Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth
| Autor: | Aakanksha Khandelwal, D R Soprano, Jhalak Mehta, Angela Brodie, Gauri Sabnis, Aashvini Belosay, Jyoti Patel, Vincent C. O. Njar |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
medicine.medical_specialty Fenretinide Receptors Retinoic Acid Cellular differentiation Transplantation Heterologous Retinoic acid Antineoplastic Agents Breast Neoplasms Tretinoin Biology Mice chemistry.chemical_compound breast cancer Cyclin D1 Internal medicine retinoic acid medicine Animals Humans skin and connective tissue diseases Cell Proliferation RAMBAs Cell growth Retinoic Acid Receptor alpha Cell Cycle Imidazoles apoptosis differentiation Cell cycle Caspase 9 Endocrinology Oncology chemistry Cancer cell Cancer research Female Growth inhibition Translational Therapeutics antitumour activity Neoplasm Transplantation medicine.drug |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| DOI: | 10.1038/sj.bjc.6603705 |
| Popis: | Antitumour effects of retinoids are attributed to their influence on cell proliferation, differentiation, apoptosis and angiogenesis. In our effort to develop useful agents for breast cancer therapy, we evaluated the effects of four representative retinoic acid metabolism blocking agents (RAMBAs, VN/14-1, VN/50-1, VN/66-1 and VN/69-1) on growth inhibition of oestrogen receptor positive (ER +ve, MCF-7 and T-47D) and oestrogen receptor negative (ER -ve, MDA-MB-231) human breast cancer cells. Additionally, we investigated the biological effects/molecular mechanism(s) underlying their growth inhibitory properties as well as their antitumour efficacies against MCF-7 and MCF-7Ca tumour xenografts in nude mice. We also assessed the effect of combining VN/14-1 and all-trans-retinoic acid (ATRA) on MCF-7 tumour xenografts. The ER +ve cell lines were more sensitive (IC(50) values between 3.0 and 609 nM) to the RAMBAs than the ER -ve MDA-MB-231 cell line (IC(50)=5.6-24.0 microM). Retinoic acid metabolism blocking agents induced cell differentiation as determined by increased expression of cytokeratin 8/18 and oestrogen receptor-alpha (ER-alpha). Similar to ATRA, they also induced apoptosis via activation of caspase 9. Cell cycle analysis indicated that RAMBAs arrested cells in the G1 and G2/M phases and caused significant downregulation (80%) of cyclin D1 protein. In vivo, the growth of MCF-7 mammary tumours was dose-dependently and significantly inhibited (92.6%, P0.0005) by VN/14-1. The combination of VN/14-1 and ATRA also inhibited MCF-7 breast tumour growth in vivo (up to 120%) as compared with single agents (P0.025). VN/14-1 was also very effective in preventing the formation of MCF-7Ca tumours and it significantly inhibited the growth of established MCF-7Ca tumours, being as effective as the clinically used aromatase inhibitors, anastrozole and letrozole. Decrease in cyclin D1 and upregulation of cytokeratins, Bad and Bax with VN/14-1 may be responsible for the efficacy of this compound in inhibiting breast cancer cell growth in vitro and in vivo. Our results suggest that our RAMBAs, especially VN/14-1 may be useful novel therapy for breast cancer. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|