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

Abstract

Persistent senescence seems to exert detrimental effects fostering ageing and age-related disorders, such as cancer. Chemotherapy is one of the most valuable treatments for cancer, but its clinical application is limited due to adverse side effects. Melatonin is a potent antioxidant and antiageing molecule, is nontoxic, and enhances the efficacy and reduces the side effects of chemotherapy. In this review, we first summarize the mitochondrial protective role of melatonin in the context of chemotherapeutic drug-induced toxicity. Thereafter, we tabulate the protective actions of melatonin against ageing and the harmful roles induced by chemotherapy and chemotherapeutic agents, including anthracyclines, alkylating agents, platinum, antimetabolites, mitotic inhibitors, and molecular-targeted agents. Finally, we discuss several novel directions for future research in this area. The information compiled in this review will provide a comprehensive reference for the protective activities of melatonin in the context of chemotherapy drug-induced toxicity and will contribute to the design of future studies and increase the potential of melatonin as a therapeutic agent.

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.

Figure 2

Protection of melatonin against chemotherapy drug-induced damage in various organs.