DEPLETION OF ESTROGEN-RECEPTOR IN HUMAN BREAST-TUMOR CELLS BY A NOVELSUBSTITUTED INDOLE THAT DOES NOT BIND TO THE HORMONE-BINDING DOMAIN

Steroidal antiestrogens appear to have at least two major modes of act ion in breast cancer cells, direct antagonism of estrogen binding to i ts receptor and depletion of estrogen receptors (ER) due to inhibition of dimerization of the receptor and a resultant destabilization of th e receptor protein. In a search for other classes of compounds which w ould act as dimerization inhibitors, a novel substituted indole droxy- 2-methyl-1H-indol-3-yl]-acetylamino}octanoic acid butyl-methyl amide, MDL 101,906) was synthesized. Binding of the ER to its consensus respo nse element (ERE) was apparently decreased in nuclear extracts from MC F-7 human breast cancer cell treated with MDL 101,906. This decreased binding was found to be due to depletion of ER based on direct measure ment of ER using an enzyme-linked immunoassay. Other transcription fac tors were apparently unaffected by MDL 101,906 treatment. Whereas depl etion of ER with a steroidal antiestrogen was almost complete after 3 h of treatment of MCF-7 cells, the effect of MDL 101,906 took signific antly longer to occur, suggesting a fundamental difference in the mech anisms of action of the two drugs. This was also evident in the lack o f binding of MDL 101,906 to the hormone binding domain of ER. MDL 101, 906 treatment also caused depletion of ER mRNA in MCF-7 cells. Depleti on of ER mRNA was noted by 3 h of drug treatment and was apparently al most complete after 24 h of treatment. Depletion of ER from MCF-7 cell s led to a dose-dependent decrease in the expression of luciferase by an ERE-driven luciferase reporter gene assay system. The mechanism of MDL 101,906 appears to be unique and additional studies with this chem ical class seem to be warranted to assess the potential for therapeuti c utility. Copyright (C) 1996 Elsevier Science Ltd.