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Antitubulin Agents
Published in David E. Thurston, Ilona Pysz, 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.
Fertilized Sea Urchin Eggs as a Model for Detecting Cell Division Inhibitors
Published in Adorjan Aszalos, Modern Analysis of Antibiotics, 2020
Robert S. Jacobs, Leslie Wilson
There are also other, less obvious, benefits to be derived from the use of this cell culture system. First, the fertilized egg is a nontransformed cell of stable karyotype. This is usually not the case when using cultures of established mammalian cell lines [7]. Second, the use of cultured mammalian cells to identify cytotoxic compounds involves considerable time and expense (the latter arising both from the cost of the medium and from such culture equipment as filtration manifolds, incubators, compressed gas, and electronic cell counters). In contrast, sea urchin embryos require only seawater as a medium, can be incubated in a simple water bath, need not be cultured under rigorously sterile conditions, and exhibit a cell cycle time of 120 min or less, thus allowing cell cycle inhibition studies to be completed within just a few hours. Third, the large size of the sea urchin embryo (75–100 ym in diameter, depending upon the species used) makes it relatively easy to examine the assembly and development of the mitotic spindle apparatus in unfixed material using simple low- or medium-power light microscopy. This is a technically more difficult undertaking with the far smaller mammalian cells. Fourth, the presence of large amounts of maternal “masked” messenger RNA present in echinoderm embryos is thought to preclude transcriptional inhibition as a cytotoxic mechanism of action in early development [8]. The sea urchin embryo is thus believed to represent a naturally occurring pharmacologically selective bioassay system that conveniently allows the exclusion of an important cytotoxic process (transcriptional inhibition) as a mechanism responsible for the inhibition of cell division. To employ a mammalian cell system counterpart would require the production and/or selection of mutant lines resistant to each and every transcriptional inhibitor, obviously a timeconsuming, expensive, and laborious undertaking. Finally, the sea urchin embryo is a totipotent zygotic cell that can be routinely cultured well beyond the gastrula stage of development. This property allows the rapid identification and study of any drug-induced alterations in the differentiation sequence that may be manifest as changes in embryo morphology. It is of course impossible to exploit this capability using cultured mammalian somatic cells.
The association between antinuclear antibody and response to rituximab treatment in adult patients with primary immune thrombocytopenia
Published in Hematology, 2020
Yan-ming Wang, Ya-fei Yu, Yu Liu, Shuang Liu, Ming Hou, Xin-guang Liu
The terms ‘ANAs’ have been outdated and come to encompass antibodies against various cellular compartments such as nuclear constituents, components of the nuclear envelop, and mitotic spindle apparatus [18]. As platelets are anucleate cytoplasts, there is still no evidence that ANAs can cross-react with platelet antigens and lead to antibody-mediated platelet destruction. Furthermore, no association was observed between ANAs and any of the patients’ baseline characteristics. Although bleeding symptoms seem to be more obvious in ANA-positive patients, no statistical significance was obtained. It has been reported that ANA positivity could act as an indicator in terms of chronicity for childhood ITP [19]. By contrast, no correlation was found between ANAs and patients’ disease duration in our study. The discrepancy maybe partly due to the fact that we only recorded the time period from disease onset to rituximab use. Moreover, the difference in patients’ age and previous treatment history might also contribute to the discrepancy about the relationship between ANA positivity and disease chronicity. More importantly, this might also be part of the difference between adult ITP and pediatric ITP.
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).
Assessment of genotoxicity induced by subchronic exposure to graphene in HaCaT human skin cell line
Published in Nanotoxicology, 2023
Javier Frontiñan-Rubio, Sonia García-Carpintero, Viviana Jehová González, Ester Vázquez, Mario Durán-Prado
Previously, Akhavan et al. (2013) reported an increase in DNA fragmentation in hMSC cells exposed for 96 h to low doses of reduced graphene oxide nanoribbons. A long-term in vivo model suggested that GO could induce DNA fragmentation in lung cells in a time- and dose-dependent manner (El-Yamany et al. 2017). Some researchers have argued that acute exposure with GBMs cannot be genotoxic (Bengtson et al. 2016; Mukherjee et al. 2018) even though the genotoxic capacity of GBMs has been appointed in vitro and in vivo (Gurcan et al. 2019; Mohamed et al. 2020; Domenech et al. 2022). Factors such as cytotoxicity, exposure time, degree of oxidation, size, and protein corona, among others, can influence genotoxicity (Fadeel et al. 2018; Gurcan et al. 2019). In a comprehensive study with five different GBMs, Chatterjee, Yang, and Choi (2016) observed DNA damage and alterations of the DNA repair systems in lung cells, probably due to an alteration to the DDR. The continued affectation of the DDR can explain the effect of GBMs in HaCaTs shown herein. Several publications argued that CNTs induce DNA damage in the short term (3–72 h) in different in vivo models (Jacobsen et al. 2008; Lindberg et al. 2009; Migliore et al. 2010; Cicchetti et al. 2011; Cavallo et al. 2012; Ursini et al. 2012). It has also been suggested that CNTs could interact with the mitotic spindle apparatus in lung cells, inducing chromosome alterations and genotoxicity (Sargent et al. 2009; Siegrist et al. 2014). If maintained over time, these alterations could derive to tumor-initiating processes (Sargent et al. 2012). Indeed, Vales, Rubio, and Marcos (2016) suggested that lung cells’ exposed for 4 weeks to CNTs suffered sustained DNA damage that resulted in cell transformation.