Abstract
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-b]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-b]pyrazole-7-carboxamides hampered the viability of all five leukemia cell lines with different potential. Optimization through structure activity relationship resulted in the following IC50 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 IC50 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 ALOX5AP, TXN, and SOD1 expression suggested that DU385 causes oxidative stress, which was confirmed by depletion of cellular glutathione and mitochondrial membrane depolarization induction. Imidazo[1,2-b]pyrazole-7-carboxamides reported herein induced apoptosis in human leukemia cells at nanomolar concentrations.
Highlights
Leukemias and lymphomas accounts for almost 10% of cancer cases worldwide [1]
Seven DU-compounds were prepared for antitumor characterization with a substitution pattern of C2 tert-butyl, C3 aliphatic (tBu, tert-octyl or cyclohexyl (Cy)), and C7 phenyl substituted secondary carboxamides with electron-donating (ED) groups, such as hydroxyl (OH) and amino (NH2 ) functions (Figure 1B)
We have shown the anti-leukemic effect of imidazo[1,2-b]pyrazole-7-carboxamides (Figure 1 and Figure S1) using the resazurin viability assay (Table 1, Figures S2–S6)
Summary
Leukemias and lymphomas accounts for almost 10% of cancer cases worldwide [1]. Leukemias are heterogeneous diseases due to differential cellular origin along with self-characteristic genetic abnormalities [2]. Based on the maturation status, differentiation level, and/or lineage commitment acute myeloid leukemia cells (AML) have been classified by the French-American-British classification (FAB) system [3,4,5]. To determine the specificity of imidazo[1,2-b]pyrazole-7-carboxamides as potential anti-leukemic agents we have focused on the following differentially matured AML cells: HL-60 acute promyelocytic leukemia, (FAB M2) [6,7], MV-4-11 biphenotypic B myelomonocytic leukemia (FAB M4) [8,9], THP-1 acute monocytic leukemia (FAB M5) [10,11], K-562 erythroleukemia, (FAB M6) [12,13]. One acute lymphoblastic leukemia cell line (ALL), the MOLT-4 acute T-lymphoblastic leukemia, was involved in the study
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