Phloretin induces cell cycle arrest and apoptosis of human glioblastoma cells through the generation of reactive oxygen species
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Phloretin, a flavonoid present in various plants, has been reported to exert anticarcinogenic effects. However, the mechanism of its chemo-preventive effect on human glioblastoma cells is not fully understood. This study aimed to investigate the molecular mechanism of phloretin and its associated chemo-preventive effect in human glioblastoma cells. The results indicate that phloretin inhibited cell proliferation by inducing cell cycle arrest at the G0–G1 phase and induced apoptosis of human glioblastoma cells. Phloretin-induced cell cycle arrest was associated with increased expression of p27 and decreased expression of cdk2, cdk4, cdk6, cyclinD and cyclinE. Moreover, the PI3K/AKT/mTOR signaling cascades were suppressed by phloretin in a dose-dependent manner. In addition, phloretin triggered the mitochondrial apoptosis pathway and generated reactive oxygen species (ROS). This was accompanied by the up-regulation of Bax, Bak and c-PARP and the down-regulation of Bcl-2. The antioxidant agents N-acetyl-l-cysteine and glutathione weakened the effect of phloretin on glioblastoma cells. In conclusion, these results demonstrate that phloretin exerts potent chemo-preventive activity in human glioblastoma cells through the generation of ROS.
KeywordsPhloretin Cell cycle arrest Apoptosis Reactive oxygen species Glioblastoma
This study was funded by Grant 2012ZX09303-005-003 from the National S&T Major Project of China, Grant 2011CB503900 from the “973” National S&T Major Project, Grants 81370235 and 81170101 from the National Natural Science Foundation of China, and Grant 7122106 from the Natural Science Foundation of Beijing.
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