粒体的能力还解释了当应用褪黑激素时，对常规化学疗法产生抗药性的肿瘤如何重新敏感于相同的治疗方法。