<p>Synergistic Effects of Resveratrol and Temozolomide Against Glioblastoma Cells: Underlying Mechanism and Therapeutic Implications</p>

Abstract

Purpose Temozolomide (TMZ) is a commonly used anti-glioblastoma (GBM) drug. However, glioblastoma cells frequently show primary and acquired resistance to TMZ. As a promising anti-GBM candidate, resveratrol (Res) faces the similar problem as TMZ. Although resveratrol combined with TMZ (Res/TMZ) has been reported to be used to treat GBMs, it remains unclear whether this combination is broad-spectrum for all glioma cells until now, especially for GBM cells/cases with dual drug resistance. The study aimed to evaluate the synergistic effects of resveratrol and TMZ against GBMs and identify the underlying mechanisms. Materials and Methods Drug sensitivities of rat RG-2, human LN-18 and LN-428 cell lines and effectiveness of Res/TMZ combinations were investigated via multiple experimental methods. O 6 -methylguanine-DNA methyltransferase (MGMT) was observed by Western blotting and immunocytochemistry (ICC). Transducer and activator of transcription 3 (STAT3) signaling pathway and expression changes of STAT3 -related gene were detected to explore the possible synergistic mechanism. Results One hundred micromolar resveratrol and 500 μM TMZ inhibited the growth of RG-2 cells and the low-dose combination (25 μM/250 μM) showed similar suppressive effects. LN-18 and, especially, LN-428 cells were neither sensitive to 100 μM resveratrol nor to 500 μM TMZ, while their growth was suppressed by combination of 75 μM Res/750 μM TMZ with the suppressive rates of 62.5% and 28.6% and apoptosis rates of 11.9% and 7.4%, respectively. Resveratrol had regulatory effect on the expression of MGMT and it could significantly down-regulate MGMT overexpression caused by TMZ. In addition, STAT3/Bcl-2/survivin signaling pathway was also remarkably inhibited in Res/TMZ-treated GBM cells. Conclusion Our results demonstrated synergistic effects of Res/TMZ on RG-2 cells and their bilaterally sensitizing effects to LN-18 and LN-428 cells. Frequent upregulation of MGMT and activation of STAT3 are the unfavorable factors for the treatment of GBMs and they may be the potential targets of Res/TMZ therapy.

Therapeutic potentials of resveratrol in combination with radiotherapy and chemotherapy during glioblastoma treatment: a mechanistic review

“…Furthermore, some studies have reported that the use of resveratrol can enhance chemotherapy-induced apoptosis in glioblastoma cell lines. The mechanisms would be either increased expression levels of apoptotic factors such as p53, BAX and caspase 3 or decreased expression levels of anti-apoptotic factors such as NF-κB and BCL-2 [ 119 – 122 ]. Li et al reported that temozolomide-induced apoptosis in glioblastoma-initiating cells is enhanced by resveratrol through DNA double-stranded breaks (DSBs)/pATM/pATR/p53 pathway activation [ 119 ].…”

Challenges and Perspectives of Standard Therapy and Drug Development in High-Grade Gliomas

“…Resveratrol (3,4′,5-trihydroxy-trans-stilbene) anti-cancer effects include anti-proliferation, cell cycle arrestment, and apoptosis promotion through multiple signaling pathways such as EGFR, p53, P13K/AKT/mTOR, STAT3, NF-κB, and oncogenic miRNAs [ 296 , 297 ]. Resveratrol suppresses tumor growth and prolongs survival in rats bearing intracranial C6 glioma [ 296 , 298 , 299 ].…”

“…Resveratrol administration decreased the expression of EGFR, MMP-9 NF-κB, PCNA, COX-2, and VEGF while increasing GFAP expression compared to the control group. Resveratrol also enhances Tmz efficacy by reducing ROS/ERK-mediated autophagy and promoting apoptosis [ 297 , 299 , 300 ]. Resveratrol in combination with Tmz suppresses the cell growth and induces apoptosis in RG-2 cell (>20%, 17%), LN-18 (62.3%, 12%), and LN-428 cells (28.6%, 8%) [ 297 ].…”

“…Resveratrol also enhances Tmz efficacy by reducing ROS/ERK-mediated autophagy and promoting apoptosis [ 297 , 299 , 300 ]. Resveratrol in combination with Tmz suppresses the cell growth and induces apoptosis in RG-2 cell (>20%, 17%), LN-18 (62.3%, 12%), and LN-428 cells (28.6%, 8%) [ 297 ]. The co-treatment also reduce MGMT protein expression RG-2 (44.9%), LN-18 (38.7%), and LN-428 (33.5%) compared to the Tmz-treated group only.…”

“…Their multitarget, high selectivity against cancer cells, capable of reducing multidrug chemoresistance, inexpensive and marginal side effects make them valuable potential therapeutics, especially when combined with current therapy advancement [ 341 ]. Phytochemicals such as thymoquinone, cannabinoids, and resveratrol have proven to enhance the anti-cancer effect in pre-clinical models when combined with Tmz [ 297 , 328 , 334 ]. Such development in pre-clinical findings further necessitates clinical studies to fully assess phytochemicals efficacy in combination with current standard therapy.…”