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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The cell cycle is the process that causes a cell to divide into two daughter cells. It includes the duplication of a cell’s DNA (i.e., DNA replication) and some of its organelles, and the partitioning of its cytoplasm and other components into two daughter cells. In eukaryotes, the cell cycle is divided into two main stages: the interphase and the mitotic (M) phase (including mitosis and cytokinesis). The interphase involves cell growth during which nutrients needed for mitosis are accumulated, and replication of the DNA and some organelles can occur. The mitotic phase involves the separation of replicated chromosomes and organelles, and cytoplasm, into two new daughter cells. Under normal control, the cell cycle (Figure 6.73) functions as a highly regulated process with several distinct phases: G0 (quiescence) followed by G1 (pre-DNA synthesis), S (DNA synthesis), G2 (pre-division), and M (cell division).
The Fight Against Cancer
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Abnormalities in cell cycle regulation may occur at any of the four major phases, known as G1, S, G2, and M. progression through these phases of the cell cycle depends on the balance of the chemical signals that promote growth or inhibition. The G1 (gap 1) phase is where the cell grows in size and prepares for DNA replication in response to growth factors. The second phase (synthesis) is when DNA replication takes place. The next interval, once the chromosomes have been copied, is G2 phase (gap 2) where the cell prepares for division. During this interval, the cell has time to check for errors in the DNA replication, and repair any damaged copies. The final phase, M (mitosis) is when cell division happens to produce two daughter cells, each containing a full set of chromosomes. The daughter cell then begins the cell cycle at the G1 phase, or may remain in a dormant phase G0.
Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Robert D. Morgan, Andrew R. Clamp, Gordon C. Jayson
The most frequently detected genetic mutations in epithelial ovarian cancer occur in BRCA1 and BRCA2; these are estimated to occur in 10–15% of all high-grade serous cases. BRCA1 and BRCA2 have a number of important cellular functions; however, it is their role in DNA repair, in particular HR repair, that is linked to carcinogenesis.15 HR repair is an error-free DNA repair mechanism able to repair DNA double-strand breaks (DSBs).16 It occurs during the S/G2-phase of the cell cycle, at which stage a sister chromatid, containing a homologous DNA sequence, can act as a template for homology-directed repair. In the absence of BRCA1/2 proteins, the alternative error-prone DNA repair pathway, non-homologous end joining (NHEJ), is relied upon to repair DSBs that have resulted from either exogenous or endogenous genotoxins.17 A greater reliance upon the error-prone NHEJ pathway potentiates the risk of acquiring somatic mutations in oncogenes/tumor suppressor genes, thereby risking tumorigenesis. A deficiency in BRCA1/2 proteins in cells containing a germline mono-allelic/heterozygous BRCA1/2 mutation often occurs through somatic loss of the remaining BRCA1/2 wild-type allele, leading to a bi-allelic/homozygous mutation; in keeping with the concept of BRCA1/2 being tumor suppressor genes.
Polysaccharides from Hemerocallis citrina Baroni Inhibit the Growth of Hepatocellular Carcinoma Cells by Regulating the Wnt/β-Catenin Pathway
Published in Nutrition and Cancer, 2023
TianYu Sang, Yue Jun Fu, Li Song
The cell cycle is a precisely regulated process that ensures genetic integrity during cell division. Tumor cells are characterized by abnormal cell cycle regulation. Therefore, some antitumor drugs inhibit tumor cell proliferation by modulating the cell cycle and causing cell cycle arrest (29, 30). Our results showed that polysaccharides HcBPS2 significantly inhibited HCC cell proliferation and induced cell cycle arrest in G2/M phase. G2/M phase is an important DNA damage checkpoint. When a cell with DNA damage cannot repair the damage present, the G2/M phase checkpoint prevents the cells from entering M phase (31). Cyclin B1 regulates the transformation from G2 to M phase. Cyclin B1 can bind with the cell cycle-dependent kinase Cdc2 and then promote the cell cycle (16). Cyclin D1 is a crucial regulator during G2 phase (32). Cyclin D1 levels are elevated during G2 phase, which allows the cell to enter the next cycle (32). P21 is a cyclin-dependent kinase inhibitor that promotes G2/M phase arrest by inhibiting the expression of Cdc2 (33). This study found that the level of P21 was significantly increased and the expression levels of cyclin B1 and cyclin D1 were notably decreased in HcBPS2-treated cells. These findings suggested that cyclin B1, cyclin D1 and P21 were involved in HcBPS2-induced G2/M phase arrest.
