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.

• Keywords
• benzimidazole carbamates, cell death, glioblastoma multiforme, microtubule-targeting agents, mitotic catastrophe,
• MeSH
• Glioblastoma * metabolism   mortality   therapy   MeSH
• G2 Phase Cell Cycle Checkpoints * MeSH
• M Phase Cell Cycle Checkpoints * MeSH
• Humans MeSH
• Mitosis * MeSH
• Brain Neoplasms * metabolism   mortality   pathology   therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Tumor suppressor p53 is mutated in about 50% of cancers. Most malignant melanomas carry wild-type p53, but p53 activity is often inhibited due to overexpression of its negative regulators Mdm2 or MdmX. We performed high throughput screening of 2448 compounds on A375 cells carrying p53 activity luciferase reporter construct to reveal compounds that promote p53 activity in melanoma. Albendazole and fenbendazole, two approved and commonly used benzimidazole anthelmintics, stimulated p53 activity and were selected for further studies. The protein levels of p53 and p21 increased upon the treatment with albendazole and fenbendazole, indicating activation of the p53-p21 pathway, while the levels of Mdm2 and MdmX decreased in melanoma and breast cancer cells overexpressing these proteins. We also observed a reduction of cell viability and changes of cellular morphology corresponding to mitotic catastrophe, i.e., G2/M cell cycle arrest of large multinucleated cells with disrupted microtubules. In summary, we established a new tool for testing the impact of small molecule compounds on the activity of p53 and used it to identify the action of benzimidazoles in melanoma cells. The drugs promoted the stability and transcriptional activity of wild-type p53 via downregulation of its negative regulators Mdm2 and MdmX in cells overexpressing these proteins. The results indicate the potential for repurposing the benzimidazole anthelmintics for the treatment of cancers overexpressing p53 negative regulators.

• Keywords
• Mdm2, MdmX, benzimidazoles, drug repurposing, melanoma, p53,
• MeSH
• Albendazole pharmacology   MeSH
• Benzimidazoles pharmacology   MeSH
• Down-Regulation MeSH
• Fenbendazole pharmacology   MeSH
• Nuclear Proteins metabolism   MeSH
• Humans MeSH
• Melanoma drug therapy   metabolism   MeSH
• MCF-7 Cells MeSH
• Cell Line, Tumor MeSH
• Tumor Suppressor Protein p53 metabolism   MeSH
• Drug Repositioning MeSH
• Cell Proliferation drug effects   MeSH
• Cell Cycle Proteins MeSH
• Proto-Oncogene Proteins c-mdm2 metabolism   MeSH
• Proto-Oncogene Proteins metabolism   MeSH
• Gene Expression Regulation, Neoplastic drug effects   MeSH
• High-Throughput Screening Assays MeSH
• Drug Screening Assays, Antitumor MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Albendazole MeSH
• Benzimidazoles MeSH
• Fenbendazole MeSH
• Nuclear Proteins MeSH
• MDM2 protein, human MeSH Browser
• MDM4 protein, human MeSH Browser
• Tumor Suppressor Protein p53 MeSH
• Cell Cycle Proteins MeSH
• Proto-Oncogene Proteins c-mdm2 MeSH
• Proto-Oncogene Proteins MeSH
• TP53 protein, human MeSH Browser

Flubendazole (FLU), an anthelmintic drug of benzimidazole type, is now considered a promising anti-cancer agent due to its tubulin binding ability and low system toxicity. The present study was aimed at determining more information about FLU reduction in human liver, because this information has been insufficient until now. Subcellular fractions from the liver of 12 human patients (6 male and 6 female patients) were used to study the stereospecificity, cellular localization, coenzyme preference, enzyme kinetics, and possible inter-individual or sex differences in FLU reduction. In addition, the risk of FLU interaction with other drugs was evaluated. Our study showed that FLU is predominantly reduced in cytosol, and the reduced nicotinamide adenine dinucleotide phosphate (NADPH) coenzyme is preferred. The strict stereospecificity of FLU carbonyl reduction was proven, and carbonyl reductase 1 was identified as the main enzyme of FLU reduction in the human liver. A higher reduction of FLU and a higher level of carbonyl reductase 1 protein were found in male patients than in female patients, but overall inter-individual variability was relatively low. Hepatic intrinsic clearance of FLU is very low, and FLU had no effect on doxorubicin carbonyl reduction in the liver and in cancer cells. All these results fill the gaps in the knowledge of FLU metabolism in human.

• Keywords
• carbonyl reduction, enzyme kinetics, flubendazole, human, sex difference, stereospecificity,
• Publication type
• Journal Article MeSH