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Imidazo[1,2-b]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells
Chemotherapy-induced differentiation of immature myeloid progenitors, such as acute myeloid leukemia (AML) cells or myeloid-derived suppressor cells (MDSCs), has remained a challenge for the clinicians. Testing our imidazo[1,2-b]pyrazole-7-carboxamide derivative on HL-60 cells, we obtained ERK phosp...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404197/ https://www.ncbi.nlm.nih.gov/pubmed/32698503 http://dx.doi.org/10.3390/ijms21145135 |
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author | Kotogány, Edit Balog, József Á. Nagy, Lajos I. Alföldi, Róbert Bertagnolo, Valeria Brugnoli, Federica Demjén, András Kovács, Anita K. Batár, Péter Mezei, Gabriella Szabó, Renáta Kanizsai, Iván Varga, Csaba Puskás, László G. Szebeni, Gábor J. |
author_facet | Kotogány, Edit Balog, József Á. Nagy, Lajos I. Alföldi, Róbert Bertagnolo, Valeria Brugnoli, Federica Demjén, András Kovács, Anita K. Batár, Péter Mezei, Gabriella Szabó, Renáta Kanizsai, Iván Varga, Csaba Puskás, László G. Szebeni, Gábor J. |
author_sort | Kotogány, Edit |
collection | PubMed |
description | Chemotherapy-induced differentiation of immature myeloid progenitors, such as acute myeloid leukemia (AML) cells or myeloid-derived suppressor cells (MDSCs), has remained a challenge for the clinicians. Testing our imidazo[1,2-b]pyrazole-7-carboxamide derivative on HL-60 cells, we obtained ERK phosphorylation as an early survival response to treatment followed by the increase of the percentage of the Bcl-xl(bright) and pAkt(bright) cells. Following the induction of Vav1 and the AP-1 complex, a driver of cellular differentiation, FOS, JUN, JUNB, and JUND were elevated on a concentration and time-dependent manner. As a proof of granulocytic differentiation, the cells remained non-adherent, the expression of CD33 decreased; the granularity, CD11b expression, and MPO activity of HL-60 cells increased upon treatment. Finally, viability of HL-60 cells was hampered shown by the depolarization of mitochondria, activation of caspase-3, cleavage of Z-DEVD-aLUC, appearance of the sub-G1 population, and the leakage of the lactate-dehydrogenase into the supernatant. We confirmed the differentiating effect of our drug candidate on human patient-derived AML cells shown by the increase of CD11b and decrease of CD33+, CD7+, CD206+, and CD38(bright) cells followed apoptosis (IC(50): 80 nM) after treatment ex vivo. Our compound reduced both CD11b+/Ly6C+ and CD11b+/Ly6G+ splenic MDSCs from the murine 4T1 breast cancer model ex vivo. |
format | Online Article Text |
id | pubmed-7404197 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-74041972020-08-11 Imidazo[1,2-b]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells Kotogány, Edit Balog, József Á. Nagy, Lajos I. Alföldi, Róbert Bertagnolo, Valeria Brugnoli, Federica Demjén, András Kovács, Anita K. Batár, Péter Mezei, Gabriella Szabó, Renáta Kanizsai, Iván Varga, Csaba Puskás, László G. Szebeni, Gábor J. Int J Mol Sci Article Chemotherapy-induced differentiation of immature myeloid progenitors, such as acute myeloid leukemia (AML) cells or myeloid-derived suppressor cells (MDSCs), has remained a challenge for the clinicians. Testing our imidazo[1,2-b]pyrazole-7-carboxamide derivative on HL-60 cells, we obtained ERK phosphorylation as an early survival response to treatment followed by the increase of the percentage of the Bcl-xl(bright) and pAkt(bright) cells. Following the induction of Vav1 and the AP-1 complex, a driver of cellular differentiation, FOS, JUN, JUNB, and JUND were elevated on a concentration and time-dependent manner. As a proof of granulocytic differentiation, the cells remained non-adherent, the expression of CD33 decreased; the granularity, CD11b expression, and MPO activity of HL-60 cells increased upon treatment. Finally, viability of HL-60 cells was hampered shown by the depolarization of mitochondria, activation of caspase-3, cleavage of Z-DEVD-aLUC, appearance of the sub-G1 population, and the leakage of the lactate-dehydrogenase into the supernatant. We confirmed the differentiating effect of our drug candidate on human patient-derived AML cells shown by the increase of CD11b and decrease of CD33+, CD7+, CD206+, and CD38(bright) cells followed apoptosis (IC(50): 80 nM) after treatment ex vivo. Our compound reduced both CD11b+/Ly6C+ and CD11b+/Ly6G+ splenic MDSCs from the murine 4T1 breast cancer model ex vivo. MDPI 2020-07-20 /pmc/articles/PMC7404197/ /pubmed/32698503 http://dx.doi.org/10.3390/ijms21145135 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kotogány, Edit Balog, József Á. Nagy, Lajos I. Alföldi, Róbert Bertagnolo, Valeria Brugnoli, Federica Demjén, András Kovács, Anita K. Batár, Péter Mezei, Gabriella Szabó, Renáta Kanizsai, Iván Varga, Csaba Puskás, László G. Szebeni, Gábor J. Imidazo[1,2-b]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells |
title | Imidazo[1,2-b]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells |
title_full | Imidazo[1,2-b]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells |
title_fullStr | Imidazo[1,2-b]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells |
title_full_unstemmed | Imidazo[1,2-b]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells |
title_short | Imidazo[1,2-b]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells |
title_sort | imidazo[1,2-b]pyrazole-7-carboxamide derivative induces differentiation-coupled apoptosis of immature myeloid cells such as acute myeloid leukemia and myeloid-derived suppressor cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404197/ https://www.ncbi.nlm.nih.gov/pubmed/32698503 http://dx.doi.org/10.3390/ijms21145135 |
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