Induction of cytotoxicity and apoptosis in FLT3 mutant expressing cells using novel pyrimido cyanoacrylates and quinoline derivatives

Sobhanifar, M. A. and Mashkani, B. and Saadatmandzadeh, M. and Sadeghnia, H. R. and Mousavi, S. H. (2018) Induction of cytotoxicity and apoptosis in FLT3 mutant expressing cells using novel pyrimido cyanoacrylates and quinoline derivatives. Biomedicine and Pharmacotherapy, 108. pp. 893-905.

[img] Text
Induction of cytotoxicity and apoptosis in FLT3 mutant expressing cells using novel pyrimido cyanoacrylates and quinoline derivatives.pdf

Download (6MB)

Abstract

Background: Aberrant activation of FMS-like tyrosine kinase 3 (FLT3) is associated with acute myeloid leukemia (AML). Leukemic cells expressing constitutively active FLT3 mutants are resistance to the current cancer therapies (radiotherapy and chemotherapy); hence, there is an increased interest to identify new agents for the treatment of AML. The main aim of this study was evaluating cytotoxic effects of novel pyrimidocyanoacrylates and quinoline derivatives on FLT3 overexpressing cells. Materials and Methods: Five novel pyrimidocyanoacrylates & 2-chloro 3-carbaldehyde quinolone derivative compounds, E1QAC1, E1QAC2, E1QAC3, E1QAC4, and E1QAC5 were designed and synthesized at the Department of Chemistry, Faculty of Sciences, Ferdowsi University, Mashhad, Iran. FDC-P1 cells expressing human wild-type FLT3 (FD-FLT3-WT) and internal tandem duplication (ITD) mutants (FD-FLT3-ITD) used in this study. The cells maintained in DMEM medium supplemented with 10 fetal calf serum (FCS) and murine granulocyte-macrophage colony stimulating factor (mGM-CSF). Potency for induction of cytotoxicity (IC 50 value) and apoptosis was determined after treating the cells with concentration of the compounds by resazurin assay. Bax and Bcl2 activation status was also investigated by Western blot analysis. Results: All the compounds had concentration-dependent effects on inhibition of cell proliferation and induction of apoptosis in both cell lines. E1QAC4 was the most potent compound for inhibition of cell proliferation (with IC50 value of 19 μM) and apoptosis induction in the FLT3-WT cells. However, FD-FLT3-ITD cells were nearly five-times more resistant to all the compounds (except than E1QAC2) that the FLT3-WT expressing cells. Western blotting results also showed that FD-FLT3-ITD cells had lower levels of Bax and higher levels of Bcl2 than the FD-FLT3-WT cells. Conclusion: The five novel heterocyclic compounds (E1QAC1-5) had cytotoxic effects and induced apoptosis in FD-FLT3 cells. Therefore, it is worthwhile to consider them as potential lead compound for development of new therapeutic agents for AML patients. © 2018 Elsevier Masson SAS

Item Type: Article
Additional Information: Cited By :1 Export Date: 16 February 2020 CODEN: BIPHE Correspondence Address: Mousavi, S.H.; Medical Toxicology Research Center, Faculty of Medicine, Mashhad University of Medical SciencesIran; email: mousavih@mums.ac.ir
Uncontrolled Keywords: Autophosphorilation inhibition Cell proliferation inhibition FLT3 ligand FMS-like tyrosine kinase 3 Small molecule inhibitors Tyrosine kinase domain Tyrosine kinase domain inhibitors cyanoacrylate derivative cytotoxic agent e 1qac 1 e 1qac 2 e 1qac 3 e 1qac 4 e 1qac 5 granulocyte macrophage colony stimulating factor heterocyclic compound protein Bax protein bcl 2 quinoline derivative quinolone derivative unclassified drug CD135 antigen FLT3 protein, human quinoline animal cell apoptosis apoptosis assay Article biological activity cell growth cell proliferation cell proliferation assay controlled study drug cytotoxicity FDC-P1 cell line fetal calf serum flow cytometry human human cell IC50 mouse nonhuman nuclear magnetic resonance spectroscopy priority journal resazurin assay Western blotting animal cell line drug effect metabolism mutation Animals Cyanoacrylates Humans Mice Proto-Oncogene Proteins c-bcl-2 Quinolines
Subjects: QU Biochemistry
QV pharmacology
Divisions: Mashhad University of Medical Sciences
Depositing User: lib2 lib2 lib2
Date Deposited: 04 May 2020 03:56
Last Modified: 04 May 2020 03:56
URI: http://eprints.mums.ac.ir/id/eprint/17540

Actions (login required)

View Item View Item