Açaí (Euterpe oleracea Mart.) presents anti-neuroinflammatory capacity in LPS-activated microglia cells
Published in Nutritional Neuroscience, 2022
Diulie Valente de Souza, Lauren Pappis, Thuany Teixeira Bandeira, Gabriela Geraldo Sangoi, Tuyla Fontana, Vitor Braga Rissi, Michele Rorato Sagrillo, Marta Maria Duarte, Thiago Duarte, David Frederick Bodenstein, Ana Cristina Andreazza, Ivana Beatrice Mânica da Cruz, Euler Esteves Ribeiro, Alfredo Antoniazzi, Aline Ferreira Ourique, Alencar Kolinski Machado
Cell cycle analysis was performed to understand how freeze-dried hydroalcoholic açaí extract affects microglia cell proliferation. The cell cycle is comprised of several phases, specifically S, G2, and sub-G0/G1. The S phase is responsible for DNA duplication, while G2 phase is the moment for mitosis protein synthesis followed by the cell division events. It is already known that PAMP agents, such as LPS, are capable to induce increased S and G2/M phases in cells responsible for inflammatory response, indicating cellular activation. In BV-2 cells activated with LPS, we observed an increase in the number of cells in the S and G2/M phases compared to untreated cells. However, treatment with 1 μg/mL of açaí was capable of reversing cell cycle alterations induced by LPS exposure. None of the treatments induced sub-G0/G1 status (condition related to cellular death), corroborating the results of the dsDNA release analysis. A study performed by Martinez et al. [46] found açaí increased the number of cells in the G0/G1 phases. On the other hand, Machado et al. [25] found açaí arrested cells in the S phase and confirming our results. In addition, it has been shown MG53, a member of the tripartite motif (TRIM) family protein, attenuates neuroinflammation in activated microglia cells via cell cycle arrest [47]. These results indicate that açaí extract is able to block the cell cycle at the S phase and prevent progression into the G2/M phases. Therefore, a possible mechanism of action of açaí and other anti-inflammatory agents is to inhibit the progression of the cell cycle, specifically at the S phase.
Differential Activation of Immune Effector Processes in Mature Compared to Immature Sacrococcygeal Teratomas
Published in Fetal and Pediatric Pathology, 2022
Mette Hambraeus, Jenny Karlsson, Ioanna Kasselaki, Catharina Hagerling, Lars Hagander, David Gisselsson
The molecular signature in immature areas of sacrococcygeal teratomas showed a remarkably high expression of histone genes when compared to mature neuroglial areas. Particularly, genes encoding parts of the H2 subunit were highly enriched. Histones constitute the main core of nucleosomes, which form the repeating units of chromatin. The chromatin is condensed during the metaphase of the cell-cycle, and the high histone expression may reflect an increased cell turn-over in immature areas [30]. However, even when compared to the control group consisting of fast-growing, malignant pediatric tumors, genes encoding histones and other DNA-binding proteins were relatively overexpressed in immature areas of sacrococcygeal teratomas. A histone family signature with pathways related to cell cycle and DNA replication has previously been correlated with increased survival in cervical cancer patients [31]. The authors proposed a DNA-protecting role of the increased histone expression and found a correlation between high histone expression and reduced DNA damage. In SCTs, DNA-protection may explain the occasional occurence of malignancy and the paucity of chromosomal abnormalities found in this and other studies in spite of the high cell turn-over in immature areas [10]. The general overexpression of DNA-binding proteins and transcription factors compared to other pediatric tumors may also reflect the broad repertoire of histological elements in SCTs.