Imidazo[1,2-<i<b</i<]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-<i<b</i<]pyrazole-7-carboxamide derivative on HL-60 cells, we...
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Autor*in:	Edit Kotogány [verfasserIn] József Á. Balog [verfasserIn] Lajos I. Nagy [verfasserIn] Róbert Alföldi [verfasserIn] Valeria Bertagnolo [verfasserIn] Federica Brugnoli [verfasserIn] András Demjén [verfasserIn] Anita K. Kovács [verfasserIn] Péter Batár [verfasserIn] Gabriella Mezei [verfasserIn] Renáta Szabó [verfasserIn] Iván Kanizsai [verfasserIn] Csaba Varga [verfasserIn] László G. Puskás [verfasserIn] Gábor J. Szebeni [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2020

Schlagwörter:	acute myeloid leukemia myeloid-derived suppressor cells differentiation apoptosis

Übergeordnetes Werk:	In: International Journal of Molecular Sciences - MDPI AG, 2003, 21(2020), 14, p 5135
Übergeordnetes Werk:	volume:21 ; year:2020 ; number:14, p 5135

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.3390/ijms21145135

Katalog-ID:	DOAJ033195722

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245	1	0	\|a Imidazo[1,2-<i<b</i<]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells
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spelling	10.3390/ijms21145135 doi (DE-627)DOAJ033195722 (DE-599)DOAJf13b185fca07460a8e4b2df564bd9d9d DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Edit Kotogány verfasserin aut Imidazo[1,2-<i<b</i<]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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-<i<b</i<]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<sup<bright</sup< and pAkt<sup<bright</sup< 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<sup<bright</sup< cells followed apoptosis (IC<sub<50</sub<: 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. acute myeloid leukemia myeloid-derived suppressor cells differentiation apoptosis Biology (General) Chemistry József Á. Balog verfasserin aut Lajos I. Nagy verfasserin aut Róbert Alföldi verfasserin aut Valeria Bertagnolo verfasserin aut Federica Brugnoli verfasserin aut András Demjén verfasserin aut Anita K. Kovács verfasserin aut Péter Batár verfasserin aut Gabriella Mezei verfasserin aut Renáta Szabó verfasserin aut Iván Kanizsai verfasserin aut Csaba Varga verfasserin aut László G. Puskás verfasserin aut Gábor J. Szebeni verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 21(2020), 14, p 5135 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:21 year:2020 number:14, p 5135 https://doi.org/10.3390/ijms21145135 kostenfrei https://doaj.org/article/f13b185fca07460a8e4b2df564bd9d9d kostenfrei https://www.mdpi.com/1422-0067/21/14/5135 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2020 14, p 5135
allfields_unstemmed	10.3390/ijms21145135 doi (DE-627)DOAJ033195722 (DE-599)DOAJf13b185fca07460a8e4b2df564bd9d9d DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Edit Kotogány verfasserin aut Imidazo[1,2-<i<b</i<]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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-<i<b</i<]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<sup<bright</sup< and pAkt<sup<bright</sup< 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<sup<bright</sup< cells followed apoptosis (IC<sub<50</sub<: 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. acute myeloid leukemia myeloid-derived suppressor cells differentiation apoptosis Biology (General) Chemistry József Á. Balog verfasserin aut Lajos I. Nagy verfasserin aut Róbert Alföldi verfasserin aut Valeria Bertagnolo verfasserin aut Federica Brugnoli verfasserin aut András Demjén verfasserin aut Anita K. Kovács verfasserin aut Péter Batár verfasserin aut Gabriella Mezei verfasserin aut Renáta Szabó verfasserin aut Iván Kanizsai verfasserin aut Csaba Varga verfasserin aut László G. Puskás verfasserin aut Gábor J. Szebeni verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 21(2020), 14, p 5135 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:21 year:2020 number:14, p 5135 https://doi.org/10.3390/ijms21145135 kostenfrei https://doaj.org/article/f13b185fca07460a8e4b2df564bd9d9d kostenfrei https://www.mdpi.com/1422-0067/21/14/5135 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2020 14, p 5135
allfieldsGer	10.3390/ijms21145135 doi (DE-627)DOAJ033195722 (DE-599)DOAJf13b185fca07460a8e4b2df564bd9d9d DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Edit Kotogány verfasserin aut Imidazo[1,2-<i<b</i<]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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-<i<b</i<]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<sup<bright</sup< and pAkt<sup<bright</sup< 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<sup<bright</sup< cells followed apoptosis (IC<sub<50</sub<: 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. acute myeloid leukemia myeloid-derived suppressor cells differentiation apoptosis Biology (General) Chemistry József Á. Balog verfasserin aut Lajos I. Nagy verfasserin aut Róbert Alföldi verfasserin aut Valeria Bertagnolo verfasserin aut Federica Brugnoli verfasserin aut András Demjén verfasserin aut Anita K. Kovács verfasserin aut Péter Batár verfasserin aut Gabriella Mezei verfasserin aut Renáta Szabó verfasserin aut Iván Kanizsai verfasserin aut Csaba Varga verfasserin aut László G. Puskás verfasserin aut Gábor J. Szebeni verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 21(2020), 14, p 5135 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:21 year:2020 number:14, p 5135 https://doi.org/10.3390/ijms21145135 kostenfrei https://doaj.org/article/f13b185fca07460a8e4b2df564bd9d9d kostenfrei https://www.mdpi.com/1422-0067/21/14/5135 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2020 14, p 5135
