Melatonin as an anti-cancer agent: mechanistic targeting of the PI3K/Akt signaling pathway

Despite substantial advances in diagnosis and treatment, cancer remains a major global health burden, and current therapeutic strategies are still limited by resistance, toxicity, and incomplete efficacy. In this context, naturally derived bioactive compounds have attracted increasing attention as potential adjuncts or alternatives in oncology. Melatonin, an endogenous indoleamine best known for regulating circadian rhythms, has emerged as a promising candidate because of its pleiotropic biological properties, including antioxidant, anti-inflammatory, immunomodulatory, and antiproliferative effects. In addition to its classical chronobiological function, melatonin appears to interfere with multiple oncogenic processes that sustain tumor growth and progression. Among these pathways, the PI3K/Akt signaling pathway is particularly relevant, as it is frequently dysregulated in cancer and contributes to proliferation, survival, metastasis, and resistance to apoptosis. Accumulating experimental evidence suggests that melatonin may suppress this pathway by modulating upstream mediators and downstream effector molecules, thereby disrupting malignant signaling networks. This narrative review summarizes the current knowledge on the anticancer potential of melatonin, with emphasis on its actions in glioblastoma, prostate cancer, breast cancer, and head and neck malignancies. This finding highlights PI3K/Akt pathway inhibition as a central mechanistic axis through which melatonin may exert tumor-suppressive effects. Collectively, the available evidence supports melatonin as a biologically plausible and clinically attractive adjunct in cancer therapy, although further mechanistic studies and well-designed clinical trials are needed to define its therapeutic value more precisely.