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
Edit KotogányGábor J Szebeni

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-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 c...Continue Reading

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Citations

May 22, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Ágnes E KulmányIstván Zupkó
Sep 4, 2021·The Journal of Steroid Biochemistry and Molecular Biology·Ágnes E KulmányIstván Zupkó

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Methods Mentioned

BETA
MDS
flow cytometry
Assay
immunoprecipitation
FCS
PCR
PCRs
FACS

Software Mentioned

viSNE
CellQuestTM
CellQuest Pro
CellQuest
CellQuest TM
GraphPad Prism
ModFit
Image Quant TL

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