The Possible Role of Melatonin in Balancing Reactive Oxygen Species (ROS) in Cancer Biology

Dear editor,

Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen that play a dual role in cancer biology. While ROS can induce apoptosis in cancer cells, excessive levels can promote tumorigenesis. Balancing the effects of ROS is critical, as this dual role presents both therapeutic opportunities and challenges.

ROS are generated endogenously during normal cellular respiration, particularly in mitochondria, but can also arise from external factors like UV radiation, chemotherapy, and inflammation. The body maintains redox homeostasis through antioxidant defenses, including enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase. In cancer therapy, ROS can be exploited to damage cancer cells, with treatments like doxorubicin and radiation therapy using ROS to induce cell death. However, excessive ROS can damage essential biomolecules, leading to mutations, genomic instability, and even aiding cancer progression.

Melatonin (MLT; N-acetyl-5-methoxytryptamine), primarily produced by the pineal gland, regulates circadian rhythms and exhibits oncostatic effects by inhibiting cancer cell proliferation. Notably, melatonin has a context-dependent influence on ROS, acting as an antioxidant in normal cells but promoting ROS accumulation and apoptosis in cancer cell lines. Mechanistically, melatonin acts through MT1 and MT2 receptors, decreasing cAMP levels and suppressing PKA and CREB phosphorylation, contributing to anti-proliferative effects. It also inhibits antioxidant enzymes like superoxide dismutase in cancer cells, increasing ROS and inducing apoptosis via pathways such as Akt and sirtuins.^1,2 Additionally, melatonin synergizes with chemotherapeutic agents like 5-fluorouracil and natural compounds like andrographolide, enhancing anticancer efficacy at lower concentrations. ³

Melatonin’s potential as an adjunct in cancer therapy is supported by clinical trials showing improved chemotherapy outcomes and reduced side effects, such as fatigue and neurotoxicity. However, caution is needed in hormone-sensitive cancers, as melatonin may alter estrogen levels, potentially exacerbating conditions like breast cancer. Interactions with medications, such as blood thinners, also warrant consideration.

In conclusion, the dual nature of ROS in cancer necessitates a balanced approach to leveraging their therapeutic benefits while minimizing harm. Melatonin’s role as a modulator of ROS offers a promising avenue for future research, potentially improving cancer treatment outcomes by fine-tuning the redox environment. Future research should elucidate the molecular mechanisms underlying melatonin’s differential ROS effects in normal and cancer cells and optimize its integration into combination therapies to maximize efficacy and safety.

Farzaneh Shomoossi, MScImam Khomeini International University, Qazvin, Iran Shayan Sheikhmiri, MDShahid Beheshti University of Medical Sciences, Tehran, Iran Reza Chaman, MDSabzevar University of Medical Sciences, Sabzevar, Iran Sara Shenavaei Zare, MDSabzevar University of Medical Sciences, Sabzevar, Iran James S. Welsh, MDLoyola University Chicago Stritch School of Medicine, Maywood, IL, USA Seyed Alireza Javadinia, MDSabzevar University of Medical Sciences, Sabzevar, Iran