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 1, 4 , Mengru Cao 1 , Shuhong Wu 1 , Li Wang 1 , Jing Hu 1 , Reza J. Mehran 1 , Jack A. Roth 1 , Stephen G. Swisher 1 , Rui-Yu Wang 2 , Hagop M. Kantarjian 2 , Michael Andreeff 2 , Xiaoping Sun 3 and Bingliang Fang 1 1 Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA 2 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA 3 Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA 4 Department of Traditional Chinese Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China Correspondence to: Bingliang Fang, email: bfang@mdanderson.org Keywords: cancer; drug development; biomarker; sulfotransferase; SULT1A1 Received: July 03, 2017     Accepted: September 30, 2017     Published: November 01, 2017 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.