Repurposing melatonin for its potential roles in gastrointestinal cancers: highlighting the molecular mechanisms

Gastrointestinal (GI) cancers are among the most common cancers of the decade, many of which have a poor prognosis. Due to the high prevalence of toxicity and adverse drug reactions (ADRs) of chemotherapeutic agents and low patient compliance, there is always a need for drugs that can be used as adjuvants to existing cancer treatments with low ADRs which can boost the efficacy of chemotherapeutics and reduce the associated toxicities. Repurposing or repositioning a drug with known pharmacological properties is of great value in this context. Drug repurposing has been applied in many illnesses in the recent decade. Melatonin is an endogenous hormone with multiple anticancer properties. It demonstrates antitumor effects by modifying several critical signaling pathways, inhibiting proliferation and metastasis, inducing apoptosis and autophagy, and also reducing oxidative stress. It also reduces toxicity of chemotherapeutics. Due to specific characteristics of melatonin and its limited toxicity, melatonin can be considered as a potential for repositioning in various cancers. Hence, melatonin can be included as an off-label adjuvant chemotherapy to improve the prognosis and overall quality of life of patients suffering from GI cancers. Herein, the action of melatonin on various GI cancers, with the emphasis on its effect on major oncogenic signaling pathways (e.g., Wnt/β-catenin signaling pathway, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and nuclear factor kappa B (NF-κB)) are discussed. Additionally, mechanisms by which melatonin halts the process of mitosis, induces apoptosis, and makes tumors more vulnerable to chemotherapy are discussed.