In vivo inhibition of the estrogen sulfatase enzyme and growth of DMBA-induced mammary tumors by melatonin.
Melatonin inhibits the growth of different kinds of neoplasias, especially breast cancer, by interacting with estrogen-responsive pathways, thus behaving as an antiestrogenic hormone. Recently, we described that melatonin reduces sulfatase expression and activity in MCF-7 human breast cancer cells, thus modulating the local estrogen biosynthesis. In this study, to investigate the in vivo sulfatase-inhibitory properties of melatonin, this indoleamine was administered to ovariectomized rats bearing DMBA-induced mammary tumors, and treated with estrone sulfate. In castrated animals, the growth of estrogen-sensitive mammary tumors depends on the local conversion of biologically inactive estrogens to bioactive unconjugated estrogens. Ovariectomy significantly reduced the size and the number of the tumors while the administration of estrone sulfate to ovariectomized animals stimulated tumor growth, an effect which was suppressed by melatonin. The uterine weight of ovariectomized rats, which depends on the local synthesis of estrogens, was increased by estrone sulfate, except in those animals which were also treated with melatonin. The growth-stimulatory effects of estrone sulfate on the uterus and tumors depend exclusively on locally formed estrogens, since no changes in serum estradiol were appreciated in estrone sulfate-treated rats. Melatonin counteracted the stimulatory effects of estrone sulfate on sulfatase activity and expression and incubation with melatonin decreased the sulfatase activity of tumors from control animals. Animals treated with melatonin had the same survival probability as the castrated animals and significantly higher than the uncastrated. We conclude that melatonin could exert its antitumoral effects on hormone-dependent mammary tumors by down-regulating the sulfatase pathway of the tumoral tissue.
González
Alicia
A
Department of Physiology and Pharmacology, School of Medicine, University of Cantabria, 39011 Santander, Spain.
Alvarez-García
Virginia
V
Martínez-Campa
Carlos
C
Mediavilla
María Dolores
MD
Alonso-González
Carolina
C
Sánchez-Barceló
Emilio J
EJ
Cos
Samuel
S
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004970:Estrone / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008550:Melatonin / Q000494:pharmacology*; D010052:Ovariectomy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013429:Sulfatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden; D014599:Uterus / Q000187:drug effects / Q000473:pathology
D018931:Antineoplastic Agents, Hormonal; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D004970:Estrone; D015127:9,10-Dimethyl-1,2-benzanthracene; D013429:Sulfatases; C039596:estrogen sulfatase; D008550:Melatonin; C017296:estrone sulfate