Auranofin Explained

Auranofin is a gold salt classified by the World Health Organization as an antirheumatic agent. It has the brand name Ridaura.

Use

Auranofin is used to treat rheumatoid arthritis. It improves arthritis symptoms including painful or tender and swollen joints and morning stiffness. Auranofin is a safer treatment compared to the more common injectable gold thiolates (gold sodium thiomalate and gold thioglucose), but meta-analysis of 66 clinical trials concluded that it is somewhat less effective.^[1]

The drug was approved for the treatment of rheumatoid arthritis in 1985. No longer a first-line treatment for rheumatoid arthritis, due to its adverse effects, "most of which are associated with long-term use for chronic disease. The most common adverse effects are gastrointestinal complaints such as loose stools, abdominal cramping and watery diarrhea, which can develop in the early months of treatment. The development of loose stools occurs in 40 % of patients, while watery diarrhea is reported in just 2–5 % of patients, and in most cases these symptoms were alleviated by reducing or splitting the dose".^[2]

Research

HIV infection

Auranofin is under investigation as a means of reducing the viral reservoir of HIV that lies latent in the body's T-cells despite treatment with antiretroviral therapy.^[3] The drug was shown to reduce the amount of latent virus in monkey trials.^[4] A human study testing auranofin and other investigational treatments is ongoing in Brazil.^[5] Preliminary results show that auranofin contributed to a decrease in the viral reservoir.^[6]

Amebiasis

Auranofin has been identified in a high-throughput drug screen as 10 times more potent than metronidazole against Entamoeba histolytica, the protozoan agent of human amebiasis. Assays of thioredoxin reductase and transcriptional profiling suggest that the effect of auranofin on the enzyme enhances the sensitivity of the trophozoites to reactive oxygen-mediated killing in mouse and hamster models; the results are marked reductions of the number of parasites, the inflammatory reaction to the infestation, and the damage to the liver.^{[7] [8] [9]}

Acanthamoeba Keratitis and Primary Amoebic Meningoencephalitis

Auranofin may be useful in the prevention and control of Acanthamoeba infections, and in the treatment of primary amoebic meningoencephalitis, caused by pathogenic free-living amoebae Acanthamoeba spp. and Naegleria fowleri, respectively.^{[10] [11]}

Tuberculosis

In a cell-based screen, auranofin showed potent activity against replicating and non-replicating M. tuberculosis as well as other gram-positive bacteria. Auranofin protected mice from an otherwise lethal infection with methicillin-resistant S. aureus (MRSA). The drug acts in a similar manner in bacteria as in parasites by inhibiting thioredoxin reductase (TrxR). Studies in humans are needed to evaluate the potential of this drug to treat Gram-positive bacterial infections in humans.^[12]

Ovarian cancer

Drug-screening reveals auranofin induces apoptosis in ovarian cancer cells in vitro.^{[13] [14]}

Lung cancer including Adenocarcinoma

When mice with Protein kinase Cι (PKCι)–dependent KP adenocarcinoma tumors that exhibited resistance to anti–PD-1 antibody therapy (α-PD-1) were treated with auranofin, the PKCι inhibitor auranofin inhibited KP tumor growth and sensitized these tumors to α-PD-1.^[15] The Mayo clinic is running a clinical trial to research the effects of auranofin and sirolimus on squamous, ras mutated lung adenocarcinoma, and small cell lung cancer. ^[16]

COVID-19

Auranofin may inhibit replication of SARS-CoV-2, the virus responsible for causing COVID-19 in cell culture. Inflammation may also be reduced.^[17]

Etymology

The brand name Ridaura was coined from the phrase Remission-Inducing Drug + Auranofin. ^[18]

Further reading

• Jeon KI, Byun MS, Jue DM . Gold compound auranofin inhibits IkappaB kinase (IKK) by modifying Cys-179 of IKKbeta subunit . Experimental & Molecular Medicine . 35 . 2 . 61–66 . April 2003 . 12754408 . 10.1038/emm.2003.9 . free .
• Kim IS, Jin JY, Lee IH, Park SJ . Auranofin induces apoptosis and when combined with retinoic acid enhances differentiation of acute promyelocytic leukaemia cells in vitro . British Journal of Pharmacology . 142 . 4 . 749–755 . June 2004 . 15159275 . 1575039 . 10.1038/sj.bjp.0705708 .
• Venardos K, Harrison G, Headrick J, Perkins A . Auranofin increases apoptosis and ischaemia-reperfusion injury in the rat isolated heart . Clinical and Experimental Pharmacology & Physiology . 31 . 5–6 . 289–294 . 2004 . 15191400 . 10.1111/j.1440-1681.2004.03993.x . 31546992 .
• Hafejee A, Winhoven S, Coulson IH . Jessner's lymphocytic infiltrate responding to oral auranofin . The Journal of Dermatological Treatment . 15 . 5 . 331–332 . September 2004 . 15370403 . 10.1080/09546630410016924 . 32504211 .
• Rigobello MP, Folda A, Baldoin MC, Scutari G, Bindoli A . Effect of auranofin on the mitochondrial generation of hydrogen peroxide. Role of thioredoxin reductase . Free Radical Research . 39 . 7 . 687–695 . July 2005 . 16036347 . 10.1080/10715760500135391 . 9443834 .
• Suarez-Almazor ME, Spooner CH, Belseck E, Shea B . Auranofin versus placebo in rheumatoid arthritis . The Cochrane Database of Systematic Reviews . 2000 . 2 . CD002048 . 2000 . 10796461 . 8436883 . 10.1002/14651858.CD002048 . Suarez-Almazor ME .

