Gold-Containing Indoles as Anticancer Agents That Potentiate the Cytotoxic Effects of Ionizing Radiation
- 30 January 2012
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 55 (5), 2437-2451
- https://doi.org/10.1021/jm2005942
Abstract
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-indole enhances apoptosis by inhibiting DNA repair. Both Au(I)-indoles 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)-indoles to potentiate the cytotoxic effects of ionizing radiation. Clinical applications of combining Au(I)-indoles with ionizing radiation are discussed as a new strategy to achieve chemosensitization of cancer cells.Keywords
This publication has 79 references indexed in Scilit:
- Structural, mechanistic and coordination chemistry of relevance to the biosynthesis of iron–sulfur and related iron cofactorsCoordination Chemistry Reviews, 2011
- Elevated c-Src and c-Yes expression in malignant skin cancersJournal of Experimental & Clinical Cancer Research, 2010
- Sucrose nonfermenting AMPK-related kinase (SNARK) mediates contraction-stimulated glucose transport in mouse skeletal muscleProceedings of the National Academy of Sciences of the United States of America, 2010
- A Coiled-Coil Enabled Split-Luciferase Three-Hybrid System: Applied Toward Profiling Inhibitors of Protein KinasesJournal of the American Chemical Society, 2010
- Cellular mechanisms of cadmium toxicity related to the homeostasis of essential metalsBioMetals, 2010
- Multiple roles of ATM in monitoring and maintaining DNA integrityFEBS Letters, 2010
- p90 ribosomal S6 kinase 2 promotes invasion and metastasis of human head and neck squamous cell carcinoma cellsJCI Insight, 2010
- Combining Targeted Therapies: Practical Issues to Consider at the Bench and BedsideThe Oncologist, 2010
- ATR-dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stallingThe EMBO Journal, 2006
- The Protein Chemistry of Antiarthritic Gold(I) Thiolates and Related ComplexesComments on Inorganic Chemistry, 1989