Resveratrol restores sensitivity of glioma cells to temozolamide through inhibiting the activation of Wnt signaling pathway

Abstract

Malignant gliomas are aggressive primary neoplasms that originate in the glial cells of the brain or the spine with notable resistance to standard treatment options. We carried out the study with the aim to shed light on the sensitization of resveratrol to temozolomide (TMZ) against glioma through the Wnt signaling pathway. Initially, glioma cell lines with strong resistance to TMZ were selected by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Then, the glioma cells were subjected to resveratrol, TMZ, Wnt signaling pathway inhibitors, and activators. Cell survival rate and inhibitory concentration at half maximum value were detected by MTT, apoptosis by flow cytometry, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, in vitro proliferation by hanging drop method and β-catenin translocation into nuclei by TOP/FOP-FLASH assay. The expressions of the Wnt signaling pathway-related and apoptosis-related factors were determined by western blot analysis. Nude mice with glioma xenograft were established to detect tumorigenic ability. Glioma cell lines T98G and U138 which were highly resistant to TMZ were selected for subsequent experiments. Resveratrol increased the efficacy of TMZ by restraining cell proliferation, tumor growth, and promoting cell apoptosis in glioma cells. Resveratrol inhibited Wnt2 and β-catenin expressions yet elevated GSK-3β expression. Moreover, the Wnt signaling pathway participates in the sensitivity enhancing of resveratrol to TMZ via regulating O 6 -methylguanine-DNA methyltransferase (MGMT) expression. Resveratrol sensitized TMZ-induced glioma cell apoptosis by repressing the activation of the Wnt signaling pathway and downregulating MGMT expression, which may confer new thoughts to the chemotherapy of glioma. K E Y W O R D S glioma, O 6 -methylguanine-DNA methyltransferase, resveratrol, sensitization, temozolomide, Wnt signaling pathway

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“…The ratio of TOP/FOP was regarded as an activation indicator of β-catenin signaling. 38 In this study, AQP1 siRNA remarkably reduced the ratio of TOP/FOP in CIA FLS, further indicating its inhibitory effect on β-catenin signaling. LiCl as an inhibitor of GSK-3β can promote the phosphorylation of GSK-3β (Ser9) and increase the protein level of β-catenin, thus this compound is used as a classic activator of β-catenin signaling.…”

The Plant-Derived Compound Resveratrol in Brain Cancer: A Review

“…As mentioned above, RES enhances the antiglioma efficacy of TMZ by inhibiting the Wnt signaling pathway, both in vitro and in vivo [157]. It has been demonstrated that the Wnt signal is essential for the self-renewal, migration, and differentiation of GBM stem cells [178].…”

“…It has been shown that RES reverses the TMZ-induced resistance of T98G GBM cells by downregulation of MGMT by the NF-κB-dependent pathway [156]. Repression of the activated Wnt signaling pathway through the downregulation of MGMT expression seems to be another way of inhibiting proliferation and facilitating the apoptosis of resistant glioma cells by the combination RES+TMZ [157]. The presence of RES forced various GBM cells (U87-MG, U-138 MG, and U251) treated with TMZ through mitosis leading to mitotic catastrophe and senescence, reducing the clonogenic capacity of cells and increasing the chronic effects of TMZ [158].…”

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“…In this regard, resveratrol was found to suppress glioblastoma cell migration and invasion by increased activation of the RhoA/ROCK pathway [116]. Resveratrol is also known to increase cancer cell sensitivity to chemotherapy such as temozolomide, the standard chemotherapeutic agent used in glioblastoma treatment [117]. In the RhoA/mDia pathway, it was a mDia agonist that inhibited all movement in U251 cells.…”