Glioblastoma multiforme (GBM) represents approximately 60% of all brain tumors in adults. This malignancy shows a high biological and genetic heterogeneity associated with exceptional aggressiveness, leading to a poor survival of patients. This review provides a summary of the basic biology of GBM cells with emphasis on cell cycle and cytoskeletal apparatus of these cells, in particular microtubules. Their involvement in the important oncosuppressive process called mitotic catastrophe will next be discussed along with select examples of microtubule-targeting agents, which are currently explored in this respect such as benzimidazole carbamate compounds. Select microtubule-targeting agents, in particular benzimidazole carbamates, induce G2/M cell cycle arrest and mitotic catastrophe in tumor cells including GBM, resulting in phenotypically variable cell fates such as mitotic death or mitotic slippage with subsequent cell demise or permanent arrest leading to senescence. Their effect is coupled with low toxicity in normal cells and not developed chemoresistance. Given the lack of efficient cytostatics or modern molecular target-specific compounds in the treatment of GBM, drugs inducing mitotic catastrophe might offer a new, efficient alternative to the existing clinical management of this at present incurable malignancy.

Department of Medical Biology and Genetics Charles University Faculty of Medicine in Hradec Kralove Zborovska 2089 500 03 Hradec Kralove Czech Republic

See more in PubMed

Louis D.N., Perry A., Reifenberger G., Von Deimling A., Figarella-Branger D., Cavenee W.K., Ohgaki H., Wiestler O.D., Kleihues P., Ellison D.W. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A summary. Acta Neuropathol. 2016;131:803–820. doi: 10.1007/s00401-016-1545-1. PubMed DOI

Rock K., McArdle O., Forde P., Dunne M., Fitzpatrick D., O’Neill B., Faul C. A clinical review of treatment outcomes in glioblastoma multiforme—The validation in a non-trial population of the results of a randomised Phase III clinical trial: Has a more radical approach improved survival? Br. J. Radiol. 2012;85:e729–e733. doi: 10.1259/bjr/83796755. PubMed DOI PMC

Verhaak R.G.W., Hoadley K.A., Purdom E., Wang V., Qi Y., Wilkerson M.D., Miller C.R., Ding L., Golub T., Mesirov J.P., et al. Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:98–110. doi: 10.1016/j.ccr.2009.12.020. PubMed DOI PMC

Cloughesy T.F., Cavenee W.K., Mischel P.S. Glioblastoma: From Molecular Pathology to Targeted Treatment. Annu. Rev. Pathol. Mech. Dis. 2014;9:1–25. doi: 10.1146/annurev-pathol-011110-130324. PubMed DOI

Aldape K., Zadeh G., Mansouri S., Reifenberger G., Von Deimling A. Glioblastoma: Pathology, molecular mechanisms and markers. Acta Neuropathol. 2015;129:829–848. doi: 10.1007/s00401-015-1432-1. PubMed DOI

Klughammer J., Kiesel B., Roetzer T., Fortelny N., Nemc A., Nenning K.-H., Furtner J., Sheffield N.C., Datlinger P., Peter N., et al. The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space. Nat. Med. 2018;24:1611–1624. doi: 10.1038/s41591-018-0156-x. PubMed DOI PMC

Tandel G.S., Biswas M., Kakde O.G., Tiwari A., Suri H.S., Turk M., Laird J.R., Asare C.K., Ankrah A.A., Khanna N.N., et al. A Review on a Deep Learning Perspective in Brain Cancer Classification. Cancers. 2019;11:111. doi: 10.3390/cancers11010111. PubMed DOI PMC

Bhargava S., Patil V., Mahalingam K., Somasundaram K. Elucidation of the genetic and epigenetic landscape alterations in RNA binding proteins in glioblastoma. Oncotarget. 2017;8:16650–16668. doi: 10.18632/oncotarget.14287. PubMed DOI PMC

Brennan C., Verhaak R.G., McKenna A., Campos B., Noushmehr H., Salama S.R., Zheng S., Chakravarty D., Sanborn J.Z., Berman S.H., et al. The Somatic Genomic Landscape of Glioblastoma. Cell. 2013;155:462–477. doi: 10.1016/j.cell.2013.09.034. PubMed DOI PMC

Pesenti C., Navone S.E., Guarnaccia L., Terrasi A., Costanza J., Silipigni R., Guarneri S., Fusco N., Fontana L., Locatelli M., et al. The Genetic Landscape of Human Glioblastoma and Matched Primary Cancer Stem Cells Reveals Intratumour Similarity and Intertumour Heterogeneity. Stem Cells Int. 2019;2019:2617030. doi: 10.1155/2019/2617030. PubMed DOI PMC

