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Pharmacokinetics, Biodistribution, and Therapeutic Applications of Recently Developed siRNA and DNA Repair Genes Recurrence
Published in Loutfy H. Madkour, Nanoparticle-Based Drug Delivery in Cancer Treatment, 2022
EphA2 is a well-known receptor tyrosine kinase belonging to the Eph family, overexpressed in many cancers including breast cancers and ovarian cancers, implicated in poor clinical outcomes [44]. Contact-dependent cell–cell interactions controlled by Eph receptors and ephrin (ligand of Eph receptors) signaling are tightly regulated in normal embryonic development and maintenance of homeostasis [45]. During oncogenesis, normal EphA2–EphrinA1 signaling is disrupted due to the loss of cell contacts, leading to overexpression of EphA2 and oncogenic signal transduction [45]. This dysregulated signaling is implicated in several critical aspects of oncogenesis such as cytoskeleton modulation, cell adhesion, migration, metastasis, proliferation, and angiogenesis [45]. Plk1, a serine/threonine-protein kinase, is responsible for cell mitosis in mammalian cells. It is overexpressed in various human cancers as a proto-oncogene, which inactivates tumor suppressor proteins like p53 [46,47]. CDKs are also serine/threonine kinases and essential for the regulation of the cell cycle progression [48]. The abnormal expression or activity of distinct CDK complexes causes cells to escape from a well-controlled cell cycle, resulting in malignant transformation [49–51]. Palbociclib, an inhibitor of CDK4/6, received breakthrough therapy designation from the FDA in April 2013, for the initial treatment of patients with breast cancer [52].
DNA Damage Response Research, Inherent and Future Nano-Based Interfaces for Personalized Medicine
Published in Yubing Xie, The Nanobiotechnology Handbook, 2012
Madhu Dyavaiah, Lauren Endres, Yiching Hsieh, William Towns, Thomas J. Begley
Activated p53 functions as a transcription factor by binding as a tetramer to a specific response element located in the promoter region of its target genes. This element consists of two repeats of a 10 bp motif, 5′ – 3 × Purine C(A/T)(A/T)G 3 × Pyrimidine-3′, separated by 1–13 bp (El-Deiry et al. 1992). On the nanoscale, this is in the range of ∼7–10 nm, with this binding interface and corresponding protein–DNA interactions being vital for the DNA damage response. Considering that nanoparticles are cell permeable and targetable, they have the potential to be coated, or functionalized, with p53 derivatives and used as an anticancer therapy aimed at eliciting either a killing or growth-arrest response in cancers that have lost p53, estimated to be ∼50% (Hollstein et al. 1996, Nigro et al. 1989). Once activated, p53 can transcriptionally regulate the expression of the CDK inhibitor p21 as well as of the proapoptotic BAX and PUMA proteins that induce cell cycle arrest, senescence, or apoptosis. Moreover, p53 promotes DNA repair and dNTP synthesis (Chen et al. 2005, Shieh et al. 1997, 2000). The p53-dependent induction of the ribonucleotide reductase (RNR) subunit p53R2 has been shown to be important for the cellular response to DNA damage.
Cell Cycle
Published in Mihai V. Putz, New Frontiers in Nanochemistry, 2020
Grdisa Mira, Ana-Matea Mikecin
The transition from one CC phase to another occurs in an orderly fashion and is regulated by different cellular proteins. Key regulatory proteins are the CDK, a family of serine/threonine protein kinases that are activated at specific points of the CC (Morgan, 1995; Pines, 1995). CDK protein levels constantly rest during the CC, in contrast to the cyclins, their activating proteins. Cyclin protein levels rise and fall during the CC, and in this way, they periodically activate CDK (Evans et al., 1983; Pines, 1991). When CDK is activated, its target proteins become phosphorylated and physiologically relevant for CC progression (Buchkovich et al., 1989; Brehm et al., 1998; Montagnoli et al., 1999).
Theoretical, antimicrobial, antioxidant, in vitro cytotoxicity, and cyclin-dependent kinase 2 inhibitor studies of metal(II) complexes with bis(imidazol-1-yl)methane-based heteroscorpionate ligands
Published in Journal of Coordination Chemistry, 2019
S. Jayakumar, D. Mahendiran, A. Kalilur Rahiman
Cell cycle progression is controlled by cyclin-dependent kinases (CDKs) counter balanced by CDK inhibitors. The CDKs are a family of heterodimeric Ser/Thr protein kinases each consisting of a catalytic CDK subunit and an activating cyclin subunit. CDKs coordinate the eukaryotic cell division cycle and serve to integrate diverse growth-regulatory signals, and also strongly inhibit the tumor cell growth [50, 51]. For this reason, we have been interested to study the interaction of the synthesized heteroscorpionate-based homoleptic metal(II) complexes with CDK2 receptor (Figure 5). The observed docked values of complexes 1-9 are –4.31, –4.51, –4.18, –4.99, –5.07, –4.93, –5.14, –6.26, and –5.09, respectively. It can be seen that the complexes most likely bind to the hydrophobic pocket. All the complexes potentially interact with CDKs via π-π, π-σ, hydrogen bonding, electrostatic and van der Waals interactions. The interaction of nickel(II) and copper(II) complexes 3, 5, 7, and 8 are explained herewith.
Exposure to long-term evolution radiofrequency electromagnetic fields decreases neuroblastoma cell proliferation via Akt/mTOR-mediated cellular senescence
Published in Journal of Toxicology and Environmental Health, Part A, 2021
Ju Hwan Kim, Sangbong Jeon, Hyung-Do Choi, Jae-Hun Lee, Jun-Sang Bae, Nam Kim, Hyung-Gun Kim, Kyu-Bong Kim, Hak Rim Kim
The cyclins bind to CDKs and then form cyclin-CDK complexes that predominantly regulate cell cycle progression (Wade Harper et al. 1993). Abbas and Dutta (2009) reported that CDK4 mainly controls the G1 phase, and that CDK2 and CDK1 regulate the S and M phases, respectively. To examine whether the rise in cyclin-CDK inhibitors p21 and p27 might be associated with the delay in G0/G1 following RF-EMF exposure, the protein expression levels of CDK1, CDK2, CDK4, and cyclin D were determined in SH-SY5Y cells. The protein expression levels of CDK2, CDK4, and cyclin D were significantly decreased after RF-EMF exposure (Figure 6b–d), with no marked change in CDK1 protein expression (Figure 6a).
Tetrazolo[1,5-a]pyrimidine-based metal(II) complexes as therapeutic agents: DNA interaction, targeting topoisomerase I and cyclin-dependent kinase studies
Published in Inorganic and Nano-Metal Chemistry, 2018
Azees Khan Haleel, Dharmasivam Mahendiran, Ummer Muhammed Rafi, Vijaykumar Veena, Sugumar Shobana, Aziz Kalilur Rahiman
Cyclin-dependent kinase (CDKs) controls the cell cycle progression, coordinating the eukaryotic cell division cycle and serves to integrate diverse growth-regulatory signals, and also strongly inhibit the tumor cell growth.[44,45] Based on the above facts, we have been interested to study the interactions of cyclin-dependent kinase (CDKs) receptor with copper(II) complexes (4–6).