PDF file - 1279K, Table S1: List of FDA-approved drug library; Table S2: Screen parameters; Table S3: Curve classification criteria; Table S4: Screening of FDA-approved drugs on Hs 919.T. cell line hits summary; Table S5: Drug structures of candidate hits; Table S6: Known pharmacological data of auranofin (Prometheus Laboratories Inc. (San Diego, CA, USA); Figure S1: Drug screen assay development; Figure S2: TrxR1, TrxR2, TrxR3 transcript expression analysis from a GIST microarray dataset GS31802; Figure S3: In vitro effects of auranofin treatment on TrxR/Trx activity; Figure S4: GIST-T1, GIST T1-10R, and GIST 882 cells were treated with or without auranofin at the concentration indicated in the figure.
ARTICLE ABSTRACT
Despite significant treatment advances over the past decade, metastatic gastrointestinal stromal tumor (GIST) remains largely incurable. Rare diseases, such as GIST, individually affect small groups of patients but collectively are estimated to affect 25 to 30 million people in the United States alone. Given the costs associated with the discovery, development, and registration of new drugs, orphan diseases such as GIST are often not pursued by mainstream pharmaceutical companies. As a result, “drug repurposing” or “repositioning,” has emerged as an alternative to the traditional drug development process. In this study, we screened 796 U.S. Food and Drug Administration (FDA)-approved drugs and found that two of these compounds, auranofin (Ridaura) and fludarabine phosphate, effectively and selectively inhibited the proliferation of GISTs, including imatinib-resistant cells. One of the most notable drug hits, auranofin, an oral, gold-containing agent approved by the FDA in 1985 for the treatment of rheumatoid arthritis, was found to inhibit thioredoxin reductase activity and induce reactive oxygen species (ROS) production, leading to dramatic inhibition of GIST cell growth and viability. Importantly, the anticancer activity associated with auranofin was independent of imatinib-resistant status, but was closely related to the endogenous and inducible levels of ROS. Coupled with the fact that auranofin has an established safety profile in patients, these findings suggest for the first time that auranofin may have clinical benefit for patients with GIST, particularly in those suffering from imatinib-resistant and recurrent forms of this disease. Mol Cancer Ther; 12(7); 1299–309. ©2013 AACR.
