SHetA2 is a novel anti-cancer compound that regulates growth and differentiation similar to retinoids, but does not directly activate RARs or RXRs. SHetA2 inhibited the growth of ovarian cancer xenografts without evidence of toxicity. Additional animal models have demonstrated that SHetA2 does not induce teratogenicity or skin irritation. Thus, SHetA2 exhibits an improved therapeutic ratio over retinoids capable of activating the retinoid receptors. Because SHetA2 is currently in pre-clinical development through the Rapid Access to Intervention and Development (RAID) program of the National Cancer Institute (NCI), additional basic science research, which is not supported by RAID, is needed to understand the mechanism of action of this compound before it is tested in humans. The hypothesis is that SHetA2 directly interacts with the mitochondria resulting in generation of reactive oxygen species, mitochondrial membrane depolarization, and inhibition of NF-kappaB activity and expression of thymidine phosphorylase and thrombospondin-4 gene expression. In endothelial cells this pathway inhibits the development of capillaries. The hyperactive metabolic state of ovarian cancer cells, increases the sensitivity of their mitochondria to the SHetA2 perturbations with the ultimate outcome being the induction of the intrinsic pathway to apoptosis. The more stable mitochondrial state of normal cells makes them more resistant to SHetA2-induced apoptosis. SHetA2 induces glandular differentiation through activation of hepatic nuclear factor-4, which regulates genes involved in glycoprotein metabolism, Galactosamine (N-acetyl)-6-sulfate sulfatase and UDP-galactose-4-epimerase and the TSP-4 glycoprotein.
The specific aims are to decipher the SHetA2 molecular pathways of: 1) differential apoptosis in cancerous versus normal ovarian cells, 2) glandular differentiation and 3) inhibition of endothelial cell capillary formation. The results of these studies will provide mechanistic information on SHetA2 required for appropriate design of clinical trials and improved compounds, and scientific information on apoptosis and differentiation. The elucidation of the proteins involved in the SHetA2 pathwayswill provide potential biomarkers for ovarian cancer diagnosis, prevention and treatment strategies. ? ?
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