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Antitubulin Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The Polo-Like Kinases (PLKs) are a family of conserved serine/threonine kinases that are important regulators of the cell cycle through G2 and some phases of mitosis, including mitotic entry and exit, and cytokinesis. The “Polo” domain is named after the original protein encoded by the Polo gene of Drosophila melanogaster. These proteins are involved in the formation of, and modifications to, the mitotic spindle, and in the activation of CDK/Cyclin complexes during the M phase of the cell cycle. The PLKs are characterized by an amino terminal catalytic domain, and a carboxy terminal noncatalytic domain consisting of three blocks of conserved sequences known as Polo boxes which form one single functional domain. Mammalian PLKs include PLK1 (also known as STPK13), PLK2 (also known as SNK), PLK3 (also known as CNK, FNK, and PRK), PLK4 (also known as SAK or STK18), and PLK5. In particular, PLK1 acts in concert with Cyclin-dependent kinase 1 (Cyclin B1) and the Aurora kinases to orchestrate a wide range of critical cell-cycle events.
Tumors of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Alternating electric field therapy has also been explored for treatment of high-grade gliomas. Optune is one such device, which generates alternating current using four pads applied to a patient's scalp, powered by a battery. The current is thought to interfere with mitotic spindle assembly and disrupt tumor cell division. Patients must maintain their heads shaved and have the device active at least 18 hours per day for efficacy. It is an FDA-approved treatment for glioblastoma, associated with a modest survival benefit in the newly diagnosed setting.
The Fight Against Cancer
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Another strategy to battle cancer is to target the structural elements of the cell division process. Disruption of mitosis will obviously impede cell proliferation. Tubulin is a structural protein that is crucial for cell division, involved in polymerisation and depolymerisation of microtubules, where it is used as protein building blocks. As the cells divide, mitotic spindle fibres link the two daughter cells. The spindle fibres are made from microtubule polymers formed from tubulin proteins. Drugs designed to bind to tubulin prevent its polymerisation to from the microtubules, and thus cell division is arrested.
Tumour treating fields in glioblastoma: is the treatment tolerable, effective, and practical in UK patients?
Published in British Journal of Neurosurgery, 2022
Farouk Olubajo, Antonia Thorpe, Charles Davis, Rohitashwa Sinha, Anna Crofton, Samantha J. Mills, Matthew Williams, Michael D. Jenkinson, Stephen J. Price, Colin Watts, Andrew R. Brodbelt
More recently, Tumour Treating Fields (TTF) has proven effective in the treatment of GBM.9–15 TTF refers to the near-constant exposure of low-intensity, alternating (100–300 kHz) electric fields to the brain and tumour. TTF is delivered via portable devices that generate electrical fields, delivered via four transducer arrays (each consisting of nine insulated electrodes) applied to the shaved scalp. Extrapolation from cell studies suggests that TTF has its therapeutic effect by affecting the alignment of dipole proteins involved in cellular partition. This disrupts the formation of mitotic spindles and contractile rings involved in mitoses of cancerous cells.11,12 There is evidence of synergism with chemotherapy16 (with tumour cells becoming more porous after TTF treatment) and radiotherapy,17 which means the treatment can be added to standard of care treatment with an additional benefit. In a randomized controlled trial, Stupp et al. showed that TTF increases survival by 4.9 months compared to Stupp protocol alone.14,15 This improvement in survival is yet to be matched by any other new or novel treatments.
Targeted drug therapy in non-small cell lung cancer: Clinical significance and possible solutions-Part I
Published in Expert Opinion on Drug Delivery, 2021
Archana Upadhya, Khushwant S. Yadav, Ambikanandan Misra
The taxanes (paclitaxel and docetaxel) inhibit depolymerization of microtubules thus changing microtubule dynamics and eventually causing cell death by blocking cellular mitosis [115]. The factors for resistance to taxane-based therapy are increased expression of class III tubulin [116] and its mutations, up-regulation of histone deacetylase 6 (HDAC 6) and impairment of the mitotic spindle checkpoint [111]. The function of the mitotic spindle checkpoint is to block the segregation of abnormal chromosomes. In lung cancer cells, the mitotic spindle checkpoint is dysregulated [79,111]. The taxanes bind specifically to class I β tubulin isoform which differs in critical binding residues from the class III β isoform [117]. Class III β – tubulin is one of the β isoforms that heterodimerize with α subunits to form microtubules essential for cell division [117] and its high expression correlates with poor survival in NSCLC [118]. Histone acetylation and deacetylation regulate transcription of DNA segments. Histone acetylases (HATs) promote transcription while histone deacetylases (HDACs) inhibit transcription by making DNA inaccessible. Histone deacetylase six interacts with histone and non-histone substrates. Non – histone interactors are α-tubulin, contractin and heat shock protein 90 (Hsp90) which when modified by HDAC6 can promote cell proliferation, metastasis, invasion, and mitosis [119].
Discovery of facile amides-functionalized rhodanine-3-acetic acid derivatives as potential anticancer agents by disrupting microtubule dynamics
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Xiang Zhou, Jiamin Liu, Jiao Meng, Yihong Fu, Zhibin Wu, Guiping Ouyang, Zhenchao Wang
Microtubules form the structural basis of the mitotic spindle, which is a pivotal structure in the process of cell division of eukaryotic cells33–36. Therefore, we next examined the effects of compound I20 on the A549 cell cycle. For these experiments, A549 cells were treated with compound I20 at 0, 4 µM, and 8 µM for 24 h and then incubated with propidium iodide, a red fluorescent dye that binds stoichiometrically to DNA, thereby enabling quantification of DNA at different stages of the cell cycle using flow cytometry. Consistent with the activity of a microtubule-stabilising agent, compound I20 incubation caused an arrest of A549 cells at G2/M. The percentage of cells in G2/M was increased from a baseline of 5.94% of cells after incubation with DMSO to 10.92% and 15.45% for cells incubated with compound I20 at 4 and 8 µM, respectively (Figure 5). Taken together, these results validate the antimitotic activity of compound I20 and are consistent with cell cycle arrest induced by disordered microtubule assembly.