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.
Highlights
Acute myeloid leukemia (AML) is characterized by the uncontrolled proliferation of immature hematopoietic precursors with reduced potential to differentiate into their downstream myeloidMolecules 2017, 22, 1444; doi:10.3390/molecules22091444 www.mdpi.com/journal/moleculesMolecules 2017, 22, 1444 counterparts [1,2]
FLT3 signaling in MV4-11 cells (Figure 6E)
We assumed that ADR inhibits protein synthesis through suppressing FLT3 signaling in MV4-11 cells
Summary
Acute myeloid leukemia (AML) is characterized by the uncontrolled proliferation of immature hematopoietic precursors with reduced potential to differentiate into their downstream myeloidMolecules 2017, 22, 1444; doi:10.3390/molecules22091444 www.mdpi.com/journal/moleculesMolecules 2017, 22, 1444 counterparts [1,2]. The receptor tyrosine kinase FLT3-ITD is known as one of the major molecular genetic abnormalities which confers chemotherapy drug resistance and high relapse risk among 23% of AML patients [7]. It is expressed in early hematopoietic progenitor cells and activates downstream PI3K/Akt and RAS/MAPK pathways governing early stem cell survival and myeloid differentiation [8,9]. 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 discovered that ADR inhibited fatty acid synthesis, cellular iron uptake and FLT3 signaling pathway in MV4-11 cells.
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