Modulation of Autophagy is a Potential Strategy for Enhancing the Anti-Tumor Effect of Mebendazole in Glioblastoma Cells

Abstract

Mebendazole (MBZ), a microtubule depolymerizing drug commonly used for the treatment of helminthic infections, has been suggested as a repositioning candidate for the treatment of brain tumors. However, the efficacy of MBZ needs further study to improve the beneficial effect on the survival of those patients. In this study, we explored a novel strategy to improve MBZ efficacy using a drug combination. When glioblastoma cells were treated with MBZ, cell proliferation was dose-dependently inhibited with an IC 50 of less than 1 µM. MBZ treatment also inhibited glioblastoma cell migration with an IC 50 of less than 3 µM in the Boyden chamber migration assay. MBZ induced G2-M cell cycle arrest in U87 and U373 cells within 24 h. Then, at 72 h of treatment, it mainly caused cell death in U87 cells with an increased sub-G1 fraction, whereas polyploidy was seen in U373 cells. However, MBZ treatment did not affect ERK1/2 activation stimulated by growth factors. The marked induction of autophagy by MBZ was observed, without any increased expression of autophagy-related genes ATG5/7 and Beclin 1. Co-treatment with MBZ and the autophagy inhibitor chloroquine (CQ) markedly enhanced the anti-proliferative effects of MBZ in the cells. Triple combination treatment with temozolomide (TMZ) (another autophagy inducer) further enhanced the anti-proliferative effect of MBZ and CQ. The combination of MBZ and CQ also showed an enhanced effect in TMZ-resistant glioblastoma cells. Therefore, we suggest that the modulation of protective autophagy could be an efficient strategy for enhancing the anti-tumor efficacy of MBZ in glioblastoma cells.

Melatonin in Combination with Albendazole or Albendazole Sulfoxide Produces a Synergistic Cytotoxicity against Malignant Glioma Cells through Autophagy and Apoptosis

“…The formation of a punctuate pattern of LC3 is associated with the initiation of autophagy, via the aggregation of LC3 and the formation of the autophagosome, and directly correlated to the increase in AVOs in glioma cells, as an indication of the fusion of the autophagosome and lysosome [ 48 ]. Previous reports indicate that benzimidazoles, as mebendazole and ALB, can induce autophagy on GB cells [ 49 ] and colon adenocarcinoma cells [ 35 ], respectively, while the blockade of autophagy in cholangiocarcinoma cells, after its induction with ALB, has been associated with increased apoptosis of tumor cells [ 50 ]. Meanwhile, MLT has shown the ability to suppress autophagy in ovarian granulosa cells [ 51 ], as well as in rat brain neurons, through the reduction of reactive oxygen species [ 52 ]; however, the oxidative capacity of MLT metabolites has also been reported [ 53 ].…”

Enhancing Anti-Cancer Therapy with Selective Autophagy Inhibitors by Targeting Protective Autophagy

“…Addition of CQ can also enhance anti-proliferative effect of TMZ or MBZ ( Kanzawa et al ., 2004 ; Lee et al ., 2015 ). Such effect is further potentiated by triple combination with TMZ ( Jo et al ., 2022 ). Combination of CQ with apatinib (VEGFR2 inhibitor) can also effectively inhibit in vivo growth of thyroid cancer cells (KHM-5M) xenografted in mice ( Feng et al ., 2018 ).…”