title: 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.
authors.affiliation: Department of Structural & Cellular Biology, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
authors.forename: Lulu
authors.initials: L
authors.lastname: Mao
authors.forename: Qi
authors.initials: Q
authors.lastname: Cheng
authors.forename: Béatrice
authors.initials: B
authors.lastname: Guardiola-Lemaître
authors.forename: Carole
authors.initials: C
authors.lastname: Schuster-Klein
authors.forename: Chunmin
authors.initials: C
authors.lastname: Dong
authors.forename: Ling
authors.initials: L
authors.lastname: Lai
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hill
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015152:Blotting, Northern; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011863:Radioimmunoassay; D051381:Rats; D044094:Receptors, Melatonin / Q000819:agonists*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071164:Trefoil Factor-2
chemical_list: D000970:Antineoplastic Agents; D047628:Estrogen Receptor alpha; D019253:Proto-Oncogene Proteins c-bcl-2; D044094:Receptors, Melatonin; C000604008:Tff2 protein, rat; D000071164:Trefoil Factor-2