Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia

Abstract

To find drugs suitable for repositioning for use against leukemia, samples from patients with chronic lymphocytic, acute myeloid and lymphocytic leukemias as well as peripheral blood mononuclear cells (PBMC) were tested in response to 1266 compounds from the LOPAC 1280 library (Sigma). Twenty-five compounds were defined as hits with activity in all leukemia subgroups ( o50% cell survival compared with control) at 10 μM drug concentration. Only one of these compounds, quinacrine, showed low activity in normal PBMCs and was therefore selected for further preclinical evaluation. Mining the NCI-60 and the NextBio databases demonstrated leukemia sensitivity and the ability of quinacrine to reverse myeloid leukemia gene expression. Mechanistic exploration was performed using the NextBio bioinformatic software using gene expression analysis of drug exposed acute myeloid leukemia cultures (HL-60) in the database. Analysis of gene enrichment and drug correlations revealed strong connections to ribosomal biogenesis nucleoli and translation initiation. The highest drug-drug correlation was to ellipticine, a known RNA polymerase I inhibitor. These results were validated by additional gene expression analysis performed in-house. Quinacrine induced early inhibition of protein synthesis supporting these predictions. The results suggest that quinacrine have repositioning potential for treatment of acute myeloid leukemia by targeting of ribosomal biogenesis.

Moving Toward Integrating Gene Expression Profiling Into High-Throughput Testing: A Gene Expression Biomarker Accurately Predicts Estrogen Receptor α Modulation in a Microarray Compendium

“…To screen for chemicals that lead to alterations of ERa function, the biomarker was compared with individual biosets in the MCF-7 compendium using the fold-change rank-based nonparametric Running Fisher algorithm (Kupershmidt et al, 2010). The approach, somewhat analogous to the Gene Set Enrichment Analysis method (Lamb, 2007;Lamb et al, 2006), has proven useful in identifying novel treatment strategies for disease (Eriksson et al, 2015). The approach finds, in an unsupervised manner, biosets with expression patterns of biomarker genes with statistically significant positive or negative correlation corresponding to activation or suppression of ERa.…”

Inhibition of Kir4.1 potassium channels by quinacrine

“…In this work, we evaluated the inhibition of Kir4.1 channels by quinacrine, an old antimalarial drug that has gained broad attention in drug-repositioning studies since it has been shown to possess anti-cancer properties (Neznanov et al, 2009; Preet et al, 2012; Khurana et al, 2015; Ericksson et al, 2015; Das et el., 2016). Here, we show that quinacrine plugs the central cavity of Kir4.1 channels in a voltage-dependent manner and with slow blocking and unblocking kinetics.…”

Repurposing Drugs for Acute Myeloid Leukemia: A Worthy Cause or a Futile Pursuit?

“…In a screen of 1266 compounds from the LOPAC 1280 library, quinacrine was the only compound that showed high cytotoxic activity (% inhibition) against primary leukemia cells and four AML cell lines with low toxicity in normal mononuclear cells in vitro. Bioinformatic analysis of gene expression suggests that quinacrine targets ribosome biogenesis by inhibiting ribosomal DNA transcription [40]. In a follow up study, quinacrine demonstrated in vivo efficacy in AML PDX mice without toxicity by decreasing the number of tumor cells in the blood by 70% and significantly prolonging survival.…”