EFFECT OF IBRUTINIB AS A BRUTON'S TYROSIN KINASE INHIBITOR IN THE TREATMENT OF VISCERAL LEISHMANIASIS
Project no. 20180 · Status: Kapanmış · 2019
Summary
Leishmania are obligate intracellular parasites, which cause a variety of clinical diseases including cutaneous Leishmaniasis (CL), mucosal Leishmaniasis, and visceral Leishmaniasis (VL). The World Health Organization classifies Leishmaniasis as a neglected tropical disease, approximately 12 million current enfections globally and 2 million new cases annually. VL is the most severe and common fatal form of Leishmania enfection. This enfection is caused by Leishmania donovani and L. infantum and is characterized by dissemination of the parasites to the reticulo endothelial system. The pentavalent antimonials remain the first-line drug for Leishmaniasis, including VL worldwide, although these drugs show cardiac, renal, and hepatic toxicity and need daily parenteral administration for a long time. Besides, the emergence of drug-resistant parasites is also increasing worldwide. Due to these disadvantages, there is a need for development of novel, effective and minimally toxic therapeutic agents to VL. Ibrutinib is a potent, orally bioavailable inhibitor of Bruton’s Tyrosine Kinase (BTK). Ibrutinib is an anticancer drug known to modulate T-helper type responses. It was approved for clinical use by FDA in Mantle Cell Lymphoma (MCL) treatment in 2013 and Chronic Lymphocytic Leukemia (CLL) in 2014. Ibrutinib has been shown to suppress cytokine production in human monocytes by impairing M1 macrophage polarization, and phagocytosis ability of human macrophages. In addition, ibrutinib has the potential to regulate immunity against enfectious disease. However, its potential use in Leishmaniasis treatment is barely investigated to date. In this study, we evaluated the efficacy of ibrutinib as a targeted therapy of VL caused by L. infantum and L. donovani using an exvivo model. To investigate the possible use of ibrutinib in Leishmaniasis treatment, we employed a strategy where we first enfect induced macrophages with promastigotes, then treat with ibrutinib, and finally seed amastigotes into NNN medium. First, we determined that macrophages express high levels of BTK in this study. Then, we showed that ibrutinib, a potent selective inhibitor of BTK, is effective in restricting in-vitro growth of L. infantum and L. donovani, which are parasitic organisms responsible for VL. We found that 10µM ibrutinib inhibited parasite growth while having no adverse effect on macrophage viability. In addition, we detected a decrease in the number of macrophages and enfected macrophages by inhibiting the BTK gene expression in macrophages. Thus, it was shown that the BTK gene might have a role in both macrophage proliferation and invasion of macrophages by Leishmania. As a result, our findings show that ibrutinib is highly effective in the treatment of VL caused by L. infantum and L. donovani, and that the BTK gene may have a role in enfecting macrophages with Leishmania. Therefore, ibrutinib may be a novel targeted drug for the treatment of VL.