Anti-leukemia activity of NSC-743380 in SULT1A1-expressing acute myeloid leukemia cells is associated with inhibitions of cFLIP expression and PI3K/AKT/mTOR activities.

Xiao Huang,Bingliang Fang,Hagop M Kantarjian,Mengru Cao,Stephen G Swisher,Xiaoping Sun,Michael Andreeff,Rui-Yu Wang,Jack A Roth,Shuhong Wu,Jing Hu,Reza J Mehran,Li Wang

doi:10.18632/oncotarget.22235

Abstract

Our recent study showed that acute myeloid leukemia (AML) cells expressing SULT1A1 are highly sensitive to NSC-743380, a small molecule that inhibits STAT3 activity and induces SULT1A1-dependent apoptosis of various cancer cell lines. In this study, we characterized the molecular mechanisms of NSC-743380–mediated anti-leukemia activity in AML cell lines and antileukemia activity of NSC-743380 in patient-derived primary leukemia cells from AML patients. Our results showed that treatment with NSC-743380 triggered robust apoptosis in SULT1A1-positive AML cells. Treatment with NSC-743380 did not increase intracellular reactive oxygen species or change of STAT3 activity in AML cells, but did dramatically and rapidly decrease cFLIP expression. Proteomic analysis with reverse phase protein microarray revealed that treatment of U937 and THP-1 AML cells with NSC-743380 led to drastic and time-dependent suppression of phosphorylation of several key nodes in the PI3K/AKT/mTOR pathway, including AKT and mTOR. Moreover, primary AML cells expressed SULT1A1 were highly sensitive to treatment with NSC-743380, which was not affected by co-culture with bone marrow mesenchymal stem cells. Thus, our results provide proof-of-concept evidence that AML cells expressing SULT1A1 can be targeted by small molecules that induce apoptosis through inhibiting the expression or activities of multiple targets.

Highlights

Acute myeloid leukemia (AML) is a group of malignant diseases of the hematopoietic system with remarkable heterogeneity in their cytogenetic and genomic alterations
Our results demonstrated that NSC-743380 induces robust apoptosis and dramatic inhibition of cFLIP expression and of the expression and/or phosphorylation of multiple key nodes in the PI3K/AKT/mTOR pathway in some acute myeloid leukemia (AML) cells, suggesting that NSC-743380 and its analogues can be candidates for AML therapy
35]. cFLIP overexpression is an independent marker of poor prognosis for most of cancers, suggesting that cFLIP plays a role in cancer progression and resistance to anticancer therapy

Summary

Introduction

Acute myeloid leukemia (AML) is a group of malignant diseases of the hematopoietic system with remarkable heterogeneity in their cytogenetic and genomic alterations. Patterns of cytogenetic aberrations and gene mutations have been used to divide AML patients into subgroups that are associated with clinical phenotype and outcome [2, 3], and such subgroups may guide selection of patients for novel pathway targeted therapies. Classical induction therapy with cytarabine and daunorubicin has been used to treat AML over the past 40 years [4, 5], www.impactjournals.com/oncotarget recent studies have demonstrated that certain innovative therapeutic approaches can dramatically improve the clinical outcomes of specific subsets of AML patients [6]. AML with aberrant DNA methylation resulting from TET2 or IDH2 mutations is susceptible to 5-azacytidine or to IDH2 inhibitor in experimental models [8], demonstrating the feasibility of improving clinical outcomes of AML patients using novel targeted agents

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