Utilizing Melatonin to Alleviate Side Effects of Chemotherapy: A Potentially Good Partner for Treating Cancer with Ageing

Figure 1

The mechanisms underlying cytoplasmic organellar dysfunction after chemotherapy and melatonin’s protective effects under these conditions. Melatonin reverses chemotherapy-induced ER stress, as well as nucleus and mitochondrial dysfunction. In the mitochondrion, chemotherapy drugs lead to electron leakage and excessive free radical production. The ROS directly causes oxidative damage to the mitochondrial respiratory chain, further resulting in elevated electron leakage, free radical production, and ATP depletion. Moreover, ROS injures mitophagy, mtDNA, and the mitochondrial membrane structure (TOM complex reduction and mitochondrial membrane lipid peroxidation increases and elevates mPTP opening), leading to membrane potential loss and proapoptosis factor release. Apart from directly scavenging free radicals, melatonin protects against mtDNA damage/mutation, activates the antioxidant defense system, activates SIRT3 to scavenge ROS, and upregulates the TOM complex, the entry gate for the majority of precursor proteins that are imported into the mitochondria. However, the role of melatonin in mitophagy is less clear. Melatonin inhibits chemotherapy-induced stimulation of ERK1/2, followed via enhanced phosphorylation of p53 by the upregulation of genes such as Bax, thus resulting in mPTP opening. In the nucleus, melatonin upregulates Nrf2 and HO-1 expression and decreases TNF-α and IL-1β levels, thus contributing to cell protection. In the ER, melatonin reverses chemotherapy-induced ER stress via the inhibition of the PI3K/AKT pathway. As a consequence, melatonin protects diverse organs after chemotherapy. Abbreviations: Akt, protein kinase B; ATP, adenosine triphosphate; IL-1β, interleukin-1β; mPTP, mitochondrial permeability transition pore; ER, endoplasmic reticulum; ERK, extracellular regulated protein kinases; HO-1, heme oxygenase-1; JNK, c-Jun-N-terminal kinases; mtDNA, mitochondrial DNA; PI3K, phosphoinositide 3 kinase; ROS, reactive oxygen species; SIRT3, silent information regulator 3; SP, substance P; TOM, translocases in the outer membrane.