Auranofin: Repurposing an Old Drug for a Golden New Age

Abstract

Drug discovery, development and registration is an expensive and time-consuming process associated with a high failure rate [Pessetto et al. (Mol Cancer Ther 12:1299–1309, 2013), Woodcock and Woosley (Annu Rev Med 59:1–12, 2008)]. Drug ‘repurposing’ is the identification of new therapeutic purposes for already approved drugs and is more affordable and achievable than novel drug discovery [Pessetto et al. (Mol Cancer Ther 12:1299–1309, 2013)]. Auranofin is a drug that is approved for the treatment of rheumatoid arthritis but is being investigated for potential therapeutic application in a number of other diseases including cancer, neurodegenerative disorders, HIV/AIDS, parasitic infections and bacterial infections [Tejman-Yarden et al. (Antimicrob Agents Chemother 57:2029–2035, 2013)]. The main mechanism of action of auranofin is through the inhibition of reduction/oxidation (redox) enzymes that are essential for maintaining intracellular levels of reactive oxygen species. Inhibition of these enzymes leads to cellular oxidative stress and intrinsic apoptosis [Pessetto et al. (Mol Cancer Ther 12:1299–1309, 2013), Fan et al. (Cell Death Dis 5:e1191, 2014), Fiskus et al. (Cancer Res 74:2520–2532, 2014), Marzano et al. (Free Radic Biol Med 42:872–881, 2007)]. Drugs such as auranofin that have already been approved for human use [Tejman-Yarden et al. (Antimicrob Agents Chemother 57:2029–2035, 2013)] can be brought into clinical use for other diseases relatively quickly and for a fraction of the cost of new drugs.

Clinically Evaluated Cancer Drugs Inhibiting Redox Signaling

“…Both these mechanisms of action result in apoptosis. Although the use of auranofin for the treatment of rheumatoid arthritis is declining because of adverse effects associated with its long-term use (90), recent clinical trials have been initiated exploring its use as an anticancer agent. A pharmacokinetic Phase I, open-label study in healthy adult subjects was initiated in 2014 to determine terminal phase pharmacokinetic parameters in blood and gold measurements in stool samples (NCT02089048).…”

“…Indirect inhibitors include the proteasome inhibitor, bortezomib, and the promiscuous curcumin (below). Bortezomib (VELCADE, previously known as PS-341), a proteasome inhibitor, was one of the first compounds used to inhibit the function of NF-jB (90). Bortezomib has shown significant efficacy in hematologic and solid tumors, including multiple myeloma as well as lung, breast, prostate, pancreatic, and head-neck carcinomas, yet it is unclear if its effect are in fact mediated through the inhibition of NF-kB (47).…”

Preclinical activity of the repurposed drug auranofin in classical Hodgkin lymphoma

“…AF, approved by the US Food and Drug Administration for clinical trials in chronic lymphocytic leukemia and in ovarian and lung cancer, seems to have application also in bacterial and parasitic infections as well as in HIV/AIDS. 3 With the goal of repurposing AF for refractory cHL, we demonstrated its antitumoral activity in in vitro and in vivo tumor models. AF inhibited proliferation ( Figure 1A) and clonogenic growth (supplemental Figure 1A, available on the Blood Web site) of L-1236, L-428, KM-H2, HDLM-2, and L-540 cHL-derived cell lines with IC50 ranging from 0.7 to 1.5 mM (supplemental Table 1).…”

Two-Year Follow-Up of Macaques Developing Intermittent Control of the Human Immunodeficiency Virus Homolog Simian Immunodeficiency Virus SIVmac251 in the Chronic Phase of Infection

“…In this context, some of us focused atten-tion on auranofin, a gold-based compound used to decrease immune activation in individuals with rheumatoid arthritis (4,8,9). Auranofin decreases immune activation, likely by causing downmodulation of the costimulatory molecule CD28 in T cells (8).…”