Explore chapters and articles related to this topic
Nanomedicine Against COVID-19
Published in Hanadi Talal Ahmedah, Muhammad Riaz, Sagheer Ahmed, Marius Alexandru Moga, The Covid-19 Pandemic, 2023
Saima Zulfiqar, Zunaira Naeem, Shahzad Sharif, Ayoub Rashid Ch., M. Zia-Ul-Haq, Marius Moga
A suitable nanocarrier selection can eliminate many limitations in drug delivery, for example, toxic auristatin conjugates for hematological cancer treatment with the disadvantage of less drug pay-loads. This limitation was solved with the development of polymeric nanoparticles giving advantage of high drug (auristatin) payload for effective tumor repression [97]. Intolerable side effects of Aurora B kinase observed in a trial phase were avoided by combining it with polyethylene glycol/polylactide nanoparticles. Moreover, nucleic acid containing drugs also face limitations associated with intracellular delivery and unstable system of circulation [98–101]. Formulation of lipid nanoparticles loaded with nucleic acid drugs eliminated its conventional limitations with the aid of targeting the liver [102]. Similarly, silica mesopo-rous nanoparticles coated with lipid offered advantages of biocompatibility and more time for systematic circulation for the delivery of an antiviral drug, ML336. A high through output method, FIND was also reported, which screen these lipid nanoparticles for the in vivo delivery promoting nanocarriers as “immuno-oncology” therapeutics with the elimination of associated toxicity [103–105].
Antitubulin Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The structure and active site of an Aurora Kinase have been determined from an Aurora-2-adenosine complex (Figure 4.27). The hinge (yellow), glycine-rich loop (blue), and activation loop (red) are key features of the protein kinase fold involved in binding adenosine. The protein backbone atoms of residues Glu-211 and Ala-213 in the hinge region of Aurora-2, and the side chain of residue Trp-277 located in the activation loop, bind adenosine through specific hydrogen bonds. Residues Lys-162 and Asp-274 are essential for Aurora-2 kinase activity but do not hydrogen bond to each other as seen in the crystal structures of several other protein kinases.
Precision Medicine and Future Therapeutics
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
The cell cycle clock and cancerous growth are intimately linked – generally, when the cell cycle clock is disrupted, the cell proliferates excessively. Independently of the various cancer-specific gene mutations, the cell cycle clock can become deregulated by an alteration of the various growth factors, other proteins and small molecules which are essential for an orderly and timely operation of ‘the clock’. There appear to be a number of crucial points, particularly when the cell cycle progresses from the G1 phase to the S phase (Figure 1.5). It is here that a cell decides either to proceed further in the cycle or stop cycling and enter the G0 phase. This ‘decision point’ is termed the ‘restriction point’ (or R) and appears to be analogous to a ‘light switch’. Lastly, the molecular basis of the Aurora B kinase-dependent ‘abscission point’, whereby the intercellular bridge separates the two daughter cells and represents the final stage of cell cytokinesis, and the complex functions of the epsilon isoform of protein kinase C (PKCε) in mitosis and cytokinesis, is now emerging.
Discovery of a novel Aurora B inhibitor GSK650394 with potent anticancer and anti-aspergillus fumigatus dual efficacies in vitro
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Yuhua He, Wei Fu, Liyang Du, Huiqiao Yao, Zhengkang Hua, Jinyu Li, Zhonghui Lin
The pGEX-dual expression plasmid containing human (Hs.) Aurora B kinase domain (aa.54–344) and a C-terminal fragment of Hs.INCENP (aa.835–904) was obtained from Prof. Hongtao Yu (Department of Life Science, Westlake University). The cDNAs of Af.Aurora B kinase domain (aa.1–396, GenBank accession no. EDP54304.1) and the C-terminal fragment of Af.INCENP (aa.1200–1297, GenBank accession no. XP_033417438.1) was synthesised in Union Biotech (China). Protein expression and purification were performed as previously described31. Briefly, The recombinant proteins of Aurora B and INCENP were coexpressed in BL21 (DE3) pLysS competent cells. For protein purification, cells co-expressing GST-INCENP and Aurora B proteins were resuspended with lysis buffer containing 50 mM Tris-HCl, pH 8.0, 200 mM NaCl, 5% glycerol, and 0.05% Triton X-100. Cells were disrupted by French Pressure (Union Biotech, China) and the supernatants were collected after centrifugation. The Aurora B/Hs.INCENP complex proteins were pooled through Glutathione columns (Smart-Lifesciences, China). The GST tag was removed by homemade precision protease and the untagged proteins were further purified through a Superdex 200 10/300 GL column (GE Healthcare), with a running buffer containing 20 mM Tris-HCl, pH 8.0, 150 mM NaCl, and 1 mM DTT.
Ultra-long silver nanowires induced mitotic abnormalities and cytokinetic failure in A549 cells
Published in Nanotoxicology, 2019
Fengbang Wang, Ying Chen, Yuanyuan Wang, Yongguang Yin, Guangbo Qu, Maoyong Song, Hailin Wang
Multinucleation is closely associated with cytokinetic failure and mitotic abnormality. To analyze mitotic events in the A549 cell line, we first used multicolor immunofluorescence to investigate centrosome amplification. As shown in Figure 2(a), in control A549 cells, during mitosis, two centrosomes formed spindle poles and directed the formation of bipolar mitotic spindles. In AgNWs-treated cells, during mitosis, centrosome amplification led to aberrant mitotic spindle formation with more than two spindle poles. Tripolar or tetrapolar mitotic spindles were observed in AgNW30- and AgNW50-treated cells. Some daughter cells from the tripolar division were viable yet suffered from severe aneuploidy. When mitotic spindles with more than three poles are formed, cells fail to undergo cytokinesis and eventually undergo cell death (Fukasawa 2008). Aurora A kinase is a major regulator of cell division and regulates the separation and maturation of centrosomes at mitotic entry, mitotic microtubule nucleation, and the integrity of spindle poles (Ohishi et al. 2010; Asteriti et al. 2014). Aurora A was upregulated in AgNWs-treated cells (Figure 2(b,c)). Another protein, p-Histone 3 (ser10), was also accumulated in A549 cells after AgNWs treatment. Phosphorylation at a highly conserved serine residue (Ser-10) in the histone H3 tail is considered a crucial event in the onset of mitosis (Crosio et al. 2002). These results suggest that aberrant upregulation of Aurora A and p-Histone 3 (ser10) perturbs proper mitotic progression and results in a generation of multinucleated cells with mitotic abnormalities.
Alisertib: a review of pharmacokinetics, efficacy and toxicity in patients with hematologic malignancies and solid tumors
Published in Expert Opinion on Investigational Drugs, 2018
Susanne Liewer, Ashley Huddleston
Aurora kinases are a group of serine/threonine kinases which are essential for centrosome maturation and division and ultimate formation of the mitotic spindle. Aurora A kinase (AAK) has been a particular focus of recent drug development as it is overexpressed in a multitude of cancer types. Inhibition of AAK in preclinical trials led to mitotic delays, defects in chromosome segregation and cell death [1]. Alisertib (MLN8237) is a selective orally administered small molecule inhibitor of AAK that is currently under investigation for a number of hematologic and non-hematologic malignancies (Box 1). This targeted agent could provide potential advantages over traditional chemotherapy including simpler dosing, fewer toxicities and potentially superior outcomes in a wide variety of malignancy types. In addition to investigating its use as monotherapy, many clinical trials are also evaluating the addition of alisertib to cytotoxic chemotherapy, with or without radiotherapy in order to elucidate cancer types most likely to benefit.