Gold-Containing Indoles as Anticancer Agents That Potentiate the Cytotoxic Effects of Ionizing Radiation

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• 作者：Sandra Craig ; Lei Gao ; Irene Lee ; Thomas Gray ; Anthony J. Berdis
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 8, 2012
• 年：2012
• 卷：55
• 期：5
• 页码：2437-2451
• 全文大小：574K
• 年卷期：v.55,no.5(March 8, 2012)
• ISSN：1520-4804

文摘

This report describes the design and application of several distinct gold-containing indoles as anticancer agents. When used individually, all gold-bearing compounds display cytostatic effects against leukemia and adherent cancer cell lines. However, two gold-bearing indoles show unique behavior by increasing the cytotoxic effects of clinically relevant levels of ionizing radiation. Quantifying the amount of DNA damage demonstrates that each gold鈥搃ndole enhances apoptosis by inhibiting DNA repair. Both Au(I)鈥搃ndoles were tested for inhibitory effects against various cellular targets including thioredoxin reductase, a known target of several gold compounds, and various ATP-dependent kinases. While neither compound significantly inhibits the activity of thioreoxin reductase, both showed inhibitory effects against several kinases associated with cancer initiation and progression. The inhibition of these kinases provides a possible mechanism for the ability of these Au(I)鈥搃ndoles to potentiate the cytotoxic effects of ionizing radiation. Clinical applications of combining Au(I)鈥搃ndoles with ionizing radiation are discussed as a new strategy to achieve chemosensitization of cancer cells.