Notes and References

1. Felson DT, Anderson JJ, Meenan RF . The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses . Arthritis and Rheumatism . 33 . 10 . 1449–1461 . October 1990 . 1977391 . 10.1002/art.1780331001 .
2. Roder C, Thomson MJ . Auranofin: repurposing an old drug for a golden new age . Drugs in R&D . 15 . 1 . 13–20 . March 2015 . 25698589 . 4359176 . 10.1007/s40268-015-0083-y . free .
3. http://www.aidsmap.com/Gold-based-drug-shows-promise-in-clearing-HIV-reservoir-in-monkey-study/page/1771585/ Gold-based drug shows promise in clearing HIV reservoir in monkey study
4. Lewis MG, DaFonseca S, Chomont N, Palamara AT, Tardugno M, Mai A, Collins M, Wagner WL, Yalley-Ogunro J, Greenhouse J, Chirullo B, Norelli S, Garaci E, Savarino A . 6 . Gold drug auranofin restricts the viral reservoir in the monkey AIDS model and induces containment of viral load following ART suspension . en-US . AIDS . 25 . 11 . 1347–1356 . July 2011 . 21505294 . 10.1097/QAD.0b013e328347bd77 . 19698337 . free .
5. News: Multi Interventional Study Exploring HIV-1 Residual Replication: a Step Towards HIV-1 Eradication and Sterilizing Cure - Full Text View - ClinicalTrials.gov. 2018-08-14. en.
6. News: Auranofin plus nicotinamide impact HIV reservoir among ART suppressed HIV individuals. MS Power Point . 2018-08-16. en.
7. Debnath A, Parsonage D, Andrade RM, He C, Cobo ER, Hirata K, Chen S, García-Rivera G, Orozco E, Martínez MB, Gunatilleke SS, Barrios AM, Arkin MR, Poole LB, McKerrow JH, Reed SL . 6 . A high-throughput drug screen for Entamoeba histolytica identifies a new lead and target . Nature Medicine . 18 . 6 . 956–960 . June 2012 . 22610278 . 3411919 . 10.1038/nm.2758 .
8. Web site: Drug Found for Parasite That Is Major Cause of Death Worldwide . Science Daily.
9. Web site: Arthritis Drug Effective Against Global Parasite, Study Suggests . Science Daily.
10. Loufouma Mbouaka A, Leitsch D, Koehsler M, Walochnik J . Antimicrobial effect of auranofin against Acanthamoeba spp . International Journal of Antimicrobial Agents . 58 . 5 . 106425 . November 2021 . 34419578 . 10.1016/j.ijantimicag.2021.106425 . 237267846 . free .
11. Peroutka-Bigus N, Bellaire BH . Antiparasitic Activity of Auranofin against Pathogenic Naegleria fowleri . The Journal of Eukaryotic Microbiology . 66 . 4 . 684–688 . July 2019 . 30520183 . 10.1111/jeu.12706 . 54468504 .
12. Harbut MB, Vilchèze C, Luo X, Hensler ME, Guo H, Yang B, Chatterjee AK, Nizet V, Jacobs WR, Schultz PG, Wang F . 6 . Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis . Proceedings of the National Academy of Sciences of the United States of America . 112 . 14 . 4453–4458 . April 2015 . 25831516 . 4394260 . 10.1073/pnas.1504022112 . free . 2015PNAS..112.4453H .
13. Park SH, Lee JH, Berek JS, Hu MC . Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53 . International Journal of Oncology . 45 . 4 . 1691–1698 . October 2014 . 25096914 . 4151813 . 10.3892/ijo.2014.2579 .
14. Oommen D, Yiannakis D, Jha AN . BRCA1 deficiency increases the sensitivity of ovarian cancer cells to auranofin . Mutation Research . 784-785 . 8–15 . 2016 . 26731315 . 10.1016/j.mrfmmm.2015.11.002 .
15. Yin N, Liu Y, Weems C, Shreeder B, Lou Y, Knutson KL, Murray NR, Fields AP . 6 . Protein kinase Cι mediates immunosuppression in lung adenocarcinoma . Science Translational Medicine . 14 . 671 . eabq5931 . November 2022 . 36383684 . 10.1126/scitranslmed.abq5931 . 253554150 .
16. Web site: PKCι & mTOR Inhibition With Auranofin+Sirolimus for Squamous Cell Lung Cancer . 2023-02-13.
17. Web site: Georgia State Researchers Find Rheumatoid Arthritis Drug Is Effective Against Coronavirus . News Hub . 15 April 2020 . 15 April 2020.
18. Book: fr . Lévy JJ, Garnier C . 2007 . La chaîne des médicaments: Perspectives pluridisciplinaires . The Drug Supply Chain: A Multidisciplinary Perspective . PUQ Presse de l'Université du Québec . 978-2760519510. Google Books .