Browse > Article
http://dx.doi.org/10.4062/biomolther.2022.122

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)
Publication Information
Biomolecules & Therapeutics / v.30, no.6, 2022 , pp. 616-624 More about this Journal
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
Mebendazole; Autophagy; Autophagy inhibitor; Chloroquine; Glioblastoma;
Citations & Related Records
Times Cited By KSCI : 2  (Citation Analysis)
연도 인용수 순위
1 Sui, X., Chen, R., Wang, Z., Huang, Z., Kong, N., Zhang, M., Han, W., Lou, F., Yang, J., Zhang, Q., Wang, X., He, C. and Pan, H. (2013) Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis. 4, e838.   DOI
2 Takahashi, T., Yamaguchi, S., Chida, K. and Shibuya, M. (2001) A single autophosphorylation site on KDR/Flk-1 is essential for VEGFA-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells. EMBO J. 20, 2768-2778.   DOI
3 Veliz, I., Loo, Y., Castillo, O., Karachaliou, N., Nigro, O. and Rosell, R. (2015) Advances and challenges in the molecular biology and treatment of glioblastoma-is there any hope for the future? Ann. Transl. Med. 3, 7.
4 Wang, Z., Gao, L., Guo, X., Feng, C., Lian, W., Deng, K. and Xing, B. (2019) Development and validation of a nomogram with an autophagy-related gene signature for predicting survival in patients with glioblastoma. Aging 11, 12246-12269.   DOI
5 Stupp, R., Hegi, M. E., Mason, W. P., van den Bent, M. J., Taphoorn, M. J., Janzer, R. C., Ludwin, S. K., Allgeier, A., Fisher, B., Belanger, K., Hau, P., Brandes, A. A., Gijtenbeek, J., Marosi, C., Vecht, C. J., Mokhtari, K., Wesseling, P., Villa, S., Eisenhauer, E., Gorlia, T., Weller, M., Lacombe, D., Cairncross, J. G. and Mirimanoff, R. O.; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10, 459-466.
6 Sung, S. J., Kim, H. K., Hong, Y. K. and Joe, Y. A. (2019) Autophagy is a potential target for enhancing the anti-angiogenic effect of mebendazole in endothelial cells. Biomol. Ther. (Seoul) 27, 117-125.   DOI
7 Zhang, L., Guo, M., Li, J., Zheng, Y., Zhang, S., Xie, T. and Liu, B. (2015) Systems biology-based discovery of a potential Atg4B agonist (Flubendazole) that induces autophagy in breast cancer. Mol. Biosyst. 11, 2860-2866.   DOI
8 Wu, W., Klockow, J. L., Zhang, M., Lafortune, F., Chang, E., Jin, L., Wu, Y. and Daldrup-Link, H. E. (2021) Glioblastoma multiforme (GBM): an overview of current therapies and mechanisms of resistance. Pharmacol. Res. 171, 105780.   DOI
9 Yun, C. W. and Lee, S. H. (2018) The roles of autophagy in cancer. Int. J. Mol. Sci. 19, 3466.   DOI
10 Zhang, H., Lu, X., Wang, N., Wang, J., Cao, Y., Wang, T., Zhou, X., Jiao, Y., Yang, L., Wang, X., Cong, L., Li, J., Li, J., Ma, H. P., Pan, Y., Ning, S. and Wang, L. (2017) Autophagy-related gene expression is an independent prognostic indicator of glioma. Oncotarget 8, 60987-61000.   DOI
11 Briceno, E., Calderon, A. and Sotelo, J. (2007) Institutional experience with chloroquine as an adjuvant to the therapy for glioblastoma multiforme. Surg. Neurol. 67, 388-391.   DOI
