New approaches of PARP-1 inhibitors in human lung cancer cells and cancer stem-like cells by some selected anthraquinone-derived small molecules
| Autor: | Yu Ru Lee, Kuo Feng Huang, Chia Chung Lee, Chun Liang Chen, Shih Jie Chou, Hsu Shan Huang, Ya Chun Liang, Shih Hwa Chiou, Dah Shyong Yu, Tsung Chih Chen |
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| Rok vydání: | 2012 |
| Předmět: |
Homeobox protein NANOG
Telomerase Lung Neoplasms DNA damage Poly (ADP-Ribose) Polymerase-1 Cancer Treatment lcsh:Medicine DNA repair Anthraquinones Antineoplastic Agents Biology Pharmacology Poly(ADP-ribose) Polymerase Inhibitors Biochemistry Lung and Intrathoracic Tumors Structure-Activity Relationship Oxidative Damage Molecular cell biology Cell Line Tumor Basic Cancer Research medicine Cancer Detection and Diagnosis Humans Enzyme Inhibitors lcsh:Science Cytotoxicity Cell Proliferation Multidisciplinary lcsh:R Cancers and Neoplasms DNA medicine.disease Small molecule Telomere Non-Small Cell Lung Cancer Nucleic acids Chemistry Oncology PARP inhibitor Medicine lcsh:Q Oncology Agents Medicinal Chemistry Ovarian cancer Cancer Prevention Research Article |
| Zdroj: | PLoS ONE PLoS ONE, Vol 8, Iss 2, p e56284 (2013) |
| ISSN: | 1932-6203 |
| Popis: | Poly (ADP-ribose) polymerase-1 (PARP-1) and telomerase, as well as DNA damage response pathways are targets for anticancer drug development, and specific inhibitors are currently under clinical investigation. The purpose of this work is to evaluate anticancer activities of anthraquinone-derived tricyclic and tetracyclic small molecules and their structure-activity relationships with PARP-1 inhibition in non-small cell lung cancer (NSCLC) and NSCLC-overexpressing Oct4 and Nanog clone, which show high-expression of PARP-1 and more resistance to anticancer drug. We applied our library selected compounds to NCI's 60 human cancer cell-lines (NCI-60) in order to generate systematic profiling data. Based on our analysis, it is hypothesized that these drugs might be, directly and indirectly, target components to induce mitochondrial permeability transition and the release of pro-apoptotic factors as potential anti-NSCLC or PARP inhibitor candidates. Altogether, the most active NSC747854 showed its cytotoxicity and dose-dependent PARP inhibitory manner, thus it emerges as a promising structure for anti-cancer therapy with no significant negative influence on normal cells. Our studies present evidence that telomere maintenance should be taken into consideration in efforts not only to overcome drug resistance, but also to optimize the use of telomere-based therapeutics. These findings will be of great value to facilitate structure-based design of selective PARP inhibitors, in general, and telomerase inhibitors, in particular. Together, the data presented here expand our insight into the PARP inhibitors and support the resource-demanding lead optimization of structurally related small molecules for human cancer therapy. |
| Databáze: | OpenAIRE |
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