Repurposing anthelmintic agents to eradicate resistant leukemia.

Autor:	Mezzatesta C; Department of Oncology and Children's Research Center, Children's Hospital Zurich, Lengghalde 5, Balgrist Campus AG, 8008, Zurich, Switzerland., Abduli L; Department of Oncology and Children's Research Center, Children's Hospital Zurich, Lengghalde 5, Balgrist Campus AG, 8008, Zurich, Switzerland., Guinot A; Department of Oncology and Children's Research Center, Children's Hospital Zurich, Lengghalde 5, Balgrist Campus AG, 8008, Zurich, Switzerland., Eckert C; Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany.; German Cancer Consortium (DKTK), Berlin, Germany., Schewe D; Department of Pediatrics, University Hospital Schleswig-Holstein, Kiel, Germany., Zaliova M; Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic., Vinti L; Department of Pediatric Haemato-Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Sapienza University of Rome, Rome, Italy., Marovca B; Department of Oncology and Children's Research Center, Children's Hospital Zurich, Lengghalde 5, Balgrist Campus AG, 8008, Zurich, Switzerland., Tsai YC; Department of Oncology and Children's Research Center, Children's Hospital Zurich, Lengghalde 5, Balgrist Campus AG, 8008, Zurich, Switzerland., Jenni S; Department of Oncology and Children's Research Center, Children's Hospital Zurich, Lengghalde 5, Balgrist Campus AG, 8008, Zurich, Switzerland., Aguade-Gorgorio J; Department of Oncology and Children's Research Center, Children's Hospital Zurich, Lengghalde 5, Balgrist Campus AG, 8008, Zurich, Switzerland., von Stackelberg A; Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany.; German Cancer Consortium (DKTK), Berlin, Germany., Schrappe M; Department of Pediatrics, University Hospital Schleswig-Holstein, Kiel, Germany., Locatelli F; Department of Pediatric Haemato-Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Sapienza University of Rome, Rome, Italy., Stanulla M; Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany., Cario G; Department of Pediatrics, University Hospital Schleswig-Holstein, Kiel, Germany., Bourquin JP; Department of Oncology and Children's Research Center, Children's Hospital Zurich, Lengghalde 5, Balgrist Campus AG, 8008, Zurich, Switzerland., Bornhauser BC; Department of Oncology and Children's Research Center, Children's Hospital Zurich, Lengghalde 5, Balgrist Campus AG, 8008, Zurich, Switzerland. beat.bornhauser@kispi.uzh.ch.
Jazyk:	angličtina
Zdroj:	Blood cancer journal [Blood Cancer J] 2020 Jun 26; Vol. 10 (6), pp. 72. Date of Electronic Publication: 2020 Jun 26.
DOI:	10.1038/s41408-020-0339-9
Abstrakt:	Despite rapid progress in genomic profiling in acute lymphoblastic leukemia (ALL), identification of actionable targets and prediction of response to drugs remains challenging. To identify specific vulnerabilities in ALL, we performed a drug screen using primary human ALL samples cultured in a model of the bone marrow microenvironment combined with high content image analysis. Among the 2487 FDA-approved compounds tested, anthelmintic agents of the class of macrocyclic lactones exhibited potent anti-leukemia activity, similar to the already known anti-leukemia agents currently used in induction chemotherapy. Ex vivo validation in 55 primary ALL samples of both precursor B cell and T-ALL including refractory relapse cases confirmed strong anti-leukemia activity with IC 50 values in the low micromolar range. Anthelmintic agents increased intracellular chloride levels in primary leukemia cells, inducing mitochondrial outer membrane depolarization and cell death. Supporting the notion that simultaneously targeting cell death machineries at different angles may enhance the cell death response, combination of anthelmintic agents with the BCL-2 antagonist navitoclax or with the chemotherapeutic agent dexamethasone showed synergistic activity in primary ALL. These data reveal anti-leukemia activity of anthelmintic agents and support exploiting drug repurposing strategies to identify so far unrecognized anti-cancer agents with potential to eradicate even refractory leukemia.
Databáze:	MEDLINE
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