Repurposing anthelmintic agents to eradicate resistant leukemia

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11130%2F20%3A10412230" target="_blank" >RIV/00216208:11130/20:10412230 - isvavai.cz</a>

Alternative codes found

RIV/00064203:_____/20:10412230

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=dvc59Pu4Mj" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=dvc59Pu4Mj</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41408-020-0339-9" target="_blank" >10.1038/s41408-020-0339-9</a>

Result language

angličtina

Original language name

Repurposing anthelmintic agents to eradicate resistant leukemia

Original language description

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 IC50 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. (

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30205 - Hematology

Project

<a href="/en/project/NU20-07-00322" target="_blank" >NU20-07-00322: Genomics for the modern diagnostics and treatment of childhood leukaemias</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2020

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Blood Cancer Journal

ISSN

2044-5385

e-ISSN

—

Volume of the periodical

10

Issue of the periodical within the volume

6

Country of publishing house

GB - UNITED KINGDOM

Number of pages

11

Pages from-to

72

UT code for WoS article

000543406900001

EID of the result in the Scopus database

2-s2.0-85086871433