Structural modulation of reactivity/activity in design of improved benzothiophene selective estrogen receptor modulators: induction of chemopreventive mechanisms.

The benzothiophene selective estrogen receptor modulators (SERM) raloxifene and arzoxifene are in clinical use and clinical trials for chemoprevention of breast cancer and other indications. These SERMs are "oxidatively labile" and therefore have potential to activate antioxidant responsive element (ARE) transcription of genes for cytoprotective phase II enzymes such as NAD(P)H-dependent quinone oxidoreductase 1 (NQO1). To study this possible mechanism of cancer chemoprevention, a family of benzothiophene SERMs was developed with modulated redox activity, including arzoxifene and its metabolite desmethylarzoxifene (DMA). The relative antioxidant activity of these SERMs was assayed and correlated with induction of NQO1 in murine and human liver cells. DMA was found to induce NQO1 and to activate ARE more strongly than other SERMs, including raloxifene and 4-hydroxytamoxifen. Livers from female, juvenile rats treated for 3 days with estradiol and/or with the benzothiophene SERMs arzoxifene, DMA, and F-DMA showed substantial induction of NQO1 by the benzothiophene SERMs. No persuasive evidence in this assay or in MCF-7 breast cancer cells was obtained of a major role for the estrogen receptor in induction of NQO1 by the benzothiophene SERMs. These results suggest that arzoxifene might provide chemopreventive benefits over raloxifene and other SERMs via metabolism to DMA and stimulation of ARE-mediated induction of phase II enzymes. The correlation of SERM structure with antioxidant activity and NQO1 induction also suggests that oxidative bioactivation of SERMs may be modulated to enhance chemopreventive activity.