Melatonin and vitamin D as potential synergistic adjuvants for cancer therapy (Review)

Abstract

Significant advancements have been made in cancer therapy; however, limitations remain with some conventional approaches. Adjuvants are agents used alongside primary treatments to enhance their efficacy and the treatment outcomes of patients. Modern lifestyles contribute to deficiencies in melatonin and vitamin D. Limited sun exposure affects vitamin D synthesis, and artificial light at night suppresses melatonin production. Both melatonin and vitamin D possess anti‑inflammatory, immune‑boosting and anticancer properties, rendering them potential adjuvants of interest. Studies suggest melatonin and vitamin D supplementation may address antioxidant imbalances in lip, oral and pharyngeal cancers. Moreover, promising results from breast, head and neck, brain, and osteosarcoma research indicate potential for tumor growth inhibition, improved survival, and a better quality of life of patients with cancer. The radioprotective properties of melatonin and vitamin D are another exciting area of exploration, potentially enhancing radiotherapy effectiveness while reducing side effects. For its part, the sleep‑promoting effects of melatonin may indirectly benefit patients with cancer by influencing the immune system. Thus, the prevalence of vitamin D and melatonin deficiencies highlights the importance of supplementation, as lower levels can worsen side‑effects from cancer treatments. The present review explores the potential of combining melatonin and vitamin D as synergistic adjuvants for cancer therapy. These agents have shown promise individually in cancer prevention and treatment, and their combined effects warrant investigation. Therefore, large‑scale controlled trials are crucial to definitively determine the optimal dosage, safety and efficacy of this combination in improving the lives of patients with cancer.

Keywords: cancer; melatonin; synergistic actions; treatment; vitamin D.

Figure 1

Antitumor activities of melatonin and vitamin D as regards different cancer hallmarks.

Figure 2

Illustration of the synthesis and potential synergistic effects of melatonin and VitD3 (cholecalciferol) in a cancer cell. During the night, melatonin is synthesized in the pineal gland from the precursor serotonin which is converted into N-acetyl-serotonin by AANAT. With the action of ASMT and SAM the final stage of melatonin production is achieved. Light inhibits the synthesis of melatonin, while increasing the levels of VitD3, which is activated with different tissue-specific hydroxylase enzymes. Melatonin can easily cross the cell membrane to act in a receptor independent response thus activating signaling pathways in the cytosol or mainly binding through their G protein-coupled receptors MT1 and MT2 to mediate numerous biological actions. The effects of VitD3 are primarily genomic and mediated by its interaction with nuclear VDR, and melatonin is documented to increase VDR transactivation. In the cytosol, VDR and VitD3 can trigger non-genomic responses by modulating various cell signaling cascades. Treatment with melatonin and VitD3 may act synergistically to inhibit cancer cell growth by increasing the levels of TGFβ-1, Smad4 and phosphorylated Smad3, thus enhancing the TGF pathway. This combination can also promote a reduction in Akt phosphorylation and MDM2 levels, thereby leading to an increase in p53 pathway and consequently causing tumor suppression and apoptosis. AANAT, alkylamine acetyltransferase; ASMT, acetyl-serotonin O-methyltransferase; SAM, S-adenosyl methionine; VDR, vitamin D receptor; TGFβ-1, transforming growth factor beta 1; Smad3, suppressors of mothers against decapentaplegic homolog 3; Smad4, suppressors of mothers against decapentaplegic homolog 4; MDM2, mouse double minute 2 homolog; p53, tumor protein p53.