Melatonin as a promising agent to treat ovarian cancer: molecular mechanisms

Abstract

Ovarian cancer (OC) has the highest mortality rate of all gynecological cancers, and most patients develop chemoresistance after first-line treatments. Despite recent advances, the 5-year relative survival is ~45% for all OC subtypes, and invasive epithelial OC has only a 17% survival rate when diagnosed at a late stage. Identification of new efficacious molecules or biomarkers represents important opportunities in the treatment of OC. The pharmacological and physiological properties of melatonin indicate this agent could be useful against OC progression and metastasis. In normal cells, melatonin has potent antioxidant and anti-apoptotic actions. Conversely, melatonin has pro-oxidant as well as anti-proliferative, anti-angiogenic and immunomodulatory properties in many cancer types including hormone-dependent cancers. Although melatonin receptors have been identified in OC cells, the exact mechanism by which melatonin induces anticancer activities remains incompletely understood. Clinical studies have reported negative correlation between aggressiveness of OC and serum levels of melatonin, reinforcing the idea that melatonin may be a critical factor determining OC development. In vitro and in vivo studies suggest melatonin differentially regulates multiple signaling pathways in OC cells. This focused review explores the potential mechanisms of action of melatonin on cultured OC cells and in experimental models of OC in an attempt to clarify how melatonin modulates the signaling pathways involved in cancer cell apoptosis, survival, inflammation, proliferation and metabolic processes. Based on the evidence presented, we feel that melatonin, as an agent that controls cellular signals associated with malignancy, may be beneficial in combination with other therapeutics for OC treatment.

Melatonin as an Anti-Inflammatory Agent Modulating Inflammasome Activation

“…Pathological inflammation has been related to several different diseases, and current anti-inflammatory drugs have significant side effects; so, it is important to identify new therapeutic approaches to reduce inflammatory processes without impairing the physiologic inflammatory response. As reported above, melatonin has many actions [ 14 , 37 , 43 , 87 – 89 ] and numerous experimental studies have shown that melatonin is not only an important antioxidant but also a widespread anti-inflammatory molecule [ 45 , 82 , 88 , 90 – 92 ]. Thus, melatonin is a molecule of high clinical interest.…”

Promising Antineoplastic Actions of Melatonin

“… Borin et al (2016) observed similar results in vitro human breast cancer cell lines MDA-MB-231 (metastatic, ERα-negative). Furthermore, melatonin has been shown to convert the human breast cancer cell line MCF-7 to a less invasive phenotype by increasing expression of E-cadherin, a prototypical member of the type-1 classical cadherins whose loss favors tumor metastasis ( Cos et al, 1998 ; Chuffa et al, 2017 ). The anti-invasive effect of melatonin on breast cancer may be also through the downregulation of the p38 pathway and suppression of metalloproteinases-2 and -9 expression and activity ( Mao et al, 2010 ).…”

PTEN/AKT/mTOR signaling mediates anticancer effects of epigallocatechin‑3‑gallate in ovarian cancer

“…Ovarian cancer occurs in women with a prevalence ~15,000 per 100,000 individuals worldwide (20). Due to a lack of specific symptoms in the early stages, 60-70% of patients with ovarian cancer are diagnosed at an advanced stage, and their 5-year survival rate is ~40% (21,22). Standard therapy strategies for advanced-stage ovarian cancer are primary debulking surgery combined with platinum and paclitaxel chemotherapy (23,24).…”