Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, 31270-901, Belo Horizonte, Minas Gerais, Brazil; Grupo de Genômica Funcional de Parasitos, Instituto René Rachou, Fundação Oswaldo Cruz, 30190-002, Belo Horizonte, Minas Gerais, Brazil.
Grupo Integrado de Pesquisa em Biomarcadores, Instituto René Rachou, Fundação Oswaldo Cruz, 30190-002, Belo Horizonte, Minas Gerais, Brazil.
Int Immunopharmacol. 2022 Sep;110:108952. doi: 10.1016/j.intimp.2022.108952. Epub 2022 Jun 15.
Visceral leishmaniasis (VL) is an infectious disease caused by Leishmania infantum (L. infantum). Currently, there are no vaccines and/or prophylactic therapies against VL, and the recentpharmacological approaches come from the drug repositioning strategy. Here, we evaluated the anticancer drug pamidronate (PAM) to identify a new therapeutic option for the treatment of human VL. We assessed its in vitro antileishmanial activity against the promastigote and amastigote forms of L. infantum by evaluating cell cytotoxicity. The antileishmanial and immunomodulatory activities were assessed using human peripheral blood leukocytes ex vivo. PAM induced the formation of vacuoles in the cytoplasm of the promastigotes and alterations in the morphology of the kinetoplast and mitochondria in vitro, which indicates anti-promastigote activity. PAM also reduced the number of infected macrophages and intracellular amastigotes in a concentration-dependent manner, with cell viability above 70%. In ex vivo, PAM reduced the internalized forms of L. infantum in the classical monocyte subpopulation. Furthermore, it enhanced IL-12 and decreased IL-10 and TGF-β by monocytes and neutrophils. Increased IFN-γ and TNF levels for CD8 and CD8 T lymphocytes and B lymphocytes, respectively, were observed after the treatment with PAM, as well as a reduction in IL-10 by the lymphocyte subpopulations evaluated. Taken together, our results suggest that PAM may be eligible as a potential therapeutic alternative for drug repurposing to treat human visceral leishmaniasis.
内脏利什曼病（VL）是一种由利什曼原虫（L. infantum）引起的传染病。目前，针对 VL 尚无疫苗和/或预防疗法，而最近的药物治疗方法来自药物再利用策略。在这里，我们评估了抗癌药物帕米膦酸（PAM），以确定治疗人类 VL 的新治疗选择。我们通过评估细胞毒性来评估其对利什曼原虫前鞭毛体和无鞭毛体形式的体外抗利什曼原虫活性。抗利什曼原虫和免疫调节活性通过体外人外周血白细胞进行评估。PAM在体外诱导前鞭毛体细胞质中形成空泡，并改变动基体和线粒体的形态，表明具有抗前鞭毛体活性。PAM还以浓度依赖性方式减少感染的巨噬细胞和细胞内无鞭毛体的数量，细胞活力高于 70%。在体外，PAM减少了经典单核细胞亚群中内化的利什曼原虫形式。此外，它增强了单核细胞和中性粒细胞产生的 IL-12，并降低了 IL-10 和 TGF-β。在用 PAM 处理后，观察到 CD8 和 CD8 T 淋巴细胞和 B 淋巴细胞的 IFN-γ和 TNF 水平分别增加，以及评估的淋巴细胞亚群中 IL-10 的减少。综上所述，我们的结果表明，PAM 可能有资格作为药物再利用的潜在治疗替代方案，用于治疗人类内脏利什曼病。
