Combined effects of FLT3 and NF‐κB selective inhibitors on acute myeloid leukemia in vivo

Abstract

FMS-like tyrosine kinase 3 (FLT3) is an independent poor prognostic marker of acute myeloid leukemia (AML), and strategies that specifically target FLT3 are therefore of substantial interest. However, previous studies with FLT3 inhibitors as single agents in patients with AML showed few clinical responses. In the present study, combined effects of FLT3 selective inhibitor (SC-203048) and NF-κB selective inhibitor (Parthenolide, PTL) on AML xenograft tumor growth in vivo were examined, and the possible antitumor mechanisms by which SC-203048 and PTL affect AML xenograft tumor growth were also detected. Results showed that the tumor growth was strongly inhibited, and increased cell apoptosis was also observed after treatments, especially in the combination group; meanwhile, the expressions of FLT3, p65, cyclin D1, and Bc1-2 decreased significantly, and the expression of nuclear Silencing mediator for retinoic acid and thyroid hormone receptors (SMRT) increased notably. All results indicate that synergism exists between FLT3 and NF-κB inhibitors, and inhibitors combination treatment may be a potential strategy for AML.

Association between TERT promoter polymorphisms and acute myeloid leukemia risk and prognosis

“…Furthermore, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to decrease the amount on several pro-inflammatory mediators as well as incidence and mortality of several cancers [ 43 ]. Wang et al observed increased cell apoptosis and demonstrated a strong inhibition of tumor growth, after inhibiting the expression of FLT3 and NFkB p65 simultaneously in THP-1 cell line, and that a combined treatment strategy may be effective for AML in humans [ 44 ]. Although, we were not able to demonstrate an increased mRNA expression of TERT , in relation to SNV genotypes, an increased IL-6 expression was clearly observed ( Supplementary Figure S1 ) and demonstrates that TERT orchestrates several activities in addition to increased telomere length and cell survival, which contributes to tumor progression.…”

Quantification of Azaserine-Induced Carboxymethylated and Methylated DNA Lesions in Cells by Nanoflow Liquid Chromatography-Nanoelectrospray Ionization Tandem Mass Spectrometry Coupled with the Stable Isotope-Dilution Method

“…1 In this vein, N -nitroso compounds (NOCs) are present in food, tobacco, and pharmaceutical products. 2,3 Despite the prevalence of exogenous sources of NOCs, it was estimated that endogenous sources constitute 45–75% of total NOC exposure in humans. 2 In a widely accepted model for the etiology of gastric cancer, DNA damage emanating from intragastric nitrosation is considered an important factor contributing to early stages of disease development.…”

“…13 DNA carboxymethylation induced by the aforementioned agents is thought to arise from a common reactive intermediate, diazoacetate (Scheme 1). 3,14 Diazoacetate can decompose to yield carboxymethyldiazonium and methyldiazonium ions, which result in the carboxymethylation and methylation of DNA, respectively. 3,14 In addition to guanine and adenine, cytosine and thymine in DNA can also be carboxymethylated by diazoacetate.…”

“…3,14 Diazoacetate can decompose to yield carboxymethyldiazonium and methyldiazonium ions, which result in the carboxymethylation and methylation of DNA, respectively. 3,14 In addition to guanine and adenine, cytosine and thymine in DNA can also be carboxymethylated by diazoacetate. 15,16 …”

Parthenolide as Cooperating Agent for Anti-Cancer Treatment of Various Malignancies

“…Abnormal activation of FMS-like tyrosine kinase 3 (FLT3) is observed in AML patients [161]. FLT3 selective inhibitor SC-203048 in combination with PN synergistically inhibited AML growth and increased cell apoptosis [162].…”