20(S)‐ginsenoside‐Rg3 reverses temozolomide resistance and restrains epithelial‐mesenchymal transition progression in glioblastoma

Abstract

Glioblastoma multiforme (GBM) is one of the most malignant human intracranial tumors. Temozolomide (TMZ) is the primary alkylating agent for GBM patients. However, many GBM patients are resistant to TMZ. Therefore, patients with GBM urgently need more effective therapeutic options. 20(S)‐ginsenoside‐Rg3 (20(S)‐Rg3) is a natural chemical with anti‐tumor effects, but at present there is little understanding of its functional mechanism. Several research reports have demonstrated that O6‐methylguanine DNA‐methyltransferase (MGMT) repairs damaged DNA and contributes to TMZ resistance in gliomas. In addition, recent studies have shown that MGMT gene expression could be regulated by the Wnt/β‐catenin pathway. However, whether 20(S)‐Rg3 inhibits MGMT expression and augments chemosensitivity to Temozolomide (TMZ) in glioma cells remains unclear. In this study, we explored the modulating effects of 20(S)‐Rg3 on MGMT. We used glioma cell lines, primary cell strain (including T98G, U118 and GBM‐XX; all of them are MGMT‐positive glioma cell lines) and xenograft glioma models to examine whether 20(S)‐Rg3 increased the sensitivity to TMZ and to reveal the underlying mechanisms. We found that the MGMT expression was effectively downregulated by 20(S)‐Rg3 via the Wnt/β‐catenin pathway in glioma cell lines, and TMZ resistance was significantly reversed by 20(S)‐Rg3. Meanwhile, 20(S)‐Rg3 shows no obvious cytotoxicity at its effective dose and is well tolerated in vivo. In addition, we found that 20(S)‐Rg3 significantly restrains the epithelial‐mesenchymal transition (EMT) progression of glioma cells. Taken together, these results indicate that 20(S)‐Rg3 may be a novel agent to use in treatment of GBM, especially in TMZ‐resistant GBM with high MGMT expression.

RETRACTED ARTICLE: Berberine reduces temozolomide resistance by inducing autophagy via the ERK1/2 signaling pathway in glioblastoma

“…However, the relatively quick development of chemoresistance to this compound limits the efficacy of this therapeutic strategy [36]. Currently, a number of different and distinct mechanisms of TMZ resistance have been identified by researchers, including mechanisms that are dependent upon DNA O 6 -methylguanine methyltransferase (MGMT), DNA mismatch repair (MMR), base excision repair (BER), and the ATP-binding cassette (ABC) protein family [37][38][39][40]. Given these diverse mechanisms and the key role of TMZ in treating GBM, it is clear that more research needs to be performed to determine how TMZ resistance develops and what strategies are effective in increasing the sensitivity of TMZ-R cell lines to chemotherapeutic treatments.…”

Ginsenoside Rg3 attenuates the osimertinib resistance by reducing the stemness of non‐small cell lung cancer cells

“…Ginsenoside is an important active ingredient of ginseng and it has been used as an anticancer Chinese medicine in the treatment of malignant tumors such as melanoma and prostate cancer . Ginsenoside Rg3, the main component of Ginsenoside, has been shown to inhibit tumor progression and chemoresistance, for example, Ginsenoside Rg3 attenuates temozolomide resistance and epithelial‐mesenchymal transition (EMT) progression in glioblastoma; Ginsenoside Rg3 inhibits prostate cancer cell proliferation through inducing cell cycle arrest . Recent studies showed that Ginsenoside Rg3 could target CSCs in colorectal cancer and Ginsenoside Rg3 could enhance cisplatin sensitivity via blocking EMT process and stemness in lung cancer cells .…”

Enhanced Inhibition of Tumorigenesis Using Combinations of miRNA-Targeted Therapeutics

“…Aberrant functions of miRNAs may impede the interactions between miRNAs and their mRNA targets, a few examples of which are miRNA-210-3p and the multidrug efflux transporter ABCC5 (also known as MRP5; Amponsah et al, 2017); miRNA-101 and DNA-dependent protein kinases (Hu et al, 2017); miRNA-125a and the pro-apoptotic protein A20 (Yao et al, 2016); miR-145 and the ribosomal protein S6 kinase p70S6K1 (Lin et al, 2016); miRNA-181b and the cylindromatosis protein CYDL (Takiuchi et al, 2013); miRNA-144-3p and the AT-rich interactive domain 1A protein ARD1A (Xiao et al, 2017); and miRNA-199a-5p and miRNA-375 with the PH domain and leucine-rich repeat protein phosphatase 1 PHLPP1 (Mussnich et al, 2015). An impaired interaction between miRNA and its mRNA target unescapably results in tumor cell resistance, since these targets are elements of key cellular signaling cascades such as NF-κβ, AKT, and JAK2/STAT3, which control apoptosis, cell cycle progression, DNA repair, RNA editing, and nucleotide synthesis (Wu et al, 2018; Chen et al, 2019). Based on these data, investigators have attempted to use combinations of miRNA-based therapeutics in conjunction with chemotherapeutics to overcome the development of resistance and to increase the efficacy of treatment.…”