Faculty Articles

PubMed Identifier

26916980

Title

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

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