期刊
DALTON TRANSACTIONS
卷 -, 期 48, 页码 10882-10888出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/b917792b
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资金
- US National Institutes of Health [CA114046]
- NATIONAL CANCER INSTITUTE [P01CA114046] Funding Source: NIH RePORTER
In this study, we investigate the anticancer properties of an inert half-sandwich metal complex scaffold. UV melting experiments with duplex DNA and H-1-NMR experiments with 9-ethylguanine reveal that the apoptotic ruthenium complex DW12 does not interact with DNA. On the other hand, diminishing the kinase inhibition properties of DW12 by methylating the maleimide nitrogen (DW12-Me) abolishes the anticancer activity. Furthermore, the incorporation of a fluorine into the pyridine moiety (NP309) improves the IC50 value for glycogen synthase kinase 3 (GSK-3) and at the same time the cytotoxicity, implying that the anticancer activity correlates with the inhibition of GSK-3 and maybe other not yet identified kinases. We demonstrate in Burkitt-like lymphoma (BJAB) cells that NP309 is not necrotic but induces apoptosis and that this apoptosis is mediated by a loss of the mitochondrial membrane potential, caspase-9 processing, and is partly dependent on Bcl-2 expression. In addition, NP309 efficiently induces apoptosis in vincristine-and cytarabine-resistant human B-cell precursor cell lines.
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