Faculty Articles
PubMed Identifier
26916980
Novel anticancer compound [trifluoromethyl-substituted pyrazole N-nucleoside] inhibits FLT3 activity to induce differentiation in acute myeloid leukemia cells.
Publication Title
Cancer letters
Volume
375
Issue
2
Publication Date / Copyright Date
6-1-2016
First Page
199
Last Page
208
Publisher
Elsevier Science Ireland
Abstract
Anticancer properties of chemically synthesized compounds have continuously been optimized for better efficacy and selectivity. Derivatives of heterocyclic compounds are well known to have selective antiproliferative effect against many types of cancer. In this study, we investigated the ability of an indigenously synthesized anticancer molecule, G-11 [1-(2",3",4",6"-Tetra-O-acetyl-β-D-glucopyranosyl)-4-(3'-trifluoromethylphenylhydrazono)-3-trifluoromethyl-1,4-dihydropyrazol-5-one], to cause selective cytotoxicity and induce differentiation in the acute myeloid leukemia HL-60 cells. G-11 was able to exert cytotoxic effect on hematological (Jurkat, U937, K562, HL-60, CCRF-SB) and solid tumor (MCF-7, HepG2, HeLa, Caco-2) cell lines, with IC50 values significantly lower than noncancerous cells (HEK-293, BJ and Vero) and normal peripheral blood mononuclear cells. G-11 induced differentiation of HL-60 cells to granulocytes and monocytes/macrophages by inhibiting the activation of FLT3 (CD135 tyrosine kinase). ITD-FLT3 mutation found in many acute myeloid leukemia patients could also be targeted by G-11 as exhibited by its inhibitory effect on MOLM-13 and MV4-11 cell lines. Molecular docking studies suggest the involvement of Leu616, Asp698, Cys694 and Cys828 residues in binding of G-11 to FLT3. The ability of G-11 to cause selective cytotoxicity and induce differentiation in cancer cells could be clinically relevant for therapeutic gains.
Disciplines
Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences
Keywords
Apoptosis, Caco-2 Cells, Cell Differentiation, Cell Proliferation, Gene Expression Regulation, Leukemic, HL-60 Cells, Humans, Leukemia, Myeloid, Acute, Leukocytes, Mononuclear, Molecular Docking Simulation, Protein Kinase Inhibitors, Pyrazoles, fms-Like Tyrosine Kinase 3
NSUWorks Citation
Saleh, Ayman M; Taha, Mutasem O; Aziz, Mohammad A; Al-Qudah, Mahmoud A; AbuTayeh, Reem F; and Rizvi, Syed A, "Novel anticancer compound [trifluoromethyl-substituted pyrazole N-nucleoside] inhibits FLT3 activity to induce differentiation in acute myeloid leukemia cells." (2016). Faculty Articles. 240.
https://nsuworks.nova.edu/hpd_corx_facarticles/240