Development of flexible-heteroarotinoids for kidney cancer

Abstract

Potential chemopreventive and therapeutic value of the lead Flexible Heteroarotinoid (Flex-Het), SHetA2, was indicated by growth inhibition of multiple cancer cell lines. The objective of this study was to evaluate the SHetA2 mechanism and in vivo activity in kidney cancer. SHetA2 induced apoptosis in the Caki-1 kidney cancer cell line through reduction of Bcl-2 protein and induction of PARP-1 and caspase 3 cleavages, whereas normal kidney epithelial cells exhibited resistance. Both normal and cancerous cells underwent G 1 arrest and loss of Cyclin D1. Tubule differentiation was induced in organotypic cultures and xenograft tumors in association with increases in E-Cadherin mRNA and protein expression. SHetA2 repressed activity of nuclear factor-κB, a transcription factor that regulates apoptosis, Bcl-2, growth, Cyclin D1, differentiation, and E-Cadherin in the opposite manner as SHetA2. Glutathione binding and generation of reactive oxygen species were not required for these activities. Oral SHetA2 inhibited growth in one of two renal cancer xenograft models without causing mortality or weight loss. Structure function analysis of related Flex-Hets for potential improvement of SHetA2 pharmaceutical properties showed that compounds with increased hydrophilicity slightly reduced the growth inhibition efficacy, but retained the differential effect on cancer over normal cells.Flex-Hets and metabolites were not mutagenic in the Ames test. In conclusion, SHetA2 regulates growth, differentiation, and apoptosis in kidney cancer cells through multiple molecular events downstream of nuclear factor-κB repression. Increasing the hydrophilicity of Flex-Hets does not attenuate the differential effect on cancer cells over normal cells, thus offering alternatives for improvement of therapeutic value.

Chemoprevention of Colon and Small Intestinal Tumorigenesis in APCmin/+ Mice By SHetA2 (NSC721689) without Toxicity

“…In this study, small intestinal polyps from both SHetA2-treatment groups exhibited reduced levels of the proliferation biomarkers, cyclin D1 and PCNA. Previous studies documented SHetA2-induction of G1 cell cycle arrest in both normal epithelial and endothelial cells and cancer cell lines (12, 13, 15). A mechanistic study in ovarian cancer cell lines demonstrated that this G1 arrest is caused by phosphorylation and ubiquitination of cyclin D1 leading to its degradation and down-stream effects on Rb phosphorylation and signal transduction, while overexpression of wild type or a degradation-resistant mutant of cyclin D1 attenuated SHetA2-induced G1 arrest (14).…”

“…In vitro , Flex-Hets regulate growth, differentiation and apoptosis in cancer cells, while the effects on normal cells are limited to growth inhibition (1, 3, 6, 7, 12–15). In organotypic culture, they reverse the cancerous phenotype of ovarian and kidney cancer cell lines and primary cultures (1, 13). Sulfur Heteroarotinoid A2 (SHetA2, Fig.…”

“…SHetA2 prevented carcinogen-induced transformation of human endometrial organotypic cultures (8). In vivo , the lead Flex-Het, Sulfur Heteroarotinoid A2 (SHetA2), inhibited xenograft tumor angiogenesis and growth without evidence of gross toxicity (4, 12, 13). …”

Anti-Cancer Activities and Interaction of Imiquimod and Flex-Het, SHetA2, in Melanoma and Ovarian Cancer

“…These flexible Hets (Flex-Hets) are potent inducers of apoptosis in vitro and in vivo, while not harming normal cells or tissues [50][51][52][53][54][55][56]. The lead Flex-Het, SHetA2, inhibited growth of ovarian cancer xenografts without producing evidence of in vivo toxicity, skin irritancy, or teratogenicity [51,57].…”

“…The lead Flex-Het, SHetA2, inhibited growth of ovarian cancer xenografts without producing evidence of in vivo toxicity, skin irritancy, or teratogenicity [51,57]. Because SHetA2 does not activate the retinoic acid receptors, it is not classified as a retinoid and does not induce toxicities associated with retinoids [49,51,55,57,58]. SHetA2 can be classified as a Retinoid-Related Molecule (RRM), which exert similar biological effects as retinoids, such as inhibition of cell growth and induction of differentiation, but also exert additional effects, such as apoptosis [59].…”