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Article

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

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Laboratory of Functional Genomics, Institute of Genetics, Biological Research Centre, Temesvári krt. 62, H6726 Szeged, Hungary
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PhD School in Biology, University of Szeged, H6726 Szeged, Hungary
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Avidin Ltd., Alsó kikötő sor 11/D, H6726 Szeged, Hungary
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AstridBio Technologies Ltd., Wimmer Fülöp u. 1, H6728 Szeged, Hungary
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Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Via Fossato di Mortara 70, 44121 Ferrara, Italy
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Department of Hematology, Faculty of Medicine, University of Debrecen, Nagyerdei körút 98, H4032 Debrecen, Hungary
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Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép fasor 52, H6726 Szeged, Hungary
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Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(14), 5135; https://doi.org/10.3390/ijms21145135
Received: 28 May 2020 / Revised: 15 July 2020 / Accepted: 17 July 2020 / Published: 20 July 2020
(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias 2.0)
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-xlbright and pAktbright 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 CD38bright cells followed apoptosis (IC50: 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. View Full-Text
Keywords: acute myeloid leukemia; myeloid-derived suppressor cells; differentiation; apoptosis acute myeloid leukemia; myeloid-derived suppressor cells; differentiation; apoptosis
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MDPI and ACS Style

Kotogány, E.; Balog, J.Á.; Nagy, L.I.; Alföldi, R.; Bertagnolo, V.; Brugnoli, F.; Demjén, A.; Kovács, A.K.; Batár, P.; Mezei, G.; Szabó, R.; Kanizsai, I.; Varga, C.; Puskás, L.G.; Szebeni, G.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. Int. J. Mol. Sci. 2020, 21, 5135. https://doi.org/10.3390/ijms21145135

AMA Style

Kotogány E, Balog JÁ, Nagy LI, Alföldi R, Bertagnolo V, Brugnoli F, Demjén A, Kovács AK, Batár P, Mezei G, Szabó R, Kanizsai I, Varga C, Puskás LG, Szebeni GJ. 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. International Journal of Molecular Sciences. 2020; 21(14):5135. https://doi.org/10.3390/ijms21145135

Chicago/Turabian Style

Kotogány, Edit, 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, and Gábor J. Szebeni 2020. "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" International Journal of Molecular Sciences 21, no. 14: 5135. https://doi.org/10.3390/ijms21145135

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