12 Wang, Y., Zhao, W., Xiao, Z., Guan, G., Liu, X. and Zhuang, M. (2020) A risk signature with four autophagy-related genes for predicting survival of glioblastoma multiforme. J. Cell. Mol. Med. 24, 3807-3821.   DOI
13 Xiao, M., Benoit, A., Hasmim, M., Duhem, C., Vogin, G., Berchem, G., Noman, M. Z. and Janji, B. (2021) Targeting cytoprotective autophagy to enhance anticancer therapies. Front. Oncol. 11, 626309.   DOI
14 Zhang, J., Stevens, M. F. and Bradshaw, T. D. (2012) Temozolomide: mechanisms of action, repair and resistance. Curr. Mol. Pharmacol. 5, 102-114.   DOI
15 Bai, R. Y., Staedtke, V., Wanjiku, T., Rudek, M. A., Joshi, A., Gallia, G. L. and Riggins, G. J. (2015b) Brain penetration and efficacy of different mebendazole polymorphs in a mouse brain tumor model. Clin. Cancer Res. 21, 3462-3470.   DOI
16 Bai, R. Y., Staedtke, V., Aprhys, C. M., Gallia, G. L. and Riggins, G. J. (2011) Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme. Neuro Oncol. 13, 974-982.   DOI
17 Bai, R. Y., Staedtke, V., Rudin, C. M., Bunz, F. and Riggins, G. J. (2015a) Effective treatment of diverse medulloblastoma models with mebendazole and its impact on tumor angiogenesis. Neuro Oncol. 17, 545-554.   DOI
18 Boyle, F. M., Eller, S. L. and Grossman, S. A. (2004) Penetration of intra-arterially administered vincristine in experimental brain tumor. Neuro Oncol. 6, 300-305.   DOI
19 Choi, A. M. K., Ryter, S. W. and Levine, B. (2013a) Autophagy in human health and disease. N. Engl. J. Med. 368, 651-662.   DOI
20 Chang, H. and Zou, Z. (2020) Targeting autophagy to overcome drug resistance: further developments. J. Hematol. Oncol. 13, 159.   DOI
21 Choi, M., Lee, H. S., Naidansaren, P., Kim, H. K., O, E., Cha, J. H., Ahn, H. Y., Yang, P. I., Shin, J. C. and Joe, Y. A. (2013b) Proangiogenic features of Wharton's jelly-derived mesenchymal stromal/ stem cells and their ability to form functional vessels. Int. J. Biochem. Cell Biol. 45, 560-570.   DOI
22 De Witt, M., Gamble, A., Hanson, D., Markowitz, D., Powell, C., Al Dimassi, S., Atlas, M., Boockvar, J., Ruggieri, R. and Symons, M. (2017) Repurposing mebendazole as a replacement for vincristine for the treatment of brain tumors. Mol. Med. 23, 50-56.
23 Doudican, N., Rodriguez, A., Osman, I. and Orlow, S. J. (2008) Mebendazole induces apoptosis via Bcl-2 inactivation in chemoresistant melanoma cells. Mol. Cancer Res. 6, 1308-1315.   DOI
24 Mukhopadhyay, T., Sasaki, J., Ramesh, R. and Roth, J. A. (2002) Mebendazole elicits a potent antitumor effect on human cancer cell lines both in vitro and in vivo. Clin. Cancer Res. 8, 2963-2969.
25 Golden, E. B., Cho, H. Y., Jahanian, A., Hofman, F. M., Louie, S. G., Schonthal, A. H. and Chen, T. C. (2014) Chloroquine enhances temozolomide cytotoxicity in malignant gliomas by blocking autophagy. Neurosurg. Focus 37, E12.
