Imidazo[1,2-b]pyrazole-7-carboxamides induce apoptosis in human leukemia cells at nanomolar concentrations

Gábor J. Szebeni, József A. Balog, András Demjén, Róbert Alföldi, Vanessza L. Végi, Liliána Z. Fehér, Imola Mán, Edit Kotogány, Barbara Gubán, Péter Batár, László Hackler, Iván Kanizsai, L. Puskás

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish
Article number2845
JournalMolecules
Volume23
Issue number11
DOIs
Publication statusPublished - Nov 1 2018

Fingerprint

leukemias
apoptosis
Leukemia
Cells
Apoptosis
Genes
cells
Lead compounds
Oxidative stress
Flow cytometry
Depolarization
Fibroblasts
Inhibitory Concentration 50
Glutathione
Monolayers
cultured cells
Toxicogenetics
Leukemia, Monocytic, Acute
genes
Population

Keywords

  • Acute myeloid leukemia
  • Apoptosis
  • Imidazole
  • Pyrazole
  • Toxicogenomics

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

Imidazo[1,2-b]pyrazole-7-carboxamides induce apoptosis in human leukemia cells at nanomolar concentrations. / 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, László; Kanizsai, Iván; Puskás, L.

In: Molecules, Vol. 23, No. 11, 2845, 01.11.2018.

Research output: Contribution to journalArticle

Szebeni, GJ, Balog, JA, Demjén, A, Alföldi, R, Végi, VL, Fehér, LZ, Mán, I, Kotogány, E, Gubán, B, Batár, P, Hackler, L, Kanizsai, I & Puskás, L 2018, 'Imidazo[1,2-b]pyrazole-7-carboxamides induce apoptosis in human leukemia cells at nanomolar concentrations', Molecules, vol. 23, no. 11, 2845. https://doi.org/10.3390/molecules23112845
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, László ; Kanizsai, Iván ; Puskás, L. / Imidazo[1,2-b]pyrazole-7-carboxamides induce apoptosis in human leukemia cells at nanomolar concentrations. In: Molecules. 2018 ; Vol. 23, No. 11.
@article{ded2b7a2b80544248878fb99fa659dc0,
title = "Imidazo[1,2-b]pyrazole-7-carboxamides induce apoptosis in human leukemia cells at nanomolar concentrations",
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.",
keywords = "Acute myeloid leukemia, Apoptosis, Imidazole, Pyrazole, Toxicogenomics",
author = "Szebeni, {G{\'a}bor J.} and Balog, {J{\'o}zsef A.} and Andr{\'a}s Demj{\'e}n and R{\'o}bert Alf{\"o}ldi and V{\'e}gi, {Vanessza L.} and Feh{\'e}r, {Lili{\'a}na Z.} and Imola M{\'a}n and Edit Kotog{\'a}ny and Barbara Gub{\'a}n and P{\'e}ter Bat{\'a}r and L{\'a}szl{\'o} Hackler and Iv{\'a}n Kanizsai and L. Pusk{\'a}s",
year = "2018",
month = "11",
day = "1",
doi = "10.3390/molecules23112845",
language = "English",
volume = "23",
journal = "Molecules",
issn = "1420-3049",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "11",

}

TY - JOUR

T1 - Imidazo[1,2-b]pyrazole-7-carboxamides induce apoptosis in human leukemia cells at nanomolar concentrations

AU - Szebeni, Gábor J.

AU - Balog, József A.

AU - Demjén, András

AU - Alföldi, Róbert

AU - Végi, Vanessza L.

AU - Fehér, Liliána Z.

AU - Mán, Imola

AU - Kotogány, Edit

AU - Gubán, Barbara

AU - Batár, Péter

AU - Hackler, László

AU - Kanizsai, Iván

AU - Puskás, L.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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.

AB - 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.

KW - Acute myeloid leukemia

KW - Apoptosis

KW - Imidazole

KW - Pyrazole

KW - Toxicogenomics

UR - http://www.scopus.com/inward/record.url?scp=85056048074&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056048074&partnerID=8YFLogxK

U2 - 10.3390/molecules23112845

DO - 10.3390/molecules23112845

M3 - Article

VL - 23

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 11

M1 - 2845

ER -