Hohmann T., Dehghani F. The Cytoskeleton-A Complex Interacting Meshwork. Cells. 2019;8:362. doi: 10.3390/cells8040362. PubMed DOI PMC

Hirabayashi Y., Gotoh Y. Stage-dependent fate determination of neural precursor cells in mouse forebrain. Neurosci. Res. 2005;51:331–336. doi: 10.1016/j.neures.2005.01.004. PubMed DOI

Murk K., Blanco-Suarez E.M., Cockbill L.M.R., Banks P., Hanley J.G. The antagonistic modulation of Arp2/3 activity by N-WASP, WAVE2 and PICK1 defines dynamic changes in astrocyte morphology. J. Cell Sci. 2013;126:3873–3883. doi: 10.1242/jcs.125146. PubMed DOI PMC

Racchetti G., D’Alessandro R., Meldolesi J. Astrocyte stellation, a process dependent on Rac1 is sustained by the regulated exocytosis of enlargeosomes. Glia. 2012;60:465–475. doi: 10.1002/glia.22280. PubMed DOI PMC

Sultana S., Sernett S.W., Bellin R.M., Robson R.M., Skalli O. Intermediate filament protein synemin is transiently expressed in a subset of astrocytes during development. Glia. 2000;30:143–153. doi: 10.1002/(SICI)1098-1136(200004)30:2<143::AID-GLIA4>3.0.CO;2-Z. PubMed DOI

Beppu T., Kamada K., Yoshida Y., Arai H., Ogasawara K., Ogawa A. Change of oxygen pressure in glioblastoma tissue under various conditions. J. Neuro Oncol. 2002;58:47–52. doi: 10.1023/A:1015832726054. PubMed DOI

Calabrese C., Poppleton H., Kocak M., Hogg T.L., Fuller C., Hamner B., Oh E.Y., Gaber M.W., Finklestein D., Allen M., et al. A Perivascular Niche for Brain Tumor Stem Cells. Cancer Cell. 2007;11:69–82. doi: 10.1016/j.ccr.2006.11.020. PubMed DOI

Caspani E.M., Echevarria D., Rottner K., Small J.V. Live imaging of glioblastoma cells in brain tissue shows requirement of actin bundles for migration. Neuron Glia Biol. 2006;2:105–114. doi: 10.1017/S1740925X06000111. PubMed DOI

Friedl P., Wolf K. Tumour-cell invasion and migration: Diversity and escape mechanisms. Nat. Rev. Cancer. 2003;3:362–374. doi: 10.1038/nrc1075. PubMed DOI

Liu C.J., Shamsan G.A., Akkin T., Odde D.J. Glioma Cell Migration Dynamics in Brain Tissue Assessed by Multimodal Optical Imaging. Biophys. J. 2019;117:1179–1188. doi: 10.1016/j.bpj.2019.08.010. PubMed DOI PMC

Ensign S.P.F., Mathews I.T., Symons M.H., Berens M.E., Tran N.L. Implications of Rho GTPase Signaling in Glioma Cell Invasion and Tumor Progression. Front. Oncol. 2013;3:241. doi: 10.3389/fonc.2013.00241. PubMed DOI PMC

Hirata E., Yukinaga H., Kamioka Y., Arakawa Y., Miyamoto S., Okada T., Sahai E., Matsuda M. In vivo fluorescence resonance energy transfer imaging reveals differential activation of Rho-family GTPases in glioblastoma cell invasion. J. Cell Sci. 2012;125:858–868. doi: 10.1242/jcs.089995. PubMed DOI

Yamaguchi H., Condeelis J. Regulation of the actin cytoskeleton in cancer cell migration and invasion. Biochim. Biophys. Acta Mol. Cell Res. 2007;1773:642–652. doi: 10.1016/j.bbamcr.2006.07.001. PubMed DOI PMC

Hoelzinger D.B., Mariani L., Weis J., Woyke T., Berens T.J., McDonough W.S., Sloan A., Coons S.W., Berens M.E. Gene Expression Profile of Glioblastoma Multiforme Invasive Phenotype Points to New Therapeutic Targets. Neoplasia. 2005;7:7–16. doi: 10.1593/neo.04535. PubMed DOI PMC

Tynninen O., Carpén O., Jääskeläinen J., Paavonen T., Paetau A. Ezrin expression in tissue microarray of primary and recurrent gliomas. Neuropathol. Appl. Neurobiol. 2004;30:472–477. doi: 10.1111/j.1365-2990.2004.00562.x. PubMed DOI

