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Andrographolide Suppresses MV4-11 Cell Proliferation through the Inhibition of FLT3 Signaling, Fatty Acid Synthesis and Cellular Iron Uptake.

The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China. pyb025@126.com. Department of Oncology, Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China. zhangjianbin@hmc.edu.cn. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China. cnylxtcm@163.com. Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore. layyifei@gmail.com. Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore. e0146526@u.nus.edu. Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore. dbslimtk@nus.edu.sg. Institute of Mental Health, Education Office, Singapore 539747, Singapore. Chye_Sun_ONG@imh.com.sg. Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore. dbslinqs@nus.edu.sg. Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore. wangjigang@u.nus.edu. Changzhou High-Tech Research Institute of Nanjing University, Institute of Biotechnology, Jiangsu Industrial Technology Research Institute and Jiangsu Target Pharma Laboratories Inc., Changzhou 213164, China. wangjigang@u.nus.edu. The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China. zchua@nju.edu.cn. Changzhou High-Tech Research Institute of Nanjing University, Institute of Biotechnology, Jiangsu Industrial Technology Research Institute and Jiangsu Target Pharma Laboratories Inc., Changzhou 213164, China. zchua@nju.edu.cn.

Molecules (Basel, Switzerland). 2017;(9)
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Abstract

Background: Andrographolide (ADR), the main active component of Andrographis paniculata, displays anticancer activity in various cancer cell lines, among which leukemia cell lines exhibit the highest sensitivity to ADR. In particular, ADR was also reported to have reduced drug resistance in multidrug resistant cell lines. However, the mechanism of action (MOA) of ADR's anticancer and anti-drug-resistance activities remain elusive. Methods: In this study, we used the MV4-11 cell line, a FLT3 positive acute myeloid leukemia (AML) cell line that displays multidrug resistance, as our experimental system. We first evaluated the effect of ADR on MV4-11 cell proliferation. Then, a quantitative proteomics approach was applied to identify differentially expressed proteins in ADR-treated MV4-11 cells. Finally, cellular processes and signal pathways affected by ADR in MV4-11 cell were predicted with proteomic analysis and validated with in vitro assays. Results: ADR inhibits MV4-11 cell proliferation in a dose- and time-dependent manner. With a proteomic approach, we discovered that ADR inhibited fatty acid synthesis, cellular iron uptake and FLT3 signaling pathway in MV4-11 cells. Conclusions: ADR inhibits MV4-11 cell proliferation through inhibition of fatty acid synthesis, iron uptake and protein synthesis. Furthermore, ADR reduces drug resistance by blocking FLT3 signaling.