In vitro and in vivo antitumor activity of melatonin receptor agonists.
J Pineal Res
; 49(3): 210-21, 2010 Oct.
Article
en En
| MEDLINE
| ID: mdl-20609073
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 10â»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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Receptores de Melatonina
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
J Pineal Res
Asunto de la revista:
ENDOCRINOLOGIA
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos