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Effects of Retinoids at the Cellular Level (Differentiation, Apoptosis, Autophagy, Cell Cycle Regulation, and Senescence)
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
The role of RA in cell cycle regulation was reported in promyelocytic leukemia and U-937 cells, derived from histiocytic lymphoma, where RA treatment induced G0/G1 arrest. Corresponding gene expression changes included downregulation of c-Myc and cyclin E, increased expression of p21WAF1/CIP1, and increased stability of p27Kip1 (79,80). Treatment with RA also affects CDK5 activity, and several papers described how RA induces cell cycle arrest (81–83). CDK5, together with its activator p35, is important for induction of neuronal differentiation (84). CDK5 also regulates the growth of various cancers, such as thyroid (85), cervical (86), and prostate (87). Activation of CDK5 leads to upregulation of p27, which is the main effector in RA-mediated cell cycle regulation (82).
Organic Chemicals
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
NMDA receptor function is also strongly regulated by chemical reduction and oxidation, via the “redox modulatory site.”33 Through this site, reductants dramatically enhance NMDA channel activity, whereas oxidants either reverse the effects of reductants or depress native responses. It is generally believed that NMDA receptors are modulated by endogenous redox agents such as glutathione, lipoic acid, and the essential nutrient pyrroloquinoline quinone. Src kinase enhances NMDA receptor currents.34 Reelin modulates NMDA function through Src family kinases and DAB1,35 significantly enhancing LTP in the hippocampus. CDK5 regulates the amount of NR2B-containing NMDA receptors on the synaptic membrane, thus affecting synaptic plasticity.36,37
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Flavopiridol (Figure 6.74) was one of the first CDK inhibitors to be discovered, and is capable of inducing apoptosis in some tumor cells. It is a flavone synthetically derived from rohitukine, a plant alkaloid isolated from the leaves and stems of Dysoxylum binectariferum and Amoora rohituka. Both of these plants are native to India and are widely used in traditional medicine. Although flavopiridol was developed as far as clinical evaluation through a collaboration between Aventis and the NCI, all studies were terminated in early 2004 following poor results from intermediate-stage Phase II clinical trials. Several other lead CDK inhibitors were described in the early days of research in this area such as olomoucine and roscovitine (Figure 6.74), the chiral (R) version of which was developed by (the then) Cyclocel Ltd (i.e., as CYC-202) and reached Phase II clinical trials, although it was not progressed beyond this due to a lack of efficacy. The paullones were another early class of CDK inhibitors that inhibit various CDKs, including CDK1 (cyclin B), 2 (cyclin A), 2 (cyclin E), and 5 (p25). However, evaluation of these compounds in the NCI’s 60 cell line screen showed that there was a lack of correlation between CDK inhibitory potency and cytotoxicity, although one derivative (alsterpaullone, Figure 6.74) had a much higher activity against CDK1 and had significant in vitro cytotoxicity and in vivo antitumor activity. However, it was eventually shown to inhibit glycogen synthase kinase-3 and CDK5/p25, suggesting that it may work through multiple targets. Structures of flavopiridol, olomoucine, (R)-roscovitine (CYC-202) and alsterpaullone.
Cell cycle deregulation in neurodegenerative diseases
Published in International Journal of Neuroscience, 2023
Xiaobo Zhang, Shuxin Song, Wenpeng Peng
Currently, very limited treatment is available for neurodegenerative disease. Evidences from above indicate that deregulation of cell cycle plays an important role in neurodegenerative disease. Only by identifying the mechanism, can we inhibit some factors of cell cycle, therefore reduce the neurodegeneration, and find new therapies of neurodegenerative disease. For example, given the key role of CDKs for driving cell cycle progression, CDKs have appeared as attractive therapeutic targets, especially inhibitors of CDK5, such as flavopiridol, roscovitine, olomoucine [65]. Emphasis has also been given to E2F1, such as necdin, and miRNA. However, considering the complexity of different pathways, it poses a challenge for us to understand this mechanism in depth. It also provides opportunities by multiplying the number of potential therapeutic targets and thereby, the chances for developing agents that selectively promote neuron survival. In addition, issues such as specificity, side effects and access to the nervous system must be considered before moving forward. Therefore, further studies are needed to deeply understand all these problems. We propose that intervention of cell cycle can be effective in treatment of neurodegenerative disease.
Overexpression of Regucalcin Suppresses the Growth of Human Osteosarcoma Cells in Vitro: Repressive Effect of Extracellular Regucalcin
Published in Cancer Investigation, 2020
Masayoshi Yamaguchi, Tomiyasu Murata
The current study demonstrates that overexpression of regucalcin suppresses the growth of Saos-2 human osteosarcoma cells in vitro. Mechanistic characterization of the suppressive effects of regucalcin overexpression on the proliferation of Saos-2 cells was investigated using various inhibitors that regulate cell signaling pathways. Suppressive effects of overexpressed regucalcin on the cells were not attenuated by butyrate, roscovitine, or sulphoraphan, which induce cell-cycle arrest. Butyrate induces an inhibition of G1 progression (45). Roscovitine is a potent and selective inhibitor of the cyclin-dependent kinase cdc2, cdk2m, and cdk5 (46). Sulforaphane induces G2/M phase cell cycle arrest (47). Notably, overexpression of regucalcin in Saos-2 cells increased the levels of p21, a regulator of cell cycle progression at G1 and S phase (20). These results suggest that overexpression of regucalcin causes the arrest of G1/S and G2/M phase cell cycle in Saos-2 human osteosarcoma cells. Further experiments, however, are required to confirm this finding using other analysis of cell cycle, including flow cytometry. Similar effects of regucalcin have been shown in various types of human cancer cells, including pancreatic cancer MIA PaCa-2 cells (32), MDA-MB-231 breast cancer cells (33), liver cancer HepG2 cells (34), lung adenocarcinoma A549 cells (35), colorectal cancer RKO cells (36), and clear cell renal cell carcinoma A498 cells (37) in vitro.
Investigation of TF-binding lectins from dietary sources and SRL on proliferation and cell cycle progression in human colon HT29 and SW620 cells
Published in Nutrition and Cancer, 2019
Shivakumar Belur, Srikanth Barkeer, Bale M. Swamy, Lu-Gang Yu, Shashikala R. Inamdar
The presence of ABL reduced CDK5 levels and SRL and ACA completely abolished in SRL and ACA- CDK5 expression. CDK5 is a proline-directed serine/threonine kinase and controls various cellular events, including cytoskeletal organization, cell adhesion, membrane trafficking, cell cycle exit, and neuronal differentiation, and thereby regulates multiple aspects of brain development and function (41). CDK5 Overexpression is shown to occur in metastatic tumors in comparison in primary colon tumors. Inhibition of CDK5 expression by gene knockdown or small molecule inhibitors reduced cell proliferation and migration, increased cell death and arrested cells in the G2/M transition in vitro and halted tumor progression and tumor weight in vivo (42). A decreased level of CDK5 in HT29 cells by the presence of SRL and ABL is in consistent with the growth inhibitory effect of these two lectins supports in those cells. Antiproliferative lectins SRL and ABL have reduced the overall expression of Cyclin D1, D2, D3, Cyclin E, and CDK5 which fall in line with their ultimate response.