Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Modulation of Autophagy is a Potential Strategy for Enhancing the Anti-Tumor Effect of Mebendazole in Glioblastoma Cells

  • Jo, Seong Bin (Cancer Research Institute, College of Medicine, The Catholic University of Korea) ;
  • Sung, So Jung (Cancer Research Institute, College of Medicine, The Catholic University of Korea) ;
  • Choi, Hong Seok (Cancer Research Institute, College of Medicine, The Catholic University of Korea) ;
  • Park, Jae-Sung (Department of Neurosurgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Hong, Yong-Kil (Department of Neurosurgery, Hallym University Sacred Heart Hospital) ;
  • Joe, Young Ae (Cancer Research Institute, College of Medicine, The Catholic University of Korea)
  • Received : 2022.09.19
  • Accepted : 2022.10.07
  • Published : 2022.11.01
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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 IC50 of less than 1 µM. MBZ treatment also inhibited glioblastoma cell migration with an IC50 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.

Keywords

Acknowledgement

This research was supported by grants from the National Research Foundation of Korea grants funded by the Korean government (NRF-2012R1A5A2047939, NRF-2020R1A2C2006189).

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