Geiger K.D., Stoldt P., Schlote W., Derouiche A. Ezrin Immunoreactivity Is Associated with Increasing Malignancy of Astrocytic Tumors but Is Absent in Oligodendrogliomas. Am. J. Pathol. 2000;157:1785–1793. doi: 10.1016/S0002-9440(10)64816-X. PubMed DOI PMC

Peraud A., Mondal S., Hawkins C., Mastronardi M., Bailey K., Rutka J.T. Expression of fascin, an actin-bundling protein, in astrocytomas of varying grades. Brain Tumor Pathol. 2003;20:53–58. doi: 10.1007/BF02483447. PubMed DOI

Gunnersen J.M., Spirkoska V., Smith P.E., Danks R.A., Tan S.S. Growth and migration markers of rat C6 glioma cells identified by serial analysis of gene expresson. Glia. 2000;32:146–154. doi: 10.1002/1098-1136(200011)32:2<146::AID-GLIA40>3.0.CO;2-3. PubMed DOI

Rickman D.S., Bobek M.P., Misek D.E., Kuick R., Blaivas M., Kurnit D.M., Taylor J., Hanash S.M. Distinctive molecular profiles of high-grade and low-grade gliomas based on oligonucleotide microarray analysis. Cancer Res. 2001;61:6885–6891. PubMed

Weeks A., Okolowsky N., Golbourn B., Ivanchuk S., Smith C., Rutka J.T. ECT2 and RASAL2 Mediate Mesenchymal-Amoeboid Transition in Human Astrocytoma Cells. Am. J. Pathol. 2012;181:662–674. doi: 10.1016/j.ajpath.2012.04.011. PubMed DOI

Oppel F., Müller N., Schackert G., Hendruschk S., Martin D., Geiger K.D., Temme A. SOX2-RNAi attenuates S-phase entry and induces RhoA-dependent switch to protease-independent amoeboid migration in human glioma cells. Mol. Cancer. 2011;10:137. doi: 10.1186/1476-4598-10-137. PubMed DOI PMC

Frankel P., Pellet-Many C., Lehtolainen P., D’Abaco G.M., Tickner M.L., Cheng L., Zachary I.C. Chondroitin sulphate-modified neuropilin 1 is expressed in human tumour cells and modulates 3D invasion in the U87MG human glioblastoma cell line through a p130Cas-mediated pathway. EMBO Rep. 2008;9:983–989. doi: 10.1038/embor.2008.151. PubMed DOI PMC

Koh I., Cha J., Park J., Choi J., Kang S.-G., Kim P. The mode and dynamics of glioblastoma cell invasion into a decellularized tissue-derived extracellular matrix-based three-dimensional tumor model. Sci. Rep. 2018;8:4608. doi: 10.1038/s41598-018-22681-3. PubMed DOI PMC

Iser I.C., Pereira M.B., Lenz G., Wink M. The Epithelial-to-Mesenchymal Transition-Like Process in Glioblastoma: An Updated Systematic Review and in Silico Investigation. Med. Res. Rev. 2016;37:271–313. doi: 10.1002/med.21408. PubMed DOI

Hagemann C., Anacker J., Ernestus R.-I., Vince G. A complete compilation of matrix metalloproteinase expression in human malignant gliomas. World J. Clin. Oncol. 2012;3:67–79. doi: 10.5306/wjco.v3.i5.67. PubMed DOI PMC

Skalli O., Wilhelmsson U., Örndahl C., Fekete B., Malmgren K., Rydenhag B., Pekny M. Astrocytoma grade IV (glioblastoma multiforme) displays 3 subtypes with unique expression profiles of intermediate filament proteins. Hum. Pathol. 2013;44:2081–2088. doi: 10.1016/j.humpath.2013.03.013. PubMed DOI

Paetau A. Glial fibrillary acidic protein, vimentin and fibronectin in primary cultures of human glioma and fetal brain. Acta Neuropathol. 1988;75:448–455. doi: 10.1007/BF00687131. PubMed DOI

Yung W.-K., Luna M., Borit A. Vimentin and glial fibrillary acidic protein in human brain tumors. J. Neuro Oncol. 1985;3:35–38. doi: 10.1007/BF00165169. PubMed DOI

Van Bodegraven E., Van Asperen J.V., Robe P.A., Hol E.M. Importance of GFAP isoform-specific analyses in astrocytoma. Glia. 2019;67:1417–1433. doi: 10.1002/glia.23594. PubMed DOI PMC

