Abstract
Retinoid X receptor (RXR) is known to play various roles in embryogenesis, metabolic processes, differentiation, and apoptosis. Recently, RXR has been studied as a target for cancer chemoprevention and treatment. To discover potential cancer chemopreventive agents acting through RXRs, we developed a cell line‐based RXR response element (RXRE)‐luciferase reporter gene assay system. Following extensive screening, 3‐amino‐6‐(3aminopropyl)‐5,6‐dihydro‐5,11‐dioxo‐11H‐indeno[1,2‐c]isoquinoline dihydrochloride (AM6‐36) was found to induce RXRE‐luciferase activities in a dose‐dependent manner. Subsequently, the substance was found to inhibit the proliferation of MCF‐7 breast cancer cells in a concentration‐dependent manner. Prompted by these results, we examined the underlying mechanism of AM6‐36 anti‐proliferative activity using MCF‐cells as a model. In brief, at lower concentrations, G2/M arrest was observed, and S phase arrest was enhanced at higher concentrations. Based on DNA microarray analysis, AM6‐36 was found to up‐regulate the expression of CDKN1A, a target gene of RXR, by ∼40‐fold. In accordance with this response, the protein level of CDKN1A (p21WAF1/CIP1) was increased in the presence of AM6‐36. Induction of p21 by AM6‐36 was abrogated following transient transfection of RXR siRNA, demonstrating the effect of AM6‐36 on the expression of p21 is closely related to modulation of RXR transcriptional activity. These data suggest AM6‐36 is a promising lead compound for the treatment or prevention of breast cancer. A synthetic procedure has been devised for large‐scale production, moderate absorption and slow metabolism has been demonstrated with rats (p.o. administration), and more advanced anti‐tumor evaluation is underway. (Supported by program project P01 CA48112 awarded by the National Cancer Institute.)
Citation Information: Cancer Prev Res 2010;3(1 Suppl):B91.
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