Identification of a Vitamin-D Receptor Antagonist, MeTC7, which Inhibits the Growth of Xenograft and Transgenic Tumors In Vivo

Vitamin-D receptor (VDR) mRNA is overexpressed in neuroblastoma and carcinomas of lung, pancreas, and ovaries and predicts poor prognoses. VDR antagonists may be able to inhibit tumors that overexpress VDR. However, the current antagonists are arduous to synthesize and are only partial antagonists, limiting their use. Here, we show that the VDR antagonist MeTC7 (5), which can be synthesized from 7-dehydrocholesterol (6) in two steps, inhibits VDR selectively, suppresses the viability of cancer cell-lines, and reduces the growth of the spontaneous transgenic TH-MYCN neuroblastoma and xenografts in vivo. The VDR selectivity of 5 against RXRα and PPAR-γ was confirmed, and docking studies using VDR-LBD indicated that 5 induces major changes in the binding motifs, which potentially result in VDR antagonistic effects. These data highlight the therapeutic benefits of targeting VDR for the treatment of malignancies and demonstrate the creation of selective VDR antagonists that are easy to synthesize

Development of Potent Forchlorfenuron Analogs and Their Cytotoxic Effect in Cancer Cell Lines

Abstract Forchlorfenuron (FCF) is a synthetic plant cytokinin widely used in agriculture to promote fruit size, that paradoxically inhibits proliferation, migration, and invasion in human cancer cell lines. FCF has also been shown to affect HIF-1α and HER2, which are both known to play a crucial role in cancer cell survival. In this study, we have developed potent FCF analogs through structural modification of FCF, coined UR214-1, UR214-7, and UR214-9. Compared to parental FCF, these analogs are more effective in decreasing viability and proliferation in both ovarian and endometrial cancer cell lines. These FCF analogs also suppress HER2 expression at a concentration lower than that of FCF. In addition, we found that treatment with either FCF or its analogs decreases the expression of human epididymis protein 4 (HE4), which is commonly upregulated in ovarian and endometrial cancers. Given the association between cancer behavior and HE4 production in gynecologic cancers, our findings may provide insight useful in the development of new treatment strategies for gynecologic cancers