Phloretin induces cell cycle arrest and apoptosis of human glioblastoma cells through the generation of reactive oxygen species

Abstract

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.

Anticancer Activity of Phloretin Against Human Gastric Cancer Cell Lines Involves Apoptosis, Cell Cycle Arrest, and Inhibition of Cell Invasion and JNK Signalling Pathway

“…In this study, we observed that Phloretin induces G2/M cell cycle arrest in gastric AGS cancer cells and the percentage of the AGS cells in G2 phase of the cell cycle increased with increased concentration of Phloretin. These results are also complimented by previous studies wherein Phloretin was reported to trigger cell cycle arrest in glioblastoma cells [ 21 ]. Cell invasion capacity is an important factor in metastasis of cancer cells [ 22 ] and in this study we observed that Phloretin could inhibit the invasion of the human gastric cancer cell lines.…”

Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy

“…Interestingly, the anticancer effects were enhanced in presence of cisplatin, which suggest a potential in adjuvant cancer therapy. Similar proapoptotic effects, associated with increased ROS and ROS-related pathways, were observed after treatment with very high (200–300 μ M) concentrations of phloretin [ 261 ].…”

“…While there is evidence that phloretin can induce cell cycle arrest in cancer cells [ 261 ], this process seems to be unrelated to senescence induction as there are no clear data about the possibility to induce senescence with phloretin.…”

Inhibition of Specificity Protein 1 Is Involved in Phloretin-Induced Suppression of Prostate Cancer

“…Phloretin has been recently attracted extensive interest and extensively studied in treating many diseases including in anticancer research. Phloretin could induce apoptosis of many types of cancer cells in vitro and inhibit growth of the transplanted tumors of multiple human cancer cell lines in vivo [5,7,42]. However, the molecular mechanism of the anticancer effect of phloretin in prostate cancer remained unclear.…”