Gambogic Acid Suppresses Hypoxia-Induced HIF-1α/VEGF Expression Via Inhibiting PI3K/Akt/mTOR Pathway in Multiple Myeloma Cells

In multiple myeloma (MM), the hypoxic environment is an important factor causing tumor angiogenesis which is strongly correlated to disease progression and unfavorable outcome by activating the key transcription factor, hypoxia-inducible factor-1α (HIF-1α). Gambogic acid (GA) is the major active ingredient of gamboge, which has been shown to possess antitumor effect by in vitro and in vivo study. However, the underlying molecular mechanism that whether GA inhibits tumor angiogenesis remains not well understood. In this study, we investigated the effects of GA on expression of HIF-1α, and its downstream target gene vascular endothelial growth factor (VEGF) in human MM U266 cells. We found that hypoxia induced increase in the level of HIF-1α subunit protein and activated the PI3K/Akt/mTOR pathway. Moreover, the treatment with GA markedly decreased HIF-1α and VEGF expression under hypoxic condition. Mechanistic studies exhibited that GA inhibited the production of HIF-1α by reducing phosphorylation of Akt and mTOR in U266 cells. Furthermore, in vivo study revealed that intravenous injection of GA once every other day for two weeks could suppress tumor volumes by antiangiogenesis activity. Taken together, our results identify GA suppress hypoxia-activated pathways that linked to MM progression, at least partly, by the inhibition of PI3K/Akt/mTOR signaling pathway. Therefore, GA may be a new potent therapeutic agent against human MM cells.