Discovery of chrysoeriol,a PI3K-AKT-mTOR pathway inhibitor with potent antitumor activity against human multiple myeloma cells <Emphasis Type="Italic">in vitro</Emphasis> |
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Authors: | Yang Yang Xiaoxi Zhou Min Xiao Zhenya Hong Quan Gong Lijun Jiang Jianfeng Zhou |
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Institution: | Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030,China |
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Abstract: | This study was designed to determine the impact of chrysoeriol on proliferation and cell cycle progression in the human multiple
myeloma cell lines RPMI 8226 and KM3, and its related molecular mechanisms. Chryseoriol was identified by using the phosphorylated
AKT-specific cytoblot high throughput assay. CCK-8 assay was employed to examine the growth inhibition rate and IC50 (48 h) in peripheral blood mononuclear cells (PBMNCs), RPMI 8226 and KM3 cells treated with chrysoeriol at various concentrations.
Cells were labeled with 5–6-carboxyfluorescein diacetate succinimidyl ester (CFSE), and the proliferation dynamics was detected
by flow cytometry and analyzed with ModFit software. The cell cycles of RPMI 8226 and KM3 cells were measured by flow cytometry
when the IC50 concentration of chrysoeriol was adopted. The alterations in cell-cycle related proteins (Cyclin B1, Cyclin D1, p21) and
proteins in PI3K-AKT-mTOR pathway were determined by Western blot analysis. The results showed the proliferation of multiple
myeloma cells was significantly inhibited by chrysoeriol, resulting in cell cycle arrest in G2/M phase. Chrysoeriol could significantly reduce the expression of p-AKT (s473) and p-4eBP1 (t37/46) protein, meanwhile enhanced
Cyclin B1 and p21 protein expression. Similar effects were not observed in PBMNCs from normal donors. It was concluded that
chrysoeriol was a selective PI3K-AKT-mTOR pathway inhibitor. It restrained the proliferation of human multiple myeloma cells,
but didn’t affect proliferation of PBMNCs from normal donors. It might exhibit the cell cycle regulatory effect via the inhibition
of PI3K-AKT-mTOR signal pathway. |
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Keywords: | chrysoeriol multiple myeloma proliferation inhibition G2/M arrest PI3K-AKT-mTOR signal pathway |
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