Melatonin, mitochondria, and the cancer cell

Abstract

The long-recognized fact that oxidative stress within mitochondria is a hallmark of mitochondrial dysfunction has stimulated the development of mitochondria-targeted antioxidant therapies. Melatonin should be included among the pharmacological agents able to modulate mitochondrial functions in cancer, given that a number of relevant melatonin-dependent effects are triggered by targeting mitochondrial functions. Indeed, melatonin may modulate the mitochondrial respiratory chain, thus antagonizing the cancer highly glycolytic bioenergetic pathway of cancer cells. Modulation of the mitochondrial respiratory chain, together with Ca²⁺ release and mitochondrial apoptotic effectors, may enhance the spontaneous or drug-induced apoptotic processes. Given that melatonin may efficiently counteract the Warburg effect while stimulating mitochondrial differentiation and mitochondrial-based apoptosis, it is argued that the pineal neurohormone could represent a promising new perspective in cancer treatment strategy.

Keywords: Cancer; Melatonin; Mitochondria; Warburg effect.

Fig. 1

Melatonin effects on mitochondria. Melatonin (M)—produced within the mitochondria and imported from the cytosol—enhances the disclosure of mitochondrial permeability transition pore (MPTP), thus modifying the mitochondrial potential (∆Ψ). Melatonin improves the electron transport chain (ETC) and the overall Kreb’s cycle activity, leading to enhanced oxidative glucose metabolism. Moreover, melatonin modulates reactive oxygen species (ROS) production in a context-dependent manner. Similarly, melatonin increases or decreases apoptosis (respectively, in cancer or normal cells) by influencing antiapoptotic (Bcl-2) or pro-apoptotic (caspase-3, Casp3; cytochrome c, Cytc) effectors. Eventually, a direct action of melatonin on mitochondrial DNA (mtDNA) activity has been proposed