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.

褪黑激素能够干预某些实验性癌症的发生、进展和转移。已经提出了多种潜在机制来描述与褪黑激素与癌细胞相互作用相关的代谢和分子事件。有一种代谢扰动是大量实体瘤所共有的，并且解释了癌细胞活跃增殖、避免细胞凋亡和易于转移的能力，即它们利用胞质有氧糖酵解（瓦尔堡效应）快速产生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）可导致癌细胞放弃有氧糖酵解，转而采用更传统的线粒体氧化磷酸化来合成 ATP，就像正常细胞一样。在此过程中，糖酵解剂还可以抑制癌症的生长。在此，我们假设褪黑激素还可以作为癌细胞中胞质糖酵解的抑制剂，其机制是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），就像其他糖酵解药物一样。在此过程中，褪黑激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细胞凋亡。这一假设是结合之前发表的报告进行讨论的。虽然褪黑激素是在正常细胞的线粒体中合成的，但我们假设由于乙酰辅酶 A 的抑制，癌细胞线粒体中不存在这种合成能力。乙酰辅酶A对于褪黑激素合成中的限速酶（芳基烷基胺-N-乙酰转移酶）是必需的。 最后，褪黑激素将葡萄糖氧化从细胞质转移到线粒体的能力也解释了对传统化疗产生耐药性的肿瘤在应用褪黑激素时如何对相同的治疗重新敏感。