Mechanism of action of aragusterol a (YTA0040), a potent anti-tumor marine steroid targeting the G1 phase of the cell cycle
| Autor: | Nagahiro Saijo, Hisao Fukumoto, Tomoko Ichihara, Kayoko Nanaumi, Takehiro Yamagishi, Kazuto Nishio, Shiro Nakaike, Kazuya Fukuoka, Kazunori Samata, Hisao Ikeya, Nobuhiro Narita, Takahiro Yoneda, Kazuo Iguchi, Noriko Hirayama, Yasuji Yamada |
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| Rok vydání: | 2000 |
| Předmět: |
Cancer Research
Lung Neoplasms Macromolecular Substances Cyclin A Antineoplastic Agents Cell Cycle Proteins Retinoblastoma Protein Proto-Oncogene Proteins p21(ras) Mice Cyclin D1 Cyclin-dependent kinase Carcinoma Non-Small-Cell Lung Cyclins Tumor Cells Cultured Animals Humans Phosphorylation Cyclin A549 cell biology Leukemia P388 Cyclin-dependent kinase 2 G1 Phase DNA Cell cycle Molecular biology Cyclin-Dependent Kinases Porifera Oncology Biochemistry Drug Resistance Neoplasm biology.protein Steroids Drug Screening Assays Antitumor Tumor Suppressor Protein p53 Cell Division CDK inhibitor |
| Zdroj: | International Journal of Cancer. 88:810-819 |
| ISSN: | 1097-0215 0020-7136 |
| DOI: | 10.1002/1097-0215(20001201)88:5<810::aid-ijc20>3.0.co;2-p |
| Popis: | Aragusterol A (YTA0040), isolated from the Okinawan marine sponge of the genus Xestospongia, is a potent anti-tumor marine steroid that possesses a unique structural component. This compound showed broad-spectrum anti-proliferative activity against a panel of 14 human cancer cell lines (IC50 = 0.01–1.6 μM). P-glycoprotein–mediated, multidrug-resistant cells showed cross-resistance to YTA0040 cells, whereas cisplatin-resistant non-small-cell lung-cancer (NSCLC) sublines showed a collateral sensitivity to YTA0040. In transplantable murine tumor models, YTA0040 displayed a broad spectrum and high degree of anti-tumor activity when administered i.p. or p.o. (life span T/C = 135–234%). In P388 murine leukemia cells, YTA0040 caused dose- and time-dependent suppression of nucleic acid and protein synthesis, with protein synthesis being more potently and rapidly inhibited than nucleic acid synthesis. Flow-cytometric analysis revealed that YTA0040 blocked the entry of human NSCLC-derived A549 cells into S phase, leading to arrest in the G1 phase of the cell cycle. Western blot analysis demonstrated that YTA0040 caused a dose-dependent decrease in the levels of expression of hyperphosphorylated pRb and cyclin A in A549 cells. The level of p53 protein expression was decreased by YTA0040 treatment. A higher concentration of YTA0040 down-regulated the levels of expression of CDK2, CDK4, cyclin D1 and cyclin E. These findings indicated that YTA0040 arrested human NSCLC cells in late G1 phase of the cell cycle through inhibition of pRb phosphorylation. Inhibition of pRb phosphorylation by YTA0040 resulted from down-regulation of levels of expression of the CDKs and cyclins involved in the G1/S transition and not from induction of p53 and/or the CDK inhibitor p21. Int. J. Cancer 88:810–819, 2000. © 2000 Wiley-Liss, Inc. |
| Databáze: | OpenAIRE |
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