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 bloodbrain 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.

Cellular electrophysiological effects of the citrus flavonoid hesperetin in dog and rabbit cardiac ventricular preparations

“…Other epidemiological studies show protective effects of citrus alkaloids against ischemic stroke 6 , 7 and cancer 8 . This latter observation is also supported by experimental data 9 .…”

Exploring the multi-targeting phytoestrogen potential of Calycosin for cancer treatment: A review

“…[97] Glioblastoma development is linked to EMT induced by matrix metalloproteinases (MMP), particularly MMP-2 and MMP-9, which promote tumor aggressiveness by degrading the extracellular matrix and promoting the EMT process. [98][99][100] TGF-β regulates EMT and MMP activation in various cancer cells. [101][102][103] In the case of U87 and U251 cells, CA has been shown to inhibit the EMT process by downregulating TGF-β and suppressing MMP-2 and MMP-9.…”

The Interplay between Glioblastoma Cells and Tumor Microenvironment: New Perspectives for Early Diagnosis and Targeted Cancer Therapy

“…This is one of the mecha-nisms by which cancer cells modulate the tumor microenvironment, and it is also possible to identify the increased concentration of HSPs in circulation [87,88]. Furthermore, it was noted through in vitro models that HSPs can easily cross the BBB [89].…”