Liberski P.P. The ultrastructure of glial tumors of astrocytic lineage: A review. Folia Neuropathol. 1998;36:161–177. PubMed

Lin L., Wang G., Ming J., Meng X., Han B., Sun B., Cai J., Jiang C. Analysis of expression and prognostic significance of vimentin and the response to temozolomide in glioma patients. Tumor Biol. 2016;37:15333–15339. doi: 10.1007/s13277-016-5462-7. PubMed DOI

Zhao J., Zhang L., Dong X., Liu L., Huo L., Chen H. High Expression of Vimentin is Associated with Progression and a Poor Outcome in Glioblastoma. Appl. Immunohistochem. Mol. Morphol. 2018;26:337–344. doi: 10.1097/PAI.0000000000000420. PubMed DOI

Abbassi R.H., Recasens A., Indurthi D.C., Johns T.G., Stringer B.W., Day B.W., Munoz L. Lower Tubulin Expression in Glioblastoma Stem Cells Attenuates Efficacy of Microtubule-Targeting Agents. ACS Pharmacol. Transl. Sci. 2019;2:402–413. doi: 10.1021/acsptsci.9b00045. PubMed DOI PMC

Katsetos C.D., Dráber P. Tubulins as therapeutic targets in cancer: From bench to bedside. Curr. Pharm. Des. 2012;18:2778–2792. doi: 10.2174/138161212800626193. PubMed DOI

Katsetos C.D., Reddy G., Dráberová E., Šmejkalová B., Del Valle L., Ashraf Q., Tadevosyan A., Yelin K., Maraziotis T., Mishra O.P., et al. Altered Cellular Distribution and Subcellular Sorting of γ-Tubulin in Diffuse Astrocytic Gliomas and Human Glioblastoma Cell Lines. J. Neuropathol. Exp. Neurol. 2006;65:465–477. doi: 10.1097/01.jnen.0000229235.20995.6e. PubMed DOI

Katsetos C.D., Reginato M.J., Baas P.W., D’Agostino L., Legido A., Dráberová E., Dráber P., Tuszynski J.A. Emerging Microtubule Targets in Glioma Therapy. Semin. Pediatr. Neurol. 2015;22:49–72. doi: 10.1016/j.spen.2015.03.009. PubMed DOI

Caracciolo V., D’Agostino L., Dráberová E., Sládková V., Crozier-Fitzgerald C., Agamanolis D.P., De Chadarévian J.-P., Legido A., Giordano A., Dráber P., et al. Differential expression and cellular distribution of γ-tubulin and βIII-tubulin in medulloblastomas and human medulloblastoma cell lines. J. Cell. Physiol. 2010;223:519–529. doi: 10.1002/jcp.22077. PubMed DOI

Katsetos C.D., Dráberová E., Šmejkalová B., Reddy G., Bertrand L., De Chadarévian J.-P., Legido A., Nissanov J., Baas P.W., Dráber P. Class III β-Tubulin and γ-Tubulin are Co-expressed and Form Complexes in Human Glioblastoma Cells. Neurochem. Res. 2007;32:1387–1398. doi: 10.1007/s11064-007-9321-1. PubMed DOI

Suzuki S.O., Kitai R., Llena J., Lee S.C., Goldman J.E., Shafit-Zagardo B. MAP-2e, a novel MAP-2 isoform, is expressed in gliomas and delineates tumor architecture and patterns of infiltration. J. Neuropathol. Exp. Neurol. 2002;61:403–412. doi: 10.1093/jnen/61.5.403. PubMed DOI

Rich J.N., Hans C., Jones B., Iversen E.S., McLendon R.E., Rasheed B.A., Dobra A., Dressman H.K., Bigner D.D., Nevins J.R., et al. Gene Expression Profiling and Genetic Markers in Glioblastoma Survival. Cancer Res. 2005;65:4051–4058. doi: 10.1158/0008-5472.CAN-04-3936. PubMed DOI

Zhou R., Wu X., Skalli O. The hyaluronan receptor RHAMM/IHABP in astrocytoma cells: Expression of a tumor-specific variant and association with microtubules. J. Neuro Oncol. 2002;59:15–26. doi: 10.1023/A:1016373015569. PubMed DOI

Suzuki S.O., McKenney R.J., Mawatari S.-Y., Mizuguchi M., Mikami A., Iwaki T., Goldman J.E., Canoll P., Vallee R.B. Expression patterns of LIS1, dynein and their interaction partners dynactin, NudE, NudEL and NudC in human gliomas suggest roles in invasion and proliferation. Acta Neuropathol. 2007;113:591–599. doi: 10.1007/s00401-006-0180-7. PubMed DOI

