Antitubulin Agents
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
The Vinca alkaloids are classed as cell cycle specific because they block mitosis by causing cell-cycle arrest at metaphase. Their cytotoxic effects result from binding to the microtubules and interfering with microtubule assembly, thus causing damage to the mitotic spindle apparatus and preventing chromosomes from traveling out to form daughter cell nuclei. This is similar to the mechanism of action of colchicine and eribulin mesylate but distinct from that of paclitaxel and the epothilones which interfere with cell division by preventing the spindles from being broken down. There is some evidence that the Vinca alkaloids may also block DNA and RNA synthesis with a degree of selectivity toward tumor cells. However, overall, the basis for the tumor cell selectivity of these agents is not fully understood, although it is assumed that, because of their mechanism of action, rapidly dividing cancer cells are more vulnerable than the nondividing cells of most healthy tissues with exceptions such as the gut and the hair follicles.
The human oocyte: Controlled-rate cooling Controlled-rate cooling
David K. Gardner, Ariel Weissman, Colin M. Howles, Zeev Shoham in Textbook of Assisted Reproductive Techniques, 2017
Another structure that can be damaged by cryopreservation is the meiotic spindle, which is composed of microtubules and is important for chromosome segregation. At the time of fertilization, upturn of meiosis takes place, separating the chromatids attached to the meiotic spindle, expelling one set into the second polar body and the other into the female pronucleus (44). The meiotic spindle apparatus is a dynamic structure and it has been demonstrated to depolymerize when exposed to low temperatures (45). Nevertheless, after a return to normal conditions, the spindle is able to significantly reassemble (21, 46, 47). This structure must work correctly to achieve accurate chromosome segregation; subsequent impaired repolymerization at warming may lead to misaggregation of chromatids and aneuploidy (48).
Genetic Susceptibility to Colorectal Cancer
Jim Cassidy, Patrick Johnston, Eric Van Cutsem in Colorectal Cancer, 2006
APC also plays a key role in the microtubule cytoskeleton, binding to microtubules as well as promoting their formation and presenting them to the kinetochore (105–106). The organization and structure of microtubules is vital to cell division and migration, and truncated forms of the APC protein appear to be unable to bind microtubules (107). Not only does APC bind microtubules but is also involved in mediating attachment of chromosomes to the spindle apparatus in order to accurately separate the sister chromatids during mitosis. Mouse cells homozygous for a truncating mutation, Apcmin~, displayed abnormal chromosome patterns when compared with wildtype counterparts (105). This suggests that APC plays an important role in maintaining fidelity of chromosome segregation and thereby control of chromosome number. This is supported by the observation that aneuploidy occurs in the majority of colorectal cancers with APC mutations and underscores the complexity of the role that APC mutations play, suppressing tumorigenesis and progression. The carboxy terminus of the APC protein not only binds microtubules but also the microtubule binding protein EB1 (108) and the tumor suppressor protein Dlg (109), both of which are implicated in tumorigenesis.
Genotoxic and mutagenic studies of teratogens in developing rat and mouse
Published in Drug and Chemical Toxicology, 2019
Eyyüp Rencüzoğulları, Muhsin Aydın
Micronucleus is a small nucleus that forms whenever a chromosome or a fragment of a chromosome is not incorporated into one of the daughter nuclei during the cell division. It is found outside the main nucleus and formed in telophase due to the acentric chromosomal or chromatid fractures. Also, it could be formed during the telophase from one or a few chromosomes or chromatids that lag behind the anaphase (anaphase bridge) (Surrallés et al. 1995). In addition, multipolar anaphase and telophase could cause MN formation (Topaktas and Rencuzogullari 2010). Chromosome loss or nondisjunction of chromosomes that may lead to MN formation is one of the important events that is observed in cancer and aging. This is probably the result of disruption in spindle apparatus and centromere or condensation of the chromosome prior to metaphase (Dellarco et al. 1985). Thus, both the clastogenic and the aneugenic effects can be determined by the MN test (Kirsch-Volders et al. 1997, Norppa and Falck 2003). In previous studies, the increase in MN frequency in peripheral blood lymphocytes from cancer patients was found to be as much as the MN frequency in the targeted cancer tissue (Cheng et al. 1996, Duffaud et al. 1997, Bonassi et al. 2007). In addition, in the study of Fenech et al. (1999), which have been conducted with an international collaboration, has clearly shown the relationship between MN and cancer in humans.
Assessment of the in vitro genotoxicity of TiO2 nanoparticles in a regulatory context
Published in Nanotoxicology, 2018
Sandrine Charles, Stéphane Jomini, Valérie Fessard, Emilie Bigorgne-Vizade, Christophe Rousselle, Cécile Michel
DNA damage can also arise through indirect mechanisms where the NPs do not physically interact with the DNA molecule, but with other cellular proteins such as those involved in cell division, DNA replication, transcription, and repair. Indeed, many of the proteins involved in the repair machinery possess metallic linked functions that may be disturbed by the NPs due to competition for biological sites or due to redox potential modification (Carriere et al. 2017). This hypothesis was highlighted in a microarray test using plasmid containing fluorescent nucleotides showing decreased nucleotide excision repair (NER) and base excision repair (BER) activities in A549 cells exposed to TiO2-NPs (Jugan et al. 2012) and confirmed in a direct in vitro test on the same cell line (Armand et al. 2016). TiO2-NPs have a very high affinity for phosphate groups, possibly engendering a high reactivity and trapping against DNA itself (DNA contains high levels of phosphate residues) and phosphorylation–dephosphorylation reactions, such as those implicated in DNA repair machinery (Carriere et al. 2017). Finally, another mode of action proposed for TiO2-NPs is an alteration of the mitotic spindle apparatus. Some publications reported disturbance of mitosis, and abnormal multipolar spindle formation, chromosomal alignment, and segregation during anaphase and telophase, as well as disturbance of the cell cycle checkpoint function (Magdolenova et al. 2014).
Global methylation profiles in buccal cells of long-term smokers and moist snuff consumers
Published in Biomarkers, 2018
Walter J. Jessen, Michael F. Borgerding, G. L. Prasad
All five MSR network analyses-identified processes are involved in cell cycle regulation (60 total genes, 5% (3) are hyper- or hypo-methylated). A prominent feature of this category is mitosis. The gene encoding cytoplasmic linker associated protein 2 (CLASP2), which promotes the stabilization of dynamic microtubules and fibronectin type III and SPRY domain containing 1 (FSD1), which associates with a subset of microtubules and may be involved in the stability and organization of microtubules during cytokinesis – were hypo-methylated and predicted to be down-regulated. A third mitosis gene, kinesin family member 15 (KIF15), maintains bipolar microtubule spindle apparatus in dividing cells and was methylated and predicted to be down-regulated.
Related Knowledge Centers
- Cell Biology
- Cell Division
- Cytoskeleton
- Eukaryote
- Sister Chromatids
- Gamete
- Meiosis
- Cell
- Mitosis
- Chromosome