The MitoNEET Ligand NL-1 Mediates Antileukemic Activity in Drug-Resistant B-Cell Acute Lymphoblastic Leukemia
| Autor: | Karen H. Martin, Debbie Piktel, Rajesh R. Nair, Werner J. Geldenhuys, Laura F. Gibson |
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| Rok vydání: | 2019 |
| Předmět: |
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 |
| Zdroj: | J Pharmacol Exp Ther |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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