Dráberová E., Vinopal S., Morfini G., Liu P.S., Sládková V., Sulimenko T., Burns M.A., Solowska J., Kulandaivel K., De Chadarévian J.-P., et al. Microtubule-Severing ATPase Spastin in Glioblastoma: Increased Expression in Human Glioblastoma Cell Lines and Inverse Roles in Cell Motility and Proliferation. J. Neuropathol. Exp. Neurol. 2011;70:811–826. doi: 10.1097/NEN.0b013e31822c256d. PubMed DOI PMC

Katsetos C.D. Emerging Molecularly—Targeted Therapeutic Strategies in Brain Cancer. Introduction. Semin. Pediatr. Neurol. 2015;22:2–4. doi: 10.1016/j.spen.2015.04.002. PubMed DOI

Visconti R., Della Monica R., Grieco D. Cell cycle checkpoint in cancer: A therapeutically targetable double-edged sword. J. Exp. Clin. Cancer Res. 2016;35:153. doi: 10.1186/s13046-016-0433-9. PubMed DOI PMC

Barnum K.J., O’Connell M.J. Cell Cycle Regulation by Checkpoints. Methods Mol. Biol. 2014;1170:29–40. doi: 10.1007/978-1-4939-0888-2_2. PubMed DOI PMC

Musacchio A. The Molecular Biology of Spindle Assembly Checkpoint Signaling Dynamics. Curr. Biol. 2015;25:R1002–R1018. doi: 10.1016/j.cub.2015.08.051. PubMed DOI

Wick W., Kessler T. New glioblastoma heterogeneity atlas—A shared resource. Nat. Rev. Neurol. 2018;14:453–454. doi: 10.1038/s41582-018-0038-3. PubMed DOI

Chen S., Le T., Harley B.A.C., Imoukhuede P.I. Characterizing Glioblastoma Heterogeneity via Single-Cell Receptor Quantification. Front. Bioeng. Biotechnol. 2018;6:92. doi: 10.3389/fbioe.2018.00092. PubMed DOI PMC

Ranjit M., Motomura K., Ohka F., Wakabayashi T., Natsume A. Applicable advances in the molecular pathology of glioblastoma. Brain Tumor Pathol. 2015;32:153–162. doi: 10.1007/s10014-015-0224-6. PubMed DOI

Puduvalli V.K., Kyritsis A.P., Hess K.R., Bondy M.L., Fuller G.N., Kouraklis G.P., Levin V.A., Bruner J.M. Patterns of expression of Rb and p16 in astrocytic gliomas, and correlation with survival. Int. J. Oncol. 2000;17:963–969. doi: 10.3892/ijo.17.5.963. PubMed DOI

Ueki K., Ono Y., Henson J.W., Efird J.T., von Deimling A., Louis D.N. CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. Cancer Res. 1996;56:150–153. PubMed

Donaires F.S., Godoy P.R., Leandro G.S., Puthier D., Hojo E.T.S. E2F transcription factors associated with up-regulated genes in glioblastoma. Cancer Biomark. 2017;18:199–208. doi: 10.3233/CBM-161628. PubMed DOI

Ohgaki H. Genetic pathways to glioblastomas. Neuropathology. 2005;25:1–7. doi: 10.1111/j.1440-1789.2004.00600.x. PubMed DOI

Ohgaki H. Genetic Pathways to Glioblastoma: A Population-Based Study. Cancer Res. 2004;64:6892–6899. doi: 10.1158/0008-5472.CAN-04-1337. PubMed DOI

Szerlip N.J., Pedraza A., Chakravarty D., Azim M., McGuire J., Fang Y., Ozawa T., Holland E.C., Huse J.T., Jhanwar S., et al. Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc. Natl. Acad. Sci. USA. 2012;109:3041–3046. doi: 10.1073/pnas.1114033109. PubMed DOI PMC

Ding Y., Hubert C.G., Herman J., Corrin P., Toledo C.M., Skutt-Kakaria K., Vazquez J., Basom R., Zhang B., Risler J.K., et al. Cancer-Specific Requirement for BUB1B/BUBR1 in Human Brain Tumor Isolates and Genetically Transformed Cells. Cancer Discov. 2012;3:198–211. doi: 10.1158/2159-8290.CD-12-0353. PubMed DOI PMC

Goidts V., Bageritz J., Puccio L., Nakata S., Zapatka M., Barbus S., Toedt G., Campos B., Korshunov A., Momma S., et al. RNAi screening in glioma stem-like cells identifies PFKFB4 as a key molecule important for cancer cell survival. Oncogene. 2011;31:3235–3243. doi: 10.1038/onc.2011.490. PubMed DOI

