title: Gold-containing indoles as anticancer agents that potentiate the cytotoxic effects of ionizing radiation.
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.
authors.affiliation: Department of Pharmacology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Craig
authors.forename: Lei
authors.initials: L
authors.lastname: Gao
authors.forename: Irene
authors.initials: I
authors.lastname: Lee
authors.forename: Thomas
authors.initials: T
authors.lastname: Gray
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Berdis
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005720:Gamma Rays; D006046:Gold; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010720:Phosphines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D009942:Organometallic Compounds; D010720:Phosphines; D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; D006046:Gold; D013880:Thioredoxin-Disulfide Reductase