Antioxidant Effect of Propofol in Gliomas and Its Association With Divalent Metal Transporter 1

Abstract

BackgroundOxidative stress enhances tumor invasion and metastasis in brain cancer. The activation of divalent metal transporter 1 (DMT1), which is regulated by glutamate receptors, can result in the increase of oxidative stress and risk of cancer development. Propofol, an anesthetic with antioxidant capacity, has been shown to decrease oxidative stress in several different types of cancer. However, the underlying mechanism remains unclear. Therefore, the present study aimed to elucidate the mechanism underlying the suppression of oxidative stress in glioma cells by propofol. It was hypothesized that propofol may inhibit oxidative stress in gliomas via suppressing Ca2+-permeable α-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA) receptor (CPAR)-DMT1 signaling.MethodsMale Wistar rats with C6 gliomas, which were established by intracranial injection of C6 glioma cells, were either treated with propofol or not for 6 h before being sacrificed. The levels of AMPA receptor subunit GluR2 and DMT1 protein expression were assessed using western blotting. The association between CPARs and DMT1 was confirmed in vitro using the AMPA receptor activator (R, S)-AMPA. Glutathione and reactive oxygen species assay kits were used to evaluate tumor oxidative stress. The effect of propofol on glioma proliferation was evaluated by determining tumor weight, cell cycles and a growth curve.ResultsPropofol infusion at either 20 or 40 mg/kg-1/h-1 increased GluR2 levels and downregulated DMT1 expression as well as glutathione content markedly in the periphery compared with that in the glioma core. The in vitro results revealed that (R, S)-AMPA increased DMT1 expression and reactive oxygen species levels, which were partly reversed by propofol treatment.ConclusionPropofol regulated DMT1 expression by modulating CPARs, resulting in the inhibition of tumor oxidative stress and glioma growth. The present study provides evidence for optimizing the selection of anesthetic drugs in perioperative management and prognosis of patients with glioma.

Ferroptosis Involvement in Glioblastoma Treatment

“…The reduction was further associated with a significant decrease in GSH/GSSG ratio and of ROS. Additionally, tumour cells in the propofol groups had a lower tumoral cell count [85]. These results could link the expression of DMT1 and iron levels to ROS production and tumour proliferation, presenting DMT1 as a potential therapeutical target.…”

Ferroptosis and Its Potential Role in Glioma: From Molecular Mechanisms to Therapeutic Opportunities

“…DMT1 may be related to increased iron levels in glioma cells and is currently a molecular marker in neurodegenerative diseases [ 76 ]. In an experimental rat model with C6 glioma cells, propofol inhibits DMT1 expression, tumor cell proliferation and eventually decreased glioma weight [ 77 ]. Additionally, this tumor suppressive effect was further found to be associated with a significant reduction in the GSH and ROS.…”

The Role of Iron in Cancer Progression

“…Consistently, targeting DMT1 can be used to potentially suppress tumor progression. For example, DMT1 inhibitors can selectively target stem cells in primary cancer cells and circulating tumor cells to inhibit the occurrence and development of tumors ( 68 ); Propofol, which is widely used in clinical practice for intraoperative general anesthesia and postoperative sedation, regulates DMT1 expression by modifying Ca2+-permeable α-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid receptors (CPARs), thereby inhibiting tumor oxidative stress and glioma tumor growth ( 69 ).…”