Molecular and Cellular Mechanisms of Melatonin in Osteosarcoma

Abstract

Osteosarcoma, the most common primary bone malignancy, occurs most frequently in adolescents with a peak of incidence at 11-15 years. Melatonin, an indole amine hormone, shows a wide range of anticancer activities. The decrease in melatonin levels simultaneously concurs with the increase in bone growth and the peak age distribution of osteosarcoma during puberty, so melatonin has been utilized as an adjunct to chemotherapy to improve the quality of life and clinical outcomes. While a large amount of research has been conducted to understand the complex pleiotropic functions and the molecular and cellular actions elicited by melatonin in various types of cancers, a few review reports have focused on osteosarcoma. Herein, we summarized the anti-osteosarcoma effects of melatonin and its underlying molecular mechanisms to illustrate the known significance of melatonin in osteosarcoma and to address cellular signaling pathways of melatonin in vitro and in animal models. Even in the same kind of osteosarcoma, melatonin has been sparingly investigated to counteract tumor growth, apoptosis, and metastasis through different mechanisms, depending on different cell lines. We highlighted the underlying mechanism of anti-osteosarcoma properties evoked by melatonin, including antioxidant activity, anti-proliferation, induction of apoptosis, and the inhibition of invasion and metastasis. Moreover, we discussed the drug synergy effects of the role of melatonin involved and the method to fortify the anti-cancer effects on osteosarcoma. As a potential therapeutic agent, melatonin is safe for children and adolescents and is a promising candidate for an adjuvant by reinforcing the therapeutic effects and abolishing the unwanted consequences of chemotherapies.

Melatonin Enhances Osteoblastogenesis from Senescent Mesenchymal Stem Cells via MMSET Mediated Chromatin Remodeling

“…Previous studies have shown that melatonin is a key molecule in a wide variety of physiological and pathological processes due to the diverse expression of melatonin and its receptors (3,4). Many of the effects of melatonin are mediated directly through membrane-bound melatonin receptors or indirectly via nuclear orphan receptors of the RORα/RZR family (5). Accumulating evidence has also indicated that melatonin is involved in bone remolding, osteoporosis, osseointegration of dental implants, and dentine formation (6,7).…”

Curcumin Analogue L48H37 Suppresses Human Osteosarcoma U2OS and MG-63 Cells’ Migration and Invasion in Culture by Inhibition of uPA via the JAK/STAT Signaling Pathway

“…Based on radiological staging, the combination of limb-sparing surgery and effective chemotherapy for osteosarcoma has increased long-term survival rates to approximately 68% recently [ 5 , 6 ]. However, early metastatic transfer to the lungs is still responsible for most treatment failure and is accountable for one of the most lethal pediatric malignancies [ 7 ].…”

Melatonin Inhibits the Progression of Oral Squamous Cell Carcinoma via Inducing miR-25-5p Expression by Directly Targeting NEDD9

“…Melatonin (N-acetyl-5-methoxytryptamine), a natural indoleamine, is mainly synthesized by the mammalian pineal gland and other tissues, such as lymphocytes, Harderian gland, liver, and gastrointestinal tract (7,8). Interestingly, melatonin can regulate the circadian rhythms in living organisms, showing a wide distribution from bacteria to humans (9,10). It has been shown that melatonin plays a vital role in the different physiological events, including the regulation of light/darkness responses, inhibition of tumor progression, improvement of immune system actions, and controlling of homeostasis in the different tissues (11)(12)(13)(14).…”