Auranofin Is an Apoptosis-Simulating Agent within Vitroandin VivoAnti-leishmanial Activity

Abstract

Cutaneous leishmaniasis remains ignored in therapeutic drug discovery programs worldwide. This is mainly because cutaneous leishmaniasis is frequently a disease of impoverished populations in countries where funds are limited for research and patient care. However, the health burden of individuals in endemic areas mandates readily available, effective, and safe treatments. Of the existing cutaneous leishmaniasis therapeutics, many are growth inhibitory to Leishmania parasites, potentially creating dormant parasite reservoirs that can be activated when host immunity is compromised, enabling the reemergence of cutaneous leishmaniasis lesions or worse spread of Leishmania parasites to other body sites. To accelerate the identification and development of novel cutaneous leishmaniasis therapeutics, we designed an integrated in vitro and in vivo screening platform that incorporated multiple Leishmania life cycles and species and probed a focused library of pharmaceutically active compounds. The objective of this phenotypic drug discovery platform was the identification and prioritization of bona fide cytotoxic chemotypes toward Leishmania parasites. We identified the Food and Drug Administration-approved drug auranofin, a known inhibitor of Leishmania promastigote growth, as a potent cytotoxic anti-leishmanial agent and inducer of apoptotic-like death in promastigotes. Significantly, the anti-leishmanial activity of auranofin transferred to cell-based amastigote assays as well as in vivo murine models. With appropriate future investigation, these data may provide the foundation for potential exploitation of gold(I)-based complexes as chemical tools or the basis of therapeutics for leishmaniasis. Thus, auranofin may represent a prototype drug that can be used to identify signaling pathways within the parasite and host cell critical for parasite growth and survival.

Auranofin: Repurposing an Old Drug for a Golden New Age

“…Auranofin is able to inhibit the action of the TrxR, TGR or TypR enzymes, hence allowing oxidative stress to damage the parasites [3, 17–20, 22]. The effects of auranofin have been studied on a number of parasitic species including Giardia lamblia [3, 18], Entamoeba histolytica [18], Trypanosoma brucei [33], Leishmania infantum [17, 19], L. major [19], Schistosoma mansoni [22, 34, 35], Echinococcus granulosus [34], Toxoplasmsa gondii [36] and P. falciparum [2, 4]. …”

“…Trypanosomatids are an order of protozoan parasites responsible for diseases such as sleeping sickness, South American Chagas disease and leishmaniasis [17, 33]. Sleeping sickness and Chagas disease are caused by Trypanosoma spp.…”

“…Leishmaniasis is caused by Leishmania spp. and is endemic in 98 countries with approximately 2 million new cases annually [17]. Treatment for sleeping sickness depends on the stage of the disease.…”

“…There is no optimal therapy and the response to any of these drugs is inconsistent. As a result, many cases of leishmaniasis go untreated, leaving the patient disfigured due to the characteristic lesions caused by these parasites [17]. Lobanov et al reported high rates of conservation of selenoproteins in Trypanosoma and Leishmania species.…”

Enhanced Eryptosis Following Auranofin Exposure

“…Auranofin has initially been used as an anti-inflammatory drug in the treatment of rheumatoid arthritis and psoriasis [1][2][3][4][5], but is more recently used for the treatment of malignancy [1,2,6,7] as well as parasitic [2,8,9], bacterial [2,10], and viral infections [2,11,12].…”