Weaver B.A., Cleveland D.W. Decoding the links between mitosis, cancer, and chemotherapy: The mitotic checkpoint, adaptation, and cell death. Cancer Cell. 2005;8:7–12. doi: 10.1016/j.ccr.2005.06.011. PubMed DOI

Dominguez-Brauer C., Thu K.L., Mason J.M., Blaser H., Bray M.R., Mak T.W. Targeting Mitosis in Cancer: Emerging Strategies. Mol. Cell. 2015;60:524–536. doi: 10.1016/j.molcel.2015.11.006. PubMed DOI

Angel M.C.-G., Julia A.P., María S.B., Luiz G.T., Castro-Gamero A., Pezuk J.A., Brassesco M.S., Tone L.G. G2/M inhibitors as pharmacotherapeutic opportunities for glioblastoma: The old, the new, and the future. Cancer Biol. Med. 2018;15:354–374. doi: 10.20892/j.issn.2095-3941.2018.0030. PubMed DOI PMC

Dumontet C., Jordan M.A. Microtubule-binding agents: A dynamic field of cancer therapeutics. Nat. Rev. Drug Discov. 2010;9:790–803. doi: 10.1038/nrd3253. PubMed DOI PMC

Patties I., Kallendrusch S., Böhme L., Kendzia E., Oppermann H., Gaunitz F., Kortmann R.-D., Glasow A. The Chk1 inhibitor SAR-020106 sensitizes human glioblastoma cells to irradiation, to temozolomide, and to decitabine treatment. J. Exp. Clin. Cancer Res. 2019;38:420. doi: 10.1186/s13046-019-1434-2. PubMed DOI PMC

Liu N., Hu G., Wang H., Li Z., Guo Z. PLK1 inhibitor facilitates the suppressing effect of temozolomide on human brain glioma stem cells. J. Cell. Mol. Med. 2018;22:5300–5310. doi: 10.1111/jcmm.13793. PubMed DOI PMC

Suzuki K., Ojima M., Kodama S., Watanabe M. Radiation-induced DNA damage and delayed induced genomic instability. Oncogene. 2003;22:6988–6993. doi: 10.1038/sj.onc.1206881. PubMed DOI

Eom Y.-W., Kim M.A., Park S.S., Goo M.J., Kwon H.J., Sohn S., Kim W.-H., Yoon G., Choi K.S. Two distinct modes of cell death induced by doxorubicin: Apoptosis and cell death through mitotic catastrophe accompanied by senescence-like phenotype. Oncogene. 2005;24:4765–4777. doi: 10.1038/sj.onc.1208627. PubMed DOI

Nakayama Y., Inoue T. Antiproliferative Fate of the Tetraploid Formed after Mitotic Slippage and Its Promotion; A Novel Target for Cancer Therapy Based on Microtubule Poisons. Molecules. 2016;21:663. doi: 10.3390/molecules21050663. PubMed DOI PMC

Bojko A., Czarnecka-Herok J., Charzynska A., Dabrowski M., Sikora E. Diversity of the Senescence Phenotype of Cancer Cells Treated with Chemotherapeutic Agents. Cells. 2019;8:1501. doi: 10.3390/cells8121501. PubMed DOI PMC

Sikora E., Mosieniak G., Śliwińska M.A. Morphological and Functional Characteristic of Senescent Cancer Cells. Curr. Drug Targets. 2016;17:377–387. doi: 10.2174/1389450116666151019094724. PubMed DOI

Lin S., Yang L., Yao Y., Xu L., Xiang Y., Zhao H., Wang L., Zuo Z., Huang X., Zhao C. Flubendazole demonstrates valid antitumor effects by inhibiting STAT3 and activating autophagy. J. Exp. Clin. Cancer Res. 2019;38:293. doi: 10.1186/s13046-019-1303-z. PubMed DOI PMC

Králova V., Hanusova V., Rudolf E., Čáňová K., Skálová L. Flubendazole induces mitotic catastrophe and senescence in colon cancer cellsin vitro. J. Pharm. Pharmacol. 2016;68:208–218. doi: 10.1111/jphp.12503. PubMed DOI

Zhou X., Liu J., Zhang J., Wei Y., Li H. Flubendazole inhibits glioma proliferation by G2/M cell cycle arrest and pro-apoptosis. Cell Death Discov. 2018;4:18. doi: 10.1038/s41420-017-0017-2. PubMed DOI PMC