allfieldsSound	10.3390/ijms21145135 doi (DE-627)DOAJ033195722 (DE-599)DOAJf13b185fca07460a8e4b2df564bd9d9d DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Edit Kotogány verfasserin aut Imidazo[1,2-<i<b</i<]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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-<i<b</i<]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<sup<bright</sup< and pAkt<sup<bright</sup< 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<sup<bright</sup< cells followed apoptosis (IC<sub<50</sub<: 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. acute myeloid leukemia myeloid-derived suppressor cells differentiation apoptosis Biology (General) Chemistry József Á. Balog verfasserin aut Lajos I. Nagy verfasserin aut Róbert Alföldi verfasserin aut Valeria Bertagnolo verfasserin aut Federica Brugnoli verfasserin aut András Demjén verfasserin aut Anita K. Kovács verfasserin aut Péter Batár verfasserin aut Gabriella Mezei verfasserin aut Renáta Szabó verfasserin aut Iván Kanizsai verfasserin aut Csaba Varga verfasserin aut László G. Puskás verfasserin aut Gábor J. Szebeni verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 21(2020), 14, p 5135 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:21 year:2020 number:14, p 5135 https://doi.org/10.3390/ijms21145135 kostenfrei https://doaj.org/article/f13b185fca07460a8e4b2df564bd9d9d kostenfrei https://www.mdpi.com/1422-0067/21/14/5135 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2020 14, p 5135
language	English
source	In International Journal of Molecular Sciences 21(2020), 14, p 5135 volume:21 year:2020 number:14, p 5135
sourceStr	In International Journal of Molecular Sciences 21(2020), 14, p 5135 volume:21 year:2020 number:14, p 5135
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	acute myeloid leukemia myeloid-derived suppressor cells differentiation apoptosis Biology (General) Chemistry
isfreeaccess_bool	true
container_title	International Journal of Molecular Sciences
authorswithroles_txt_mv	Edit Kotogány @@aut@@ József Á. Balog @@aut@@ Lajos I. Nagy @@aut@@ Róbert Alföldi @@aut@@ Valeria Bertagnolo @@aut@@ Federica Brugnoli @@aut@@ András Demjén @@aut@@ Anita K. Kovács @@aut@@ Péter Batár @@aut@@ Gabriella Mezei @@aut@@ Renáta Szabó @@aut@@ Iván Kanizsai @@aut@@ Csaba Varga @@aut@@ László G. Puskás @@aut@@ Gábor J. Szebeni @@aut@@
publishDateDaySort_date	2020-01-01T00:00:00Z
hierarchy_top_id	316340715
id	DOAJ033195722
language_de	englisch
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spellingShingle	Edit Kotogány misc QH301-705.5 misc QD1-999 misc acute myeloid leukemia misc myeloid-derived suppressor cells misc differentiation misc apoptosis misc Biology (General) misc Chemistry Imidazo[1,2-<i<b</i<]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells
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topic_title	QH301-705.5 QD1-999 Imidazo[1,2-<i<b</i<]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells acute myeloid leukemia myeloid-derived suppressor cells differentiation apoptosis
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title	Imidazo[1,2-<i<b</i<]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells
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title_full	Imidazo[1,2-<i<b</i<]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells
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author_browse	Edit Kotogány József Á. Balog Lajos I. Nagy Róbert Alföldi Valeria Bertagnolo Federica Brugnoli András Demjén Anita K. Kovács Péter Batár Gabriella Mezei Renáta Szabó Iván Kanizsai Csaba Varga László G. Puskás Gábor J. Szebeni
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title_sort	imidazo[1,2-<i<b</i<]pyrazole-7-carboxamide derivative induces differentiation-coupled apoptosis of immature myeloid cells such as acute myeloid leukemia and myeloid-derived suppressor cells
callnumber	QH301-705.5
title_auth	Imidazo[1,2-<i<b</i<]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells
abstract	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-<i<b</i<]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<sup<bright</sup< and pAkt<sup<bright</sup< 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<sup<bright</sup< cells followed apoptosis (IC<sub<50</sub<: 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.
abstractGer	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-<i<b</i<]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<sup<bright</sup< and pAkt<sup<bright</sup< 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<sup<bright</sup< cells followed apoptosis (IC<sub<50</sub<: 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.
abstract_unstemmed	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-<i<b</i<]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<sup<bright</sup< and pAkt<sup<bright</sup< 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<sup<bright</sup< cells followed apoptosis (IC<sub<50</sub<: 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.
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title_short	Imidazo[1,2-<i<b</i<]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells
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Imidazo[1,2-<i<b</i<]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells

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