PURPOSE: Hypoxia-inducible factor-alpha (HIF-alpha) is a transcription factor that regulates the response to hypoxia. HIF-alpha protein is found at high levels in many cancers, and the redox protein thioredoxin-1 (Trx-1) increases both aerobic and hypoxia-induced HIF-alpha. Therefore, Trx-1 and HIF-alpha are attractive molecular targets for novel cancer therapeutics. EXPERIMENTAL DESIGN: We investigated whether two novel anticancer drugs AJM290 and AW464 (quinols), which inhibit Trx-1 function, can inhibit the HIF pathway. RESULTS: Treatment of several cancer cell lines with AJM290 or AW464 prevented the hypoxia-induced increase of vascular endothelial growth factor (VEGF) at subtoxic concentrations. AJM290 and AW464 also decreased VEGF in pVHL mutant renal cell carcinoma cells that constitutively overexpress HIF-alpha protein. They surprisingly up-regulated HIF-alpha expression in breast cancer cell lines in normoxia and hypoxia as well as in pVHL mutant cells. In the MDA-MB-468 breast cancer cell line, the compounds inhibited RNA and protein expression of the HIF-alpha target genes, carbonic anhydrase IX, VEGF, and BNIP3, concordantly with HIF-alpha up-regulation. Both compounds specifically inhibited HIF-alpha-dependent induction of hypoxia regulatory element-luciferase and HIF-1alpha hypoxia regulatory element-DNA binding. To analyze the HIF-1alpha domain inhibited by AJM290, we transfected cells with plasmids expressing a fusion protein of Gal linked to HIF-1alpha or HIF-1alpha COOH-terminal transactivation domain (CAD) with a Gal4-responsive luciferase reporter gene. AJM290 inhibited both the full-length HIF-1alpha and HIF-1alpha CAD transcriptional activity. CONCLUSIONS: AJM290 and AW464 are inhibitors of HIF-1alpha CAD transcription activity and DNA binding, but they also inhibit degradation of HIF, in contrast to other Trx inhibitors.

Type

Journal article

Journal

Clin Cancer Res

Publication Date

2006

Volume

12

Pages

5384 - 5394