Vitale I., Galluzzi L., Castedo M., Kroemer G. Mitotic catastrophe: A mechanism for avoiding genomic instability. Nat. Rev. Mol. Cell Biol. 2011;12:385–392. doi: 10.1038/nrm3115. PubMed DOI

Wäsch R., Engelbert D. Anaphase-promoting complex-dependent proteolysis of cell cycle regulators and genomic instability of cancer cells. Oncogene. 2005;24:1–10. doi: 10.1038/sj.onc.1208017. PubMed DOI

Haschka M., Karbon G., Fava L.L., Villunger A. Perturbing mitosis for anti-cancer therapy: Is cell death the only answer? EMBO Rep. 2018;19:e45440. doi: 10.15252/embr.201745440. PubMed DOI PMC

Prokhorova E., Egorshina A.Y., Zhivotovsky B., Kopeina G.S. The DNA-damage response and nuclear events as regulators of nonapoptotic forms of cell death. Oncogene. 2020;39:1–16. doi: 10.1038/s41388-019-0980-6. PubMed DOI

Ianzini F., Domann F.E., Kosmacek E.A., Phillips S.L., Mackey M.A. Human glioblastoma U87MG cells transduced with a dominant negative p53 (TP53) adenovirus construct undergo radiation-induced mitotic catastrophe. Radiat. Res. 2007;168:183–192. doi: 10.1667/0033-7587(2007)168[183:HGUCTW]2.0.CO;2. PubMed DOI

Chang B.-D., Swift M.E., Shen M., Fang J., Broude E.V., Roninson I.B. Molecular determinants of terminal growth arrest induced in tumor cells by a chemotherapeutic agent. Proc. Natl. Acad. Sci. USA. 2002;99:389–394. doi: 10.1073/pnas.012602599. PubMed DOI PMC

Sorokina I.V., Denisenko T.V., Imreh G., Tyurin-Kuzmin P.A., Kaminskyy V., Gogvadze V., Zhivotovsky B. Involvement of autophagy in the outcome of mitotic catastrophe. Sci. Rep. 2017;7:14571. doi: 10.1038/s41598-017-14901-z. PubMed DOI PMC

Sharma K., Le N., Alotaibi M., Gewirtz D.A. Cytotoxic Autophagy in Cancer Therapy. Int. J. Mol. Sci. 2014;15:10034–10051. doi: 10.3390/ijms150610034. PubMed DOI PMC

Altinoz M.A., Bilir A., Del Maestro R.F., Tuna S., Ozcan E., Gedikoglu G. Noscapine and diltiazem augment taxol and radiation-induced S-phase arrest and clonogenic death of C6 glioma in vitro. Surg. Neurol. 2006;65:478–484. doi: 10.1016/j.surneu.2005.06.024. PubMed DOI

Landen J.W. Noscapine Crosses the Blood-Brain Barrier and Inhibits Glioblastoma Growth. Clin. Cancer Res. 2004;10:5187–5201. doi: 10.1158/1078-0432.CCR-04-0360. PubMed DOI

Newcomb E.W., Lukyanov Y., Schnee T., Ali M.A., Lan L., Zagzag D. Noscapine inhbits hypoxia-mediated HIF-1alpha expression and angiogenesis in vitro: A novel function for an old drug. Int. J. Oncol. 2006;28:1121–1130. PubMed

Newcomb E.W., Lukyanov Y., Smirnova I., Schnee T., Zagzag D. Noscapine induces apoptosis in human glioma cells by an apoptosis-inducing factor-dependent pathway. Anti-Cancer Drugs. 2008;19:553–563. doi: 10.1097/CAD.0b013e3282ffd68d. PubMed DOI

Jhaveri N., Cho H., Torres S., Wang W., Schonthal A.H., Petasis N.A., Louie S.G., Hofman F.M., Chen T.C. Noscapine inhibits tumor growth in TMZ-resistant gliomas. Cancer Lett. 2011;312:245–252. doi: 10.1016/j.canlet.2011.08.015. PubMed DOI

Shen W., Liang B., Yin J., Li X., Cheng J. Noscapine Increases the Sensitivity of Drug-Resistant Ovarian Cancer Cell Line SKOV3/DDP to Cisplatin by Regulating Cell Cycle and Activating Apoptotic Pathways. Cell Biochem. Biophys. 2015;72:203–213. doi: 10.1007/s12013-014-0438-y. PubMed DOI

Chougule M.B., Patel A.R., Jackson T., Singh M. Antitumor Activity of Noscapine in Combination with Doxorubicin in Triple Negative Breast Cancer. PLoS ONE. 2011;6:e17733. doi: 10.1371/journal.pone.0017733. PubMed DOI PMC

