Hesperetin ameliorates glioblastoma by inhibiting proliferation, inducing apoptosis, and suppressing metastasis.

ABSTRACT

Background: Glioblastoma is the most common type of malignant tumor of the brain. Despite substantial improvements in therapy, the 5-year survival rate of patients with glioblastoma remains low. Antitumor drug development has encountered considerable obstacles, which can be attributed to metastasis and the blood-brain barrier (BBB). Hesperetin (HSP), derived from citrus fruits, exhibits several biological properties, including anticancer and anti-inflammatory activities. In addition, in vitro models have shown that HSP can easily cross the BBB. The purpose of the present study was to explore the effects and underlying mechanisms of HSP on glioblastoma cells. Methods: GL261 cell were cultured and treated with different dose HSP. The cell viability was assessed with Cell Counting Kit-8 (CCK-8) assay. The cell apoptosis was determined using an Annexin V/propidine iodide (PI) staining and Hoechst staining and detection assay, cell migration and invasion were observed on GL261 cells using Matrigel-coated Transwells and Wound-Healing assay. The expression of proteins was detected by Western blotting. Results: HSP suppressed cell proliferation and could induce apoptosis, the latter of which might be regulated through the Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and nuclear factor-kappa B (NF-κB) pathways. Furthermore, HSP inhibited cell migration and invasion by downregulating the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, and inhibited epithelial-mesenchymal transition (EMT) by upregulating the expression of E-cadherin while downregulating N-cadherin and vimentin expression. Conclusions: These findings suggest HSP to be an alternative preventive and therapeutic antiglioblastoma drug that may be especially useful for patients with recurrent glioblastoma.