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Development of flexible-heteroarotinoids for kidney cancer
Tongzu Liu1, Chioniso Patience Masamha, Shylet Chengedza
1Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
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.
Insights
The Flexible Heteroarotinoid (Flex-Het) SHetA2 shows promise for kidney cancer treatment by inducing apoptosis and differentiation in cancer cells while sparing normal cells. Further development of related compounds maintains this differential efficacy.
Area of Science:
- Pharmacology
- Oncology
- Molecular Biology
Background:
- Flexible Heteroarotinoids (Flex-Hets), including SHetA2, demonstrate potential in inhibiting cancer cell growth.
- Understanding the precise mechanism of action and in vivo efficacy of SHetA2 in kidney cancer is crucial for therapeutic development.
Purpose of the Study:
- To elucidate the molecular mechanism by which SHetA2 exerts its effects on kidney cancer cells.
- To evaluate the in vivo anti-cancer activity of SHetA2 in preclinical models of renal cancer.
- To explore structure-activity relationships of related Flex-Hets for improved pharmaceutical properties.
Main Methods:
- Assessed SHetA2's impact on apoptosis markers (Bcl-2, PARP-1, caspase 3) and cell cycle regulators (Cyclin D1) in Caki-1 kidney cancer cells.
- Investigated SHetA2's effect on tubule differentiation and E-Cadherin expression in organotypic cultures and xenografts.
- Analyzed nuclear factor-κB (NF-κB) activity and its downstream targets.
- Conducted in vivo studies using renal cancer xenograft models.
- Performed structure-function analysis of related Flex-Hets and Ames mutagenicity tests.
Main Results:
- SHetA2 induced apoptosis and G(1) cell cycle arrest in Caki-1 cells, with minimal effects on normal kidney cells.
- SHetA2 promoted tubule differentiation and increased E-Cadherin expression, while repressing NF-κB activity.
- Oral SHetA2 inhibited tumor growth in one of two renal cancer xenograft models without significant toxicity.
- Modifications to increase hydrophilicity of Flex-Hets slightly reduced efficacy but preserved differential effects on cancer cells.
- Flex-Hets and their metabolites were found to be non-mutagenic.
Conclusions:
- SHetA2 effectively regulates kidney cancer cell growth, differentiation, and apoptosis via NF-κB repression and downstream molecular events.
- The differential effect of SHetA2 on cancer versus normal cells is maintained even with modifications aimed at improving pharmaceutical properties.
- These findings support the therapeutic potential of SHetA2 and related Flex-Hets for kidney cancer treatment.
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