26 Hori, Y. S., Hosoda, R., Akiyama, Y., Sebori, R., Wanibuchi, M., Mikami, T., Sugino, T., Suzuki, K., Maruyama, M., Tsukamoto, M., Mikuni, N., Horio, Y. and Kuno, A. (2015) Chloroquine potentiates temozolomide cytotoxicity by inhibiting mitochondrial autophagy in glioma cells. J. Neurooncol. 122, 11-20.   DOI
27 Kanzawa, T., Germano, I. M., Komata, T., Ito, H., Kondo, Y. and Kondo, S. (2004) Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ. 11, 448-457.   DOI
28 Kaur, R., Kaur, G., Gill, R. K., Soni, R. and Bariwal, J. (2014) Recent developments in tubulin polymerization inhibitors: an overview. Eur. J. Med. Chem. 87, 89-124.   DOI
29 Lacey, E. (1988) The role of the cytoskeletal protein, tubulin, in the mode of action and mechanism of drug resistance to benzimidazoles. Int. J. Parasitol. 18, 885-936.   DOI
30 Laclette, J. P., Guerra, G. and Zetina, C. (1980) Inhibition of tubulin polymerization by Mebendazole. Biochem. Biophys. Res. Commun. 92, 417-423.   DOI
31 Munst, G. J., Karlaganis, G. and Bircher, J. (1980) Plasma concentrations of mebendazole during treatment of echinococcosis: preliminary results. Eur. J. Clin. Pharmacol. 17, 375-378.   DOI
32 Jung, Y. Y., Baek, S. H., Ha, I. J. and Ahn, K. S. (2022) Regulation of apoptosis and autophagy by albendazole in human colon adenocarcinoma cells. Biochimie 198, 155-166.   DOI
33 Bellodi, C., Lidonnici, M. R., Hamilton, A., Helgason, G. V., Soliera, A. R., Ronchetti, M., Galavotti, S., Young, K. W., Selmi, T., Yacobi, R., Van Etten, R. A., Donato, N., Hunter, A., Dinsdale, D., Tirro, E., Vigneri, P., Nicotera, P., Dyer, M. J., Holyoake, T., Salomoni, P. and Calabretta, B. (2009) Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosomepositive cells, including primary CML stem cells. J. Clin. Invest. 119, 1109-1123.   DOI
34 Compter, I., Eekers, D. B. P., Hoeben, A., Rouschop, K. M. A., Reymen, B., Ackermans, L., Beckervordersantforth, J., Bauer, N. J. C., Anten, M. M., Wesseling, P., Postma, A. A., De Ruysscher, D. and Lambin, P. (2021) Chloroquine combined with concurrent radiotherapy and temozolomide for newly diagnosed glioblastoma: a phase IB trial. Autophagy 17, 2604-2612.   DOI
35 Friedman, P. A. and Platzer, E. G. (1980) Interaction of anthelmintic benzimidazoles with Ascaris suum embryonic tubulin. Biochim. Biophys. Acta, Gen. Subj. 630, 271-278.   DOI
36 Singh, N., Miner, A., Hennis, L. and Mittal, S. (2021) Mechanisms of temozolomide resistance in glioblastoma - a comprehensive review. Cancer Drug Resist. 4, 17-43.
37 Pantziarka, P., Bouche, G., Meheus, L., Sukhatme, V. and Sukhatme, V. P. (2014) Repurposing Drugs in Oncology (ReDO)-mebendazole as an anti-cancer agent. Ecancermedicalscience 8, 443.
38 Pinto, L. C., Soares, B. M., Pinheiro Jde, J., Riggins, G. J., Assumpcao, P. P., Burbano, R. M. and Montenegro, R. C. (2015) The anthelmintic drug mebendazole inhibits growth, migration and invasion in gastric cancer cell model. Toxicol. In Vitro 29, 2038-2044.   DOI
39 Shin, D. W. (2020) Dual roles of autophagy and their potential drugs for improving cancer therapeutics. Biomol. Ther. (Seoul) 28, 503-511.   DOI
40 Kim, H. K., Oh, D. S., Lee, S. B., Ha, J. M. and Joe, Y. A. (2008) Antimigratory effect of TK1-2 is mediated in part by interfering with integrin alpha2beta1. Mol. Cancer Ther. 7, 2133-2141.   DOI
41 Lee, S. W., Kim, H. K., Lee, N. H., Yi, H. Y., Kim, H. S., Hong, S. H., Hong, Y. K. and Joe, Y. A. (2015) The synergistic effect of combination temozolomide and chloroquine treatment is dependent on autophagy formation and p53 status in glioma cells. Cancer Lett. 360, 195-204.   DOI
42 Poole, B. and Ohkuma, S. (1981) Effect of weak bases on the intralysosomal pH in mouse peritoneal macrophages. J. Cell Biol. 90, 665-669.   DOI
43 Stupp, R., Mason, W. P., van den Bent, M. J., Weller, M., Fisher, B., Taphoorn, M. J., Belanger, K., Brandes, A. A., Marosi, C., Bogdahn, U., Curschmann, J., Janzer, R. C., Ludwin, S. K., Gorlia, T., Allgeier, A., Lacombe, D., Cairncross, J. G., Eisenhauer, E. and Mirimanoff, R. O.; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987-996.   DOI
44 Paglin, S., Hollister, T., Delohery, T., Hackett, N., McMahill, M., Sphicas, E., Domingo, D. and Yahalom, J. (2001) A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer Res. 61, 439-444.