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The Scientific Basis of Medicine
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Chris O'Callaghan, Rachel Allen
In order to divide successfully, a cell must copy its DNA so that each daughter cell receives its full set of chromosomes. This is achieved by a tightly regulated mitosis following the cell cycle pathway (Figure 2.6). Passage through the cell cycle is controlled by cyclin proteins, in a cascade of phosphorylation events. Each cyclin acts as a catalytic subunit in partnership with a cyclin-dependent kinase (CDK). Upon cyclin binding, CDKs phosphorylate target proteins that are required for cell-cycle progression. CDK-specific inhibitors (CDKIs) bind cyclin–CDK complexes to regulate their activity and can themselves be regulated by other proteins. During mitosis, one member of each chromosome pair becomes attached to a centriole. Centrioles move to opposite ends of the cell, taking the chromosomes with them. In order to prevent inappropriate proliferation of cells, mitosis is tightly controlled, with various checkpoints to ensure that every part of the mitotic process is completed correctly before the next stage begins. Because uncontrolled proliferation is a hallmark of cancer, the cell cycle provides an obvious target for therapy. CDKIs often act as tumour suppressors and are potentially useful anticancer agents.
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The cyclins form the regulatory subunits, and CDKs the catalytic subunits, of an activated heterodimer complex. Thus, the cyclins have no catalytic activity of their own, and the CDKs are inactive until associated with a partner cyclin. When bound by an appropriate cyclin, CDKs perform a phosphorylation reaction that activates or inactivates target proteins to facilitate entry into the next phase of the cell cycle. The various downstream proteins are targeted by different cyclin-CDK combinations. It follows that CDKs are constitutively expressed in cells, whereas cyclins are synthesized during different stages of the cell cycle in response to specific molecular signals. Thus, the CDK proteins have been the most sought-after targets for drug discovery purposes due to their constitutive expression during all the cell-cycle phases.
The Fight Against Cancer
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Among the mechanisms in place to control the cell cycle are cascades involving a variety of proteins called cyclins, along with enzymes called cyclin-dependent kinases (CDK). Different types of each are responsible for the regulation of the different phases of the cell cycle. Binding of a cyclin with its enzyme activates the enzyme and serves to move the cell cycle from one phase to the next. Progression through the cell cycle is regulated by sequential activation of cyclins and CDKs. The process can also be down-regulated by CDK inhibiters.
High Glucose Induced Upregulation of Cyclin a Associating with a Short Survival of Patients with Cholangiocarcinoma: A Potential Target for Treatment of Patients with Diabetes Mellitus
Published in Nutrition and Cancer, 2022
Charupong Saengboonmee, Marutpong Detarya, Sakkarn Sangkhamanon, Kanlayanee Sawanyawisuth, Wunchana Seubwai, Sopit Wongkham
Cyclin A has multiple and probably cancer type-specific functions as described in different reports. Cyclin A is associated with both chemosensitivity and chemoresistance of cancer cells. High expression of cyclin A is associated with a better prognosis and chemosensitivity of gastric cancer (30), anal cancer (31), head and neck squamous cell carcinoma (32), and esophageal cancer (33). In contrast, cyclin A was associated with poor prognosis and chemoresistance of ovarian cancer (34), lung cancer (35), colorectal cancer (36), laryngeal cancer (37), and prostate cancer (38). The correlation between cyclin A and clinical outcome is, however, controversial for breast cancer of different sub-types (39–44), The present study is the first report to show the significance of expression and localization of cyclin A in tumor tissues from CCA patients.
Benzo(a)pyrene affects proliferation with reference to metabolic genes and ROS/HIF-1α/HO-1 signaling in A549 and MCF-7 cancer cells
Published in Drug and Chemical Toxicology, 2022
Meili Gao, Aqun Zheng, Lan Chen, Fan Dang, Xiaojing Liu, Jianghong Gao
The proliferation of cancer cells is associated with the proportion of cells that enter the cell cycle. Our results were similar to those of previous reports, which showed that BaP exposure caused S phase arrest, with enlarged cell sizes in A549 cells (Wang et al. 2009) and lengthened the S phase interval, resulting in G2/M accumulation in MCF-7 cells (Jeffy et al.2000). The results of the present study indicated the induction of cell cycle progression in the examined cancer cell lines. Cell cycle progression is regulated by interactions between cyclins and CDKs. The cyclin A–CDK2 interaction activates DNA synthesis and promotes DNA replication and is essential for the G1⁄S phase transition and progression through the S phase (Copeland et al. 2015). Mitosis is triggered by the activation of CDK1/cyclin B, also known as M-phase promoting factor (Ma et al.2016). A previous study reported that BaP exposure increased the expression levels of cyclin D1, CDK4, and CDK2, but no change in cyclin A expression was reported in A549 cells (Wang et al.2009). Our findings provided evidence for CDK1-cyclin B involvement in the regulation of the BaP-mediated effects on cell cycle progression in A549 cells. We also demonstrated that cyclin A-CDK2 and CDK1-cyclin B are strongly involved in the regulation of the BaP-mediated effects on the cell cycle progression of MCF-7 cells. To the best of our knowledge, the findings of increased CDK1 and cyclin B expression induced by BaP in A549 and MCF-7 cell lines have not been previously reported in the literature.
Alpinetin Inhibits Oral Squamous Cell Carcinoma Proliferation via miR-211-5p Upregulation and Notch Pathway Deactivation
Published in Nutrition and Cancer, 2020
Yanjun Guo, Yong Chen, Hongli Liu, Wei Yan
The ALP-induced inhibition of OSCC proliferation was indicated by survival rate decrease, G1 cell cycle arrest, upregulation of p-p53, p21, and c-PARP levels, and downregulation of cyclin D1 expression. The tumor suppressor gene p53 can regulate the cell cycle, especially by inducing its downstream signaling molecule p21 to block cell cycle progression out of G1 (27). p21 is a well-known negative modulator of cell cycle progression by inhibiting the activity of cyclin/CDK2 complexes to affect the G1/S phase in tumor cells (28). Cyclin D1 and CDK2 can regulate G1 to S-phase transition (29). Cyclin D1 is overexpressed in many human malignant tumors and is closely related to tumor progression. As a programmed cell death early molecule, PARP is also involved in apoptosis in organisms (30). Thus, our results demonstrated the inhibition of cell proliferation after ALP treatment, and they provide evidence of the anticancer effect of ALP on OSCC.