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

• Published in: International journal of molecular sciences Vol. 21; no. 14; p. 5135
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 20.07.2020; MDPI
• Subjects: Acute myeloid leukemia; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Bcl-x protein; Bone marrow; Breast cancer; Cancer therapies; Caspase-3; CD11b antigen; CD7 antigen; Cell differentiation; Cell Differentiation - drug effects; Chemotherapy; Cytotoxicity; Depolarization; differentiation; Differentiation (biology); Female; Gene expression; HL-60 Cells; Humans; JunB protein; Kinases; Lactic acid; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Male; Mice, Inbred BALB C; Middle Aged; Mitochondria; Myeloid cells; Myeloid leukemia; myeloid-derived suppressor cells; Myeloid-Derived Suppressor Cells - cytology; Myeloid-Derived Suppressor Cells - drug effects; Myeloid-Derived Suppressor Cells - metabolism; Phosphorylation; Proteins; Pyrazole; Pyrazoles - chemistry; Pyrazoles - pharmacology; Spleen; Stem cells; Suppressor cells; Transcription factors; Tumor Cells, Cultured; Young Adult; apoptosis; differentiation; acute myeloid leukemia; myeloid-derived suppressor cells
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21145135

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- ]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 and pAkt 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 cells followed apoptosis (IC : 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.