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Mosaic Variegated Aneuploidy Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The BUB1B (budding uninhibited by benzimidazoles 1 homolog beta) gene on chromosome 15q15.1 spans 60 kb with 23 exons and encodes a 1050 aa, 120 kDa kinase (BubR1), which is homologous to yeast Mad3, with mitotic spindle checkpoint function.
The Anticancer Potential of the Bacterial Protein Azurin and Its Derived Peptide p28
Published in Ananda M. Chakrabarty, Arsénio M. Fialho, Microbial Infections and Cancer Therapy, 2019
Ana Rita Garizo, Nuno Bernardes, Ananda M. Chakrabarty, Arsénio M. Fialho
Nowadays, chemotherapy includes DNA-damaging and antimitotic agents. DNA-damaging agents intercalate with DNA, inducing double strand breaks that induce ataxia-telangiectasia mutated (ATM)-dependent nuclear accumulation of p53 [57]. In addition, the apoptotic pathway via Bcl-2/Bax and the caspase cascade, as well as the necrotic pathway through toll-like receptors are targets for DNA-damaging agents [58]. On the other hand, antimitotic agents bind to the β-tubulin subunits of microtubules. This interaction leads to prolonged activation of the mitotic spindle checkpoint and mitotic arrest, followed by mitotic slippage and induction of apoptosis. These agents, also called taxanes, still induce post-transcriptional acetylation and phosphorylation of p53, which leads to its intracellular increase, upregulation of p21 protein, and inhibition of the cell cycle and also leads to apoptosis [59].
Cell death after irradiation: How, when and why cells die
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Several checkpoints in G2 and throughout mitosis exist to prevent mitotic catastrophe. These include two genetically distinct G2 checkpoints that are activated by the DDR following radiation-induced DNA damage (discussed in Chapter 2). Cells that show defects in checkpoint activation enter into mitosis prematurely and die through mitotic catastrophe. The failure to prevent entry into mitosis is thought to account for much of the enhanced radiosensitivity observed in ATM-deficient cells. Bypass of these checkpoints permits premature entry into mitosis even if the DNA has not been fully replicated or repaired, leading to an enhancement of mitotic catastrophe. Additional mitotic checkpoints ensure proper spindle assembly and attachment prior to cytokinesis. The spindle checkpoint is regulated by a number of different kinases, including the aurora kinases, polo kinases as well as the BUB1 and BUBR1 spindle checkpoint kinases. Deregulation of these kinases has been shown to lead to enhanced mitotic catastrophe. Many of the genes involved in the DDR and mitotic checkpoints are altered during cancer and consequently, the propensity to undergo mitotic catastrophe can also vary significantly among different tumours.
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].
Further insights into testicular germ cell tumor oncogenesis: potential therapeutic targets
Published in Expert Review of Anticancer Therapy, 2020
Paolo Chieffi, Marco De Martino, Francesco Esposito
This kinase phosphorylates the H3 histone at serine 10, regulating chromosome condensation, alignment, and segregation. Also, spindle checkpoint function and cytokinesis are controlled by Aurora B kinase [54]. Furthermore, centrosome amplification has been connected to aneuploidy of TGCTs as reported by several research works [54]. Notably, in GC1 and TCam-2 testis-derived cell lines, the cell growth rate is strongly reduced following the inhibition of Aurora B kinase activity [55]. Definitely, AZD1152, ZM447439, Hesperadin 8, and VX-680 are Aurora B inhibitors that have been tested [55,56]. In particular, AZD1152 was tested in an extensive panel of human cancer xenograft considerably preventing the growth of tumors. Importantly, AZD1152 and other Aurora B inhibitors (ZM2, ZM3, GSK1070916) which block the phosphorylation of H3 histone on serine 10 [56], then abolishing cell division, show a reversible neutropenia as a main side effect, and they are in early clinical evaluation [55].
Aurora kinase inhibitors: a patent review (2014-2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Cancer is the second leading cause of death globally. There were 18.1 million new cases and 9.6 million cancer-related deaths worldwide in 2018. Moreover, this prevalence is expected to increase in the upcoming years [1,2]. Typically, tumor cells are characterized by an uncontrolled cell proliferation and interfering with mitosis is one of the cornerstones of cancer therapy [3]. The Aurora kinases are the family of serine/threonine kinases that function to establish mitotic spindles by controlling centrosome duplication and separation, as well as microtubule-kinetochore attachment, spindle checkpoint, and cytokinesis.