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The MitoNEET Ligand NL-1 Mediates Antileukemic Activity in Drug-Resistant B-Cell Acute Lymphoblastic Leukemia
- Source :
- J Pharmacol Exp Ther
- Publication Year :
- 2019
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 2019.
-
Abstract
- Disease relapse in B-cell acute lymphoblastic leukemia (ALL), either due to development of acquired resistance after therapy or because of de novo resistance, remains a therapeutic challenge. In the present study, we have developed a cytarabine (Ara-C)-resistant REH cell line (REH/Ara-C) as a chemoresistance model. REH/Ara-C 1) was not crossresistant to vincristine or methotrexate; 2) showed a similar proliferation rate and cell surface marker expression as parental REH; 3) demonstrated decreased chemotaxis toward bone marrow stromal cells; and 4) expressed higher transcript levels of cytidine deaminase (CDA) and mitoNEET (CISD1) than the parental REH cell line. Based on these findings, we tested NL-1, a mitoNEET inhibitor, which induced a concentration-dependent decrease in cell viability with a comparable IC(50) value in REH and REH/Ara-C. Furthermore, NL-1 decreased cell viability in six different ALL cell lines and showed inhibitory activity in a hemosphere assay. NL-1 also impaired the migratory ability of leukemic cells, irrespective of the chemoattractant used, in a chemotaxis assay. More importantly, NL-1 showed specific activity in inducing death in a drug-resistant population of leukemic cells within a coculture model that mimicked the acquired resistance and de novo resistance observed in the bone marrow of relapsed patients. Subsequent studies indicated that NL-1 mediates autophagy, and inhibition of autophagy partially decreased NL-1–induced tumor cell death. Finally, NL-1 showed antileukemic activity in an in vivo mouse ALL model. Taken together, our study demonstrates that mitoNEET has potential as a novel antileukemic drug target in treatment refractory or relapsed ALL.
- Subjects :
- 0301 basic medicine
Vincristine
Stromal cell
Cell
Population
Antineoplastic Agents
Ligands
Mitochondrial Proteins
Drug Discovery and Translational Medicine
03 medical and health sciences
0302 clinical medicine
Recurrence
Cell Line, Tumor
Drug Discovery
Autophagy
medicine
Humans
Viability assay
education
Pharmacology
education.field_of_study
Chemistry
Chemotaxis
Cytarabine
Precursor Cell Lymphoblastic Leukemia-Lymphoma
030104 developmental biology
medicine.anatomical_structure
Drug Resistance, Neoplasm
Cell culture
Cancer research
Molecular Medicine
Bone marrow
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 15210103 and 00223565
- Volume :
- 370
- Database :
- OpenAIRE
- Journal :
- Journal of Pharmacology and Experimental Therapeutics
- Accession number :
- edsair.doi.dedup.....d6f979558125b28b0fbc89af904e3e09