Gambogic acid suppresses hypoxia-induced hypoxia-inducible factor-1α/vascular endothelial growth factor expression via inhibiting phosphatidylinositol 3-kinase/Akt/mammalian target protein of rapamycin pathway in multiple myeloma cells.
Bottom Line: We found that hypoxia induced increase in the level of HIF-1α subunit protein and activated the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target protein of rapamycin (mTOR) pathway.Mechanistic studies exhibited that GA inhibited the production of HIF-1α by reducing phosphorylation of Akt and mTOR in U266 cells.Taken together, our results identify that GA suppresses hypoxia-activated pathways that are linked to MM progression, at least partly, by the inhibition of the PI3K/Akt/mTOR signaling pathway.
Affiliation: Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Medical School, Zhongda Hospital, Southeast University, Nanjing, China.Show MeSH
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Mentions: To confirm the macroscopic observations and address the potential effect of GA in vivo, immunohistochemistry was performed. The results showed that the presence of endothelial-specific antibody CD31-stained capillaries in xenografts was dose-dependently reduced by GA treatment (Fig. 6a,b), suggesting GA attenuated the tumor angiogenesis. To investigate whether the anti-angiogenesis effect of GA was due to the decreased level of VEGF and HIF-1α, immunohistochemistry for VEGF and HIF-1α was performed. The same as CD31, the tumor sections treated with GA showed significantly lower levels of VEGF and HIF-1α than that of control tumor tissue (Fig. 6a,c). These results further supported that GA, a HIF-1α inhibitor, is a potential compound for MM therapy.
Affiliation: Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Medical School, Zhongda Hospital, Southeast University, Nanjing, China.