Combination of metformin and cold atmospheric plasma induces glioma cell death to associate with c-Fos

Abstract

Glioma is the most common type of brain cancer. Chemotherapy combination with surgery and radiotherapy is a standard treatment for patients. Although there are many advances in glioma therapy, the prognosis of glioma patients has not significantly been improved over the past decades. Hence, there is still an urgent need to develop a new therapy to treat glioma. Cell viability was assessed by CellTiter Blue assay; flow cytometry (FCM) was used for detecting cell apoptosis; ROS detection was detected by ROS Assay; H 2 O 2 detection was performed by hydrogen peroxide detection kits; real-time PCR and WB were used to determine gene expression. Using the glioma cell line U251 and U87, we investigated a possible combination inhibitory effect includes metformin and cold atmospheric plasma (CAP). The combinatio n treatment showed a synergistic inhibitory effect on cell viability, significantly inducing cell apoptosis. Furthermore, we also found H 2 O 2 produced by CAP has an important role in the synergistic inhibitory effect, eliminating H 2 O 2 with catalase reversed the synergistic inhibitory effect. In addition, the transcript and protein levels of c-FOS were robustly increased after co-treated with metformin and CAP. Taken together, we propose that pre-treatment glioma cells with metformin sensitize tumor cells to CAP, which may serve as a potential therapeutic strategy for glioma.

Cold atmospheric plasma (CAP) treatment increased reactive oxygen and nitrogen species (RONS) levels in tumor samples obtained from patients with low-grade glioma

“…Previous studies have shown the effectiveness of CAP jet in inducing RONS accumulation in brain cancer cells without affecting normal cells [43][44][45][46][47][48]. The anti-cancer properties of CAP can be attributed to RONS as CAP generated RONS blocked PI3K/AkT pathway, downregulated JNK and ERK1/2 signaling and activated p53, caspase-3 & 7 and PARP leading to apoptosis in brain cancer cells [44].…”

“…Intracranial CAP jet treatment inhibits tumor growth in glioblastoma bearing mice [45]. Furthermore, combination of metformin and CAP showed synergistic anti-cancer effects in glioma cell lines U251 and U87 [47].…”

Intracellular Responses Triggered by Cold Atmospheric Plasma and Plasma-Activated Media in Cancer Cells

“…However, only 4 and 2 genes, respectively, were found commonly regulated by H 2 O 2 and CAP, indicating that non-ROS constituents are responsible for the regulation of the majority of CAP-regulated genes, including both PTGER3 and HSPA6 [ 67 ]. CAPs also deregulate the expression of several transcription factors, including c-FOS [ 68 ] and Yes-associated protein YAP/transcriptional enhancer associated domain TEAD [ 29 ]. In MCF-7 breast cancer cells, up and downregulation of ZNRD1 gene (DNA directed RNA-polymerase 1 subunit) correlated with long and short CAP treatment scheme.…”

Physical and chemical enhancement of cancer cell death induced by cold atmospheric plasma

“…cisplatin, metformin) in colorectal cancer, glioblastoma, oral squamous cell carcinoma, glioma cells, and others. [53][54][55][56] CAP is extensively praised for its selective cancer targeting via ROS-mediated oxidative stress. However, in contrast, it is also essential to consider that CAP induced massive ROS formation extracellularly.…”