Leishmaniasis is a vector-borne disease caused by protozoal Leishmania parasites. Previous studies have shown that endoperoxides (EP) can selectively kill Leishmania in host cells. Therefore, we studied in this work a set of new anthracene-derived EP (AcEP) together with their non-endoperoxidic analogs in model systems of Leishmania tarentolae promastigotes (LtP) and J774 macrophages for their antileishmanial activity and selectivity. The mechanism of effective compounds was explored by studying their reaction with iron (II) in chemical systems and in Leishmania. The correlation of structural parameters with activity demonstrated that in this compound set, active compounds had a LogPOW larger than 3.5 and a polar surface area smaller than 100 Å2. The most effective compounds (IC50 in LtP < 2 µM) with the highest selectivity (SI > 30) were pyridyl-/tert-butyl-substituted AcEP. Interestingly, also their analogs demonstrated activity and selectivity. In mechanistic studies, it was shown that EP were activated by iron in chemical systems and in LtP due to their EP group. However, the molecular structure beyond the EP group significantly contributed to their differential mitochondrial inhibition in Leishmania. The identified compound pairs are a good starting point for subsequent experiments in pathogenic Leishmania in vitro and in animal models.
Central nervous system (CNS) tumors with BCOR internal tandem duplications (CNS-BCOR ITD) are aggressive malignancies recently included in the 2021 WHO Classification of CNS tumors. This entity is characterized by ITDs within the PUFD domain of BCOR, potentially interfering with protein-protein interactions and preventing non-canonical polycomb repressive complex 1.1 (ncPRC1.1) complex formation. Additionally, other BCOR alterations like frame shift mutations and gene fusions have been described. However, the underlying molecular mechanisms promoting tumor aggressiveness remain unknown. We established cell models from one patient harboring a BCOR frameshift mutation and another one with a concomitant BCORL1-fusion. Two additional models were derived from a patient with a CNS-BCOR ITD tumor. Multidrug screening uncovered high sensitivity against defined receptor tyrosine kinase (RTK) inhibitors (TKIs). In detail, ponatinib, nintedanib, and dovitinib reduced cell viability at half maximal inhibitory concentrations (IC50) in the low micro-molar range (<2.5 µM). Expression analyses of the respective TKI targets suggested fibroblast growth factor receptor 3 (FGFR3) and platelet derived growth factor receptor A (PDGFRA) as central players in this response. RTK inhibition resulted in strongly impaired downstream MAPK and Pi3K/AKT signaling. Vice versa, exposure to the RTK ligands bFGF and PDGFAA increased S6, Erk and Akt phosphorylation. Next, we treated two patients – one with a BCOR frame shift mutation/BCORL1-gene fusion and one with an ITD with nintedanib – within a multimodal treatment approach and achieving complete remission and disease stabilization, respectively. Ultimately, we analyzed respective RTK ligands in patient cerebral spinal fluid (CSF) and found FGF18 and PDGFA to correlate with tumor treatment response and progression. Summarizing, we uncover a central role of defined RTK signaling modules in the malignant phenotype of CNS-BCOR-ITD and tumors harboring BCOR alterations and elucidate their potential as therapeutic targets. Currently, we aim to dissect the interconnection between BCOR/BCORL1 alterations and RTK hyperactivation.
Ependymomas (EPN) account for 10% of pediatric CNS tumors. Among the ten subgroups characterized by DNA methylation profiling, tumors located in the supratentorial region that harbor ZFTA fusions (e.g. ZFTA-RELA), and tumors in the posterior fossa region group A (PF-A) represent the most aggressive entities. As currently therapy success relies on the extent of tumor resection and druggable targets are so far widely missing, new therapeutic approaches are urgently needed. Epigenetic dysfunction, resulting in aberrant histone modifications as well as altered DNA methylation patterns, majorly contributes to the aggressiveness of high-risk EPN. In earlier studies, we discovered that high-risk EPN is composed of a cellular hierarchy initiating from stem-cell like populations, frequently showing telomerase re-activation. Considering that epigenetic mechanisms regulate stemness maintenance and telomerase reverse transcriptase (TERT), we studied the impact of epigenetically active drugs on differentiation and telomerase re-activation in these tumors. Accordingly, we first investigated the basal expression levels of TERT and EZH2 in a panel of patient-derived high-risk EPN cell models of different subtypes (n=7). Interestingly, both, TERT and EZH2, were highly expressed predominantly in ZFTA-RELA cell models. Corroboratively, increased sensitivity of ZFTA-RELA cells towards the EZH2 inhibitor DZNep was observed in cell viability and clonogenic assays. While HDAC inhibitors were similarly active across high-risk EPN cell models, the BET inhibitor JQ1 more efficiently reduced survival of ZFTA-RELA cells. Treatment with DZNep resulted in a loss of H3K27me3 histone marks accompanied by decreased ubiquitination of H2AK119 in the investigated ZFTA-RELA cell models, and induced apoptosis indicated by PARP cleavage. Currently, impacts of direct or pharmacological EZH2 blockade on TERT promoter methylation, induction of senescence and differentiation are analyzed. Summarizing, we proof varying efficacy of epigenetically active drugs in high-risk EPN subgroups, in particular EZH2 inhibition in ZFTA-RELA cell models.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.