Biology of Glioblastoma Multiforme—Exploration of Mitotic Catastrophe as a Potential Treatment Modality

Abstract

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.

M2 Muscarinic Receptor Activation Impairs Mitotic Progression and Bipolar Mitotic Spindle Formation in Human Glioblastoma Cell Lines

“…In 2012, mitotic catastrophe was defined by the International Nomenclature Committee on Cell Death as an oncosuppressive mechanism that prevents the genomic instability of cells through the induction of mitosis-related cell death or permanent cell cycle arrest [ 23 ]. At least three mechanisms of mitotic catastrophe have been described: (I) Activation of the death machinery while the cell is still in mitosis; (II) “mitotic checkpoint adaptation,” i.e., arrested cells enter the interphase without chromosome segregation, and cell death is triggered at the following interphase; (III) development of the senescent phenotype after aberrant mitosis [ 24 , 25 ]. Depending on the status of cell cycle checkpoints, several cytotoxic agents could induce aberrant mitosis/mitotic catastrophe, activating different pathways.…”

Thiabendazole Inhibits Glioblastoma Cell Proliferation and Invasion Targeting Mini-chromosome Maintenance Protein 2

“…The mechanism of action of many microtubule inhibitors involves inhibition of the G2/M phase (Castro-Gamero et al, 2018). These drugs may be synergistic with the current standard of GBM therapy (temozolomide or radiotherapy) either by facilitating DNA damage or sensitizing malignant cells to standard therapy (Vitovcova et al, 2020). In future studies, we plan to explore the effect of the combination treatment of TBZ, TMZ and radiotherapy on GBM.…”

MCDB: A comprehensive curated mitotic catastrophe database for retrieval, protein sequence alignment, and target prediction

“…MC is a form of programmed cell death caused by the deregulation of mitotic process as an intrinsic onco-suppressive mechanism 2 , 3 . Studies have identified that DNA lesions, mitotic defects, failure of cytokinesis could cause MC, and even tumor cells are more susceptible to this mitotic abnormality than normal cells 4 , 5 . At present, in addition to photo and proton radiotherapy, there are a variety of chemotherapeutic drugs that could exert anti-tumor effects by inducing MC, covering microtubule regulators, CHK1 inhibitors, PARPs inhibitors, WEE1 inhibitors, PLKs inhibitors, and so on 6 , 7 , 8 , 9 , 10 .…”

“…At present, in addition to photo and proton radiotherapy, there are a variety of chemotherapeutic drugs that could exert anti-tumor effects by inducing MC, covering microtubule regulators, CHK1 inhibitors, PARPs inhibitors, WEE1 inhibitors, PLKs inhibitors, and so on 6 , 7 , 8 , 9 , 10 . Currently, with the in-depth exploration of relevant studies on MC, the significance of MC in tumor prevention, treatment, drug resistance and radiosensitivity gradually developed 11 , 12 , 13 , 14 , which has attracted widespread attention from chemists to biologists in the fields of medicinal chemistry, molecular biology, and bioinformatics 5 , 15 , 16 , 17 , 18 , 19 .…”