Imidazo[1,2- b ]pyrazole-7-carboxamides Induce Apoptosis in Human Leukemia Cells at Nanomolar Concentrations

Leukemia, the malignancy of the hematopoietic system accounts for 10% of cancer cases with poor overall survival rate in adults; therefore, there is a high unmet medical need for the development of novel therapeutics. Eight imidazo[1,2- ]pyrazole-7-carboxamides have been tested for cytotoxic activit...

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Bibliographic Details
Published in:	Molecules (Basel, Switzerland) Vol. 23; no. 11; p. 2845
Main Authors:	Szebeni, Gábor J, Balog, József A, Demjén, András, Alföldi, Róbert, Végi, Vanessza L, Fehér, Liliána Z, Mán, Imola, Kotogány, Edit, Gubán, Barbara, Batár, Péter, Hackler, Jr, László, Kanizsai, Iván, Puskás, László G
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 01-11-2018 MDPI
Subjects:	Acute monocytic leukemia acute myeloid leukemia Acute promyeloid leukemia Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis Apoptosis - drug effects Breast cancer Cell Line, Tumor Cell Survival - drug effects Cytotoxicity Depletion Depolarization Dose-Response Relationship, Drug Drug development Drug dosages Erythroleukemia Evolution, Molecular Fibroblasts Flow cytometry Gene expression Genes Hematopoietic system HL-60 Cells Humans imidazole Investigations Lead compounds Leukemia Lymphatic leukemia Malignancy Membrane potential Mitochondria Molting Monocytes Monocytic leukemia Myelomonocytic leukemia Necrosis Optimization Oxidative stress Oxidative Stress - drug effects Population studies Promyeloid leukemia Pyrazole Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacology Superoxide dismutase Survival toxicogenomics Tumor cell lines Tumor necrosis factor-TNF pyrazole apoptosis acute myeloid leukemia imidazole toxicogenomics
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Summary:	Leukemia, the malignancy of the hematopoietic system accounts for 10% of cancer cases with poor overall survival rate in adults; therefore, there is a high unmet medical need for the development of novel therapeutics. Eight imidazo[1,2- ]pyrazole-7-carboxamides have been tested for cytotoxic activity against five leukemia cell lines: Acute promyelocytic leukemia (HL-60), acute monocytic leukemia (THP-1), acute T-lymphoblastic leukemia (MOLT-4), biphenotypic B myelomonocytic leukemia (MV-4-11), and erythroleukemia (K-562) cells in vitro. Imidazo[1,2- ]pyrazole-7-carboxamides hampered the viability of all five leukemia cell lines with different potential. Optimization through structure activity relationship resulted in the following IC values for the most effective lead compound DU385: 16.54 nM, 27.24 nM, and 32.25 nM on HL-60, MOLT-4, MV-4-11 cells, respectively. Human primary fibroblasts were much less sensitive in the applied concentration range. Both monolayer or spheroid cultures of murine 4T1 and human MCF7 breast cancer cells were less sensitive to treatment with 1.5⁻10.8 μM IC values. Flow cytometry confirmed the absence of necrosis and revealed 60% late apoptotic population for MV-4-11, and 50% early apoptotic population for HL-60. MOLT-4 cells showed only about 30% of total apoptotic population. Toxicogenomic study of DU385 on the most sensitive MV-4-11 cells revealed altered expression of sixteen genes as early (6 h), midterm (12 h), and late response (24 h) genes upon treatment. Changes in , , and expression suggested that DU385 causes oxidative stress, which was confirmed by depletion of cellular glutathione and mitochondrial membrane depolarization induction. Imidazo[1,2- ]pyrazole-7-carboxamides reported herein induced apoptosis in human leukemia cells at nanomolar concentrations.
ISSN:	1420-3049 1420-3049
DOI:	10.3390/molecules23112845