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

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.

HAMP Downregulation Contributes to Aggressive Hepatocellular Carcinoma via Mechanism Mediated by Cyclin4-Dependent Kinase-1/STAT3 Pathway

“…The liver is the most important metabolism organ, and many bioprocesses such as energy metabolism, gene expression, and pathway signal transduction participate in hepatocellular carcinoma, including tumor proliferation, invasion, and metastasis [5,6,7]. Recently, a boom of studies has shown the role of iron in multiple cancers’ progression, invasion, migration, and death [8,9,10], as the liver is the most common iron metabolism and storage organ. Hence, the carcinogenesis and metastasis of hepatocellular carcinoma are highly related to iron [11].…”

Study on the Antitumor Effect and Glycolysis of Andrographolide in Anaplastic Thyroid Carcinoma

“…Jada et al [16] reported the semisynthesis of andrographolide derivatives and their anticancer activities in vitro, which might be associated with cell cycle progression; ADR reduced VSMC cell proliferation by inducing apoptosis through ceramidep47phox-ROS signaling cascade [17]. Furthermore, it has been studied that andrographolide-induced cell proliferation decrease may be attributed to the inhibition of fatty acid synthesis, iron uptake, protein synthesis, and FLT3 signaling in MV4-11 cells [18]. In esophageal cancer, Andrographis paniculata has also been reported to exert an antitumor effect and is related to multiple signaling pathways including WNT, TGF-β, MAPK, and ErbB pathways [19].…”

FLT3 Receptor Heterogeneity Strictly Specifies the Dimensions of Malignant Transformation Events in Acute Myeloid Leukemia

“…Andrographolide (an active component of Andrographis paniculata) suppresses MV4-11 cell proliferation through inhibition of FLT3 signaling with also inhibition of fatty acid synthesis and cellular iron uptake [15]. FLT3 LIGAND The FLT3 receptor ligand FL functionality is mechanistically homologous to the KIT receptor and dynamics of each ligand type and is projected towards the further creation of established states of autophosphorylation of the tyrosine kinase domain.…”