In vitro and in vivo antitumor activity of melatonin receptor agonists

Abstract: Melatonin has been shown to inhibit the proliferation of estrogen receptor α (ERα)‐positive human breast cancer cells in vitro and suppress the growth of carcinogen‐induced mammary tumors in rats. Melatonin’s antiproliferative effect is mediated, at least in part, through the MT1 melatonin receptor and mechanisms involving modulation of the estrogen‐signaling pathway. To develop melatonin analogs with greater therapeutic effects, we have examined the in vitro and in vivo antimitotic activity of two MT1/MT2 melatonin receptor agonists, S23219‐1 and S23478‐1. In our studies, both agonists are quite effective at suppressing the growth of MCF‐7 human breast cancer cells. At a concentration of 10^?6 m , S23219‐1 and S23478‐1 inhibited the growth of MCF‐7 cells by 60% and 73%, respectively. However, S23478‐1 is more effective than melatonin and S23219‐1 at repressing the expression and transactivation of the ERα, and modulating the expression of pancreatic spasmolytic polypeptide (pS2), an estrogen‐regulated gene. The melatonin agonist S23478‐1 exhibited enhanced antitumor potency in the subsequent studies in our animal model. At a dosage of 25 mg/kg/day, S23478‐1 is more efficacious than melatonin at inducing regression of the established N‐nitroso‐N‐methyl‐urea‐induced rat mammary tumors. This dose of S23478‐1 (25 mg/kg/day) generated a significant (P < 0.05) overall regression response of 52%. Furthermore, at this dosage, S23478‐1 is more effective than melatonin at suppressing the estrogen‐signaling pathway and promoting tumor cell apoptosis, significantly increasing the expression of the pro‐apoptotic protein Bax, while decreasing the expression of ERα and the anti‐apoptotic protein Bcl‐2.