Abstract
Melatonin has been indicated as a possible oncostatic agent in different types of cancer, its antiproliferative role being demonstrated in several in vitro and in vivo experimental models of tumors. Specifically, melatonin was proven to inhibit cell growth of both androgen-dependent and independent prostate cancer cells, through various mechanisms. A number of melatonin derivatives have been developed and tested for their role in the prevention and treatment of neoplastic diseases. We recently proved the in vitro and in vivo anticancer activity of UCM 1037, a newly-synthetized melatonin analogue, on melanoma and breast cancer cells. In this study we evaluated UCM 1037 effects on cell proliferation, cell cycle distribution, and cytotoxicity in LNCaP, PC3, DU145, and 22Rv1 prostate cancer cells. We demonstrated significant dose- and time-dependent UCM 1037 antiproliferative effects in androgen-sensitive LNCaP and 22Rv1 cells. Data from flow cytometric studies suggest that UCM 1037 is highly cytotoxic in androgen-sensitive prostate cancer cells, although no substantial increase in the apoptotic cell fraction has been observed. UCM 1037 cytotoxic effects were much less evident in androgen-insensitive PC3 and DU145 cells. Experiments performed to gain insights into the possible mechanism of action of the melatonin derivative revealed that UCM 1037 down-regulates androgen receptor levels and Akt activation in LNCaP and 22Rv1 cells.
Highlights
Melatonin is an indolic hormone which plays pleiotropic roles and is widely distributed in most living organisms, where it is involved in various physiological functions [1]
Two case-control studies were conducted on prostate cancer patients indicating that men with urinary melatonin levels below the median had a statistically significant increased risk to develop advanced disease compared with men with levels above the median [5,6]
We previously characterized a number of melatonin receptor ligands and we demonstrated the in vitro and in vivo anticancer activity of newly-synthetized melatonin analogues on melanoma and breast cancer cells [17]
Summary
Melatonin is an indolic hormone which plays pleiotropic roles and is widely distributed in most living organisms, where it is involved in various physiological functions [1]. Binding of melatonin to MT2 receptors triggers a number of signal transduction pathways including phosphoinositide production, the inhibition of adenylyl cyclase and the inhibition of soluble guanylyl cyclase pathway [10]. Both membrane receptors can activate other signaling pathways involved in multiple regulatory processes, including phospholipase C/protein kinase C, mitogen-activated protein kinases, and extracellular-signal-regulated kinase pathways [3,11]. Melatonin receptor-independent mechanisms have been demonstrated in prostate cancer suggesting a scenario where the indole triggers signaling cascades that hamper prostate cancer cell growth [7]. Experiments were performed to gain insights into the possible mechanism of action of the melatonin derivative and its crosstalk with the androgen signaling pathway
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