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  • The combination of Aurora kinase inhibitors with

    2024-05-15

    The combination of Aurora kinase inhibitors with standard chemotherapeutics or radiotherapeutics are currently in progress, such as AZD1152 plus radiotherapy in various solid cancer models. In addition, Azzariti et al. found that AZD1152-HQPA enhanced oxaliplatin and gemcitabine effectiveness in the colon and pancreatic cancer, respectively (Azzariti et al., 2011). However, little is known about the mechanism of action of Aurora kinase inhibitors in combination with radio- and chemotherapy at the molecular level. Azzariti et al. suggested that the potential mechanism for AZD1152-HQPA enhanced chemotherapy effectiveness is due to the DNA fragmentation associated with apoptosis occur in a cell population that has undergone endoreduplication to become >4N (Azzariti et al., 2011). Additionally, the M phase and G2 phase are the most sensitive stage to radiotherapy or DNA damage agents. Therefore, chemotherapy and fractionated radiotherapy may work better in concurrent of the Aurora B kinase inhibitors by partial synchronization of cancer carboxypeptidase a in the most radiosensitive G2/M phase (Pawlik and Keyomarsi, 2004). In summary, our in vitro and in vivo results suggest that deguelin is a bioavailable and potent Aurora B kinase inhibitor for ESCC treatment. Importantly, neoadjuvant chemotherapy or radiotherapy followed by surgery has emerged as a new standard treatment for ESCC currently (Markar et al., 2015, Matsuda et al., 2016, Pasquali et al., 2017, Sudo et al., 2014). Thus, a single treatment with deguelin or combination with conventional chemotherapy/radiotherapy deserves further investigation and development for clinic translation. The following are the supplementary data related to this article.
    Conflicts of Interest
    Author Contributions
    Materials and methods
    Introduction The filamentous fungi are a fascinating group of organisms with important beneficial ecological, pharmaceutical and industrial impact, but which also have devastating effects as pathogens and agents of food spoilage (Borkovich and Ebbole, 2010). As such understanding filamentous fungal biology is both fundamentally and economically important. Mitosis and cytokinesis are complex processes whose regulation is critical to ensure genetic stability. In most cell types cytokinesis is linked to mitosis such that cell division follows nuclear division. One notable exception occurs during the formation of the syncytial hyphae of filamentous fungi. In the model filamentous fungus Aspergillus nidulans germinating uninucleate conidiospores generally undergo 2 rounds of synchronous mitotic nuclear division in which septation, the fungal equivalent of cytokinesis, is suppressed (Clutterbuck, 1970, Harris, 2001). Subsequent to this, septation becomes linked to the synchronous mitoses of tip cells although septa do not form between every post mitotic nucleus thereby maintaining the multinucleate nature of hyphae. Another feature of hyphal septation is that it is an incomplete process in which septal cell walls do not seal resulting in the formation of a central septal pore which connects the hyphal cells facilitating communication and nutrient exchange (Jedd and Pieuchot, 2012). Although many genes involved in regulating septation have been identified (Bruno et al., 2001, De Souza et al., 2013, Harris, 2001, Harris et al., 1994, Kim et al., 2006, Kim et al., 2009, Morris, 1976, Si et al., 2010, Takeshita et al., 2007, Westfall and Momany, 2002), little is known about how septation is initially suppressed following mitosis, spatially regulated along hyphae and halted to form septal pores. Mitosis is in large part orchestrated by members of the mitotic Cdk, Polo, NIMA related kinase (NEK) and Aurora kinase families which are found in all eukaryotes (Ma and Poon, 2011, Nigg, 2001). A critical feature impacting the function of these kinases is the dynamic localization pattern each displays as cells progress from G2 and through mitosis. For example, as mammalian cells complete mitosis the Aurora B kinase sequentially locates to chromosomal arms, centromeres and the spindle midzone and these locations are important for its roles in regulating chromatin and mitotic spindle formation and function (Carmena et al., 2012, van der Waal et al., 2012). Aurora B is also present at the equatorial cortex during anaphase where it has been suggested to be involved in contractile ring assembly and to initiate cleavage furrow ingression (Carmena et al., 2012, Kitagawa et al., 2013). As cells exit mitosis Aurora B remains associated with microtubules as they rearrange to form the midbody present in the intercellular bridge connecting daughter cells where Aurora B helps coordinate cytokinesis (Agromayor and Martin-Serrano, 2013, Carmena et al., 2012, Murata-Hori et al., 2002).