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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2018-11, Vol.23 (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: Article
• Language: English
• 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
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules23112845

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.