cgp-52608 and Breast-Neoplasms

Melatonin may influence directly tumor cells through the specific binding sites. The best known melatonin binding sites are membrane receptors. Recently, the participation of nuclear signalling via estrogen as well as RZR/ROR receptors in oncostatic action of melatonin on the breast cancer has been widely discussed. The aim of present study was to investigate effects of melatonin, the selective ligand for nuclear RZR/ROR receptors - CGP 52608, and methotrexate on growth of murine 16/C breast cancer cells.. The experiment was performed in vitro. The breast cancer cells were incubated for 2 days in the presence of melatonin, CGP 52608 (at concentrations of 10(-5)M, 10(-7)M, 10(-9)M, 10-(11)M ) and methotrexate (at concentrations of 0.25 and 0.125 microg/ml). The growth of cells was measured using the modified Mossman method.. All examined compounds significantly inhibited the growth of cancer cells. The effects of MLT and CGP 52 608 were comparable with suppression caused by methotrexate. The significant differences of efficacy between two examined concentrations of methotrexate were not observed.. The obtained data together with our previous results indicate that nuclear receptors RZR/ROR play an important, although not sufficiently recognized role in the oncostatic action of melatonin.

Topics: Adenocarcinoma; Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Melatonin; Methotrexate; Mice; Nuclear Receptor Subfamily 1, Group F, Member 2; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Statistics, Nonparametric; Thiazoles; Thiosemicarbazones

The RNA expression levels of human catalytic subunit (TERT) and the RNA subunit (TR) of telomerase were analysed after treatment with the agonists of the membrane receptor (S 20098) and the nuclear receptor (CGP 52608) for melatonin in the MCF-7 human breast tumor cell line. Neither membrane nor nuclear signalling affected the RNA steady-state levels of the TR subunit of telomerase. On the contrary, we observed a significant decreased in the RNA levels of TERT after treatment with CGP 52608 while S 20098 produced a significant increase in the RNA levels of TERT. These results support a cross-talk between membrane and nuclear melatonin signalling and provide new data on the hormonal regulation of telomerase function.

Topics: Acetamides; Breast Neoplasms; Catalytic Domain; Female; Humans; Hypnotics and Sedatives; Melatonin; Receptors, Melatonin; RNA; Signal Transduction; Telomerase; Thiazoles; Thiosemicarbazones; Tumor Cells, Cultured

Two putative melatonin receptors have been described including the cell surface G-protein-linked receptors, mt1 and MT2, and the nuclear retinoic orphan receptor alpha (RORalpha). The mt1 receptor, but not the MT2 receptor, is expressed in human breast tumor cell lines, and melatonin-induced growth suppression can be mimicked by the mt1 and MT2 agonist, AMMTC, and blocked by the antagonist, CBPT. RORalpha receptors are also expressed in MCF-7 breast cancer cells and the putative RORalpha agonist CPG-52608 inhibits MCF-7 cell growth but with a very different dose-response than melatonin. Finally, melatonin and AMMTC, but not CPG-52608, can repress RORalpha transcriptional activity in MCF-7 cells.

Topics: Breast Neoplasms; Carbazoles; Cell Division; Dose-Response Relationship, Drug; Humans; Immunoblotting; Luciferases; Melatonin; Nuclear Receptor Subfamily 1, Group F, Member 1; Receptors, Cell Surface; Receptors, Cytoplasmic and Nuclear; Receptors, Melatonin; Recombinant Fusion Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thiazoles; Thiosemicarbazones; Trans-Activators; Tumor Cells, Cultured