Newcomb E.W., Lukyanov Y., Alonso-Basanta M., Esencay M., Smirnova I., Schnee T., Shao Y., Devitt M.L., Zagzag D., McBride W., et al. Antiangiogenic Effects of Noscapine Enhance Radioresponse for GL261 Tumors. Int. J. Radiat. Oncol. Biol. Phys. 2008;71:1477–1484. doi: 10.1016/j.ijrobp.2008.04.020. PubMed DOI PMC

Ajeawung N.F., Joshi H.C., Kamnasaran D. The microtubule binding drug EM011 inhibits the growth of paediatric low grade gliomas. Cancer Lett. 2013;335:109–118. doi: 10.1016/j.canlet.2013.02.004. PubMed DOI

Debono A., Capuano B., Scammells P.J. Progress Toward the Development of Noscapine and Derivatives as Anticancer Agents. J. Med. Chem. 2015;58:5699–5727. doi: 10.1021/jm501180v. PubMed DOI

Aneja R., Vangapandu S.N., Joshi H.C. Synthesis and biological evaluation of a cyclic ether fluorinated noscapine analog. Bioorgan. Med. Chem. 2006;14:8352–8358. doi: 10.1016/j.bmc.2006.09.012. PubMed DOI

Verma A.K., Bansal S., Singh J., Tiwari R.K., Sankar V.K., Tandon V., Chandra R. Synthesis and in vitro cytotoxicity of haloderivatives of noscapine. Bioorgan. Med. Chem. 2006;14:6733–6736. doi: 10.1016/j.bmc.2006.05.069. PubMed DOI

Kamnasaran D. Investigation of Targetin, a Microtubule Binding Agent which Regresses the Growth of Pediatric High and Low Grade Gliomas. J. Pediatr. Oncol. 2013;1:32–40. doi: 10.14205/2309-3021.2013.01.01.5. PubMed DOI PMC

Cumino A.C., Elissondo M.C., Denegri G.M. Flubendazole interferes with a wide spectrum of cell homeostatic mechanisms in Echinococcus granulosus protoscoleces. Parasitol. Int. 2009;58:270–277. doi: 10.1016/j.parint.2009.03.005. PubMed DOI

Lacey E. Mode of action of benzimidazoles. Parasitol. Today. 1990;6:112–115. doi: 10.1016/0169-4758(90)90227-U. PubMed DOI

Pourgholami M.H., Akhter J., Wang L., Lu Y., Morris D.L. Antitumor activity of albendazole against the human colorectal cancer cell line HT-29: In vitro and in a xenograft model of peritoneal carcinomatosis. Cancer Chemother. Pharmacol. 2005;55:425–432. doi: 10.1007/s00280-004-0927-6. PubMed DOI

Sasaki J., Ramesh R., Chada S., Gomyo Y., Roth J.A., Mukhopadhyay T. The anthelmintic drug mebendazole induces mitotic arrest and apoptosis by depolymerizing tubulin in non-small cell lung cancer cells. Mol. Cancer Ther. 2002;1:1201–1209. PubMed

Nygren P., Fryknäs M., Ågerup B., Larsson R. Repositioning of the anthelmintic drug mebendazole for the treatment for colon cancer. J. Cancer Res. Clin. Oncol. 2013;139:2133–2140. doi: 10.1007/s00432-013-1539-5. PubMed DOI PMC

Nygren P., Larsson R. Drug repositioning from bench to bedside: Tumour remission by the antihelmintic drug mebendazole in refractory metastatic colon cancer. Acta Oncol. 2013;53:427–428. doi: 10.3109/0284186X.2013.844359. PubMed DOI

Hou Z.-J., Luo X., Zhang W., Peng F., Cui B., Wu S.-J., Zheng F.-M., Xu J., Xu L.-Z., Long Z.-J., et al. Flubendazole, FDA-approved anthelmintic, targets breast cancer stem-like cells. Oncotarget. 2015;6:6326–6340. doi: 10.18632/oncotarget.3436. PubMed DOI PMC

Bai R.-Y., Staedtke V., Aprhys C.M., Gallia G.L., Riggins G.J. Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme. Neuro-Oncology. 2011;13:974–982. doi: 10.1093/neuonc/nor077. PubMed DOI PMC

Prognostic Factors for Survival in Glioblastoma: A Retrospective Analysis Focused on the Role of Hemoglobin

Plectin plays a role in the migration and volume regulation of astrocytes: a potential biomarker of glioblastoma