scholarly journals Design, Synthesis and Pharmacological Evaluation of Three Novel Dehydroabietyl Piperazine Dithiocarbamate Ruthenium (II) Polypyridyl Complexes as Potential Antitumor Agents: DNA Damage, Cell Cycle Arrest and Apoptosis Induction

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1453
Author(s):  
Haoran Wang ◽  
Jianhua Wei ◽  
Hong Jiang ◽  
Ye Zhang ◽  
Caina Jiang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Antitumor Agents ◽  
Mechanistic Study ◽  
Ros Generation ◽  
Polypyridyl Complexes ◽  
Expression Levels ◽  
Cycle Arrest ◽  
Study Results

The use of cisplatin is severely limited by its toxic side-effects, which has spurred chemists to employ different strategies in the development of new metal-based anticancer agents. Here, three novel dehydroabietyl piperazine dithiocarbamate ruthenium (II) polypyridyl complexes (6a–6c) were synthesized as antitumor agents. Compounds 6a and 6c exhibited better in vitro antiproliferative activity against seven tumor cell lines than cisplatin, they displayed no evident resistance in the cisplatin-resistant cell line A549/DPP. Importantly, 6a effectively inhibited tumor growth in the T-24 xenograft mouse model in comparison with cisplatin. Gel electrophoresis assay indicated that DNA was the potential targets of 6a and 6c, and the upregulation of p-H2AX confirmed this result. Cell cycle arrest studies demonstrated that 6a and 6c arrested the cell cycle at G1 phase, accompanied by the upregulation of the expression levels of the antioncogene p27 and the down-regulation of the expression levels of cyclin E. In addition, 6a and 6c caused the apoptosis of tumor cells along with the upregulation of the expression of Bax, caspase-9, cytochrome c, intracellular Ca2+ release, reactive oxygen species (ROS) generation and the downregulation of Bcl-2. These mechanistic study results suggested that 6a and 6c exerted their antitumor activity by inducing DNA damage, and consequently causing G1 stage arrest and the induction of apoptosis.

Hematopoietic Progenitors in Myelodysplastic Syndrome (MDS) Demonstrate Cell Cycle Arrest, Mitotic Failure, and DNA Damage.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2375-2375
Author(s):  
David R. Head ◽  
James W. Jacobberger ◽  
Madan H. Jagasia ◽  
Stacey A. Goodman ◽  
Leanne Flye ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Annexin V ◽  
Phase Cell ◽  
Consecutive Series ◽  
Hematopoietic Progenitors ◽  
Erythroid Progenitors ◽  
Cycle Arrest ◽  
Study Results

Abstract To assess biologic characteristics of marrow progenitors in MDS, we studied a consecutive series of MDS patients receiving no current treatment. Methods: Patients’ (n=17) clinical histories, lab data, cytogenetics, and morphology were reviewed for confirmation of diagnosis and blinded to study results. Patients lacking primary marrow disease (n=9) were used as controls. Marrow samples were studied at 2-5 hours after procurement (mean 3.1 hours), and re-assessed at 24 hours. A small number of marrow samples were fixed within minutes of procurement to validate findings. Each sample was assessed for CD45 antigen density, log side scatter, CD34, CD71, DRAQ 5 (DNA content), MPM-2, p-H2A.X (serine 139), and Annexin V with an FC500 (Beckman-Coulter) flow cytometer. Analysis was performed using Winlist 5.0 software (Verity Software) with DDE links to ModfitLT3.0 using modifications of published methods along with Esoterix Center for Innovation generated algorithms. Analyses were blinded to clinical results. Results: Most MDS patients demonstrated increased S-phase cell cycle fractions. Despite this, neither myeloid nor erythroid progenitors in MDS demonstrated an increased mean mitotic index vs. normals (0.315/0.359 and 1.33/1.48 respectively), and 7 MDS patients demonstrated no mitotic events in myeloid precursors (never observed in the normal dataset). DNA damage (H2A.X binding) was increased in myeloid and erythroid progenitors in MDS vs. normals (19/4% and 9/1.6% respectively). Annexin V staining was modestly elevated in maturing progenitors in MDS patients vs. normals (16.4% vs. 10.9%), and increased 4% in each group at 24 hours. Stem cells (CD34+) and lymphocytes were negative for both H2A.X and Annexin V binding. Discussion: These results indicate abnormalities in MDS marrow biology that may be useful as diagnostic tests for MDS. They suggest a model of MDS characterized by DNA damage in maturing hematopoietic progenitors in MDS, with late cell cycle arrest, accumulation of cells in S or G2, and decreased cell division (mitotic events) despite cellular marrow. In this model, DNA damage may initiate apoptosis in cells, but the findings are inconsistent with massive successful programmed cell death as a central event in MDS pathogenesis. The model has therapeutic implications for MDS.

Apigenin induces autophagic cell death in human papillary thyroid carcinoma BCPAP cells

2015 ◽  
Vol 6 (11) ◽  
pp. 3464-3472 ◽  
Author(s):  
Li Zhang ◽  
Xian Cheng ◽  
Yanyan Gao ◽  
Jie Zheng ◽  
Qiang Xu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Cell Cycle Arrest ◽  
Autophagic Cell Death ◽  
Ros Generation ◽  
Papillary Thyroid ◽  
Cycle Arrest

Apigenin-induced autophagic cell death in human papillary thyroid carcinoma BCPAP cells is associated with ROS generation, DNA damage and cell cycle arrest.

scholarly journals ERK activation mediates cell cycle arrest and apoptosis after DNA damage independently of p53.

2002 ◽  
Vol 277 (23) ◽  
pp. 21110 ◽  
Author(s):  
Damu Tang ◽  
Dongcheng Wu ◽  
Atsushi Hirao ◽  
Jill M. Lahti ◽  
Lieqi Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Erk Activation ◽  
Cycle Arrest

scholarly journals P28-10 Cisplatin induces DNA damage associated with cell cycle arrest and apoptosis in PC9 cells

2021 ◽  
Vol 32 ◽  
pp. S346
Author(s):  
Md Mohiuddin ◽  
Hideharu Kimura ◽  
Takashi Sone ◽  
Hiroki Matsuoka ◽  
Keigo Saeki ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Cycle Arrest

scholarly journals Cannabidiol Induces Cell Cycle Arrest and Cell Apoptosis in Human Gastric Cancer SGC-7901 Cells

Biomolecules ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 302 ◽  
Author(s):  
Xin Zhang ◽  
Yao Qin ◽  
Zhaohai Pan ◽  
Minjing Li ◽  
Xiaona Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Protein Expression ◽  
Cell Cycle Arrest ◽  
Phase Cell ◽  
G1 Phase ◽  
Therapeutic Effects ◽  
Human Gastric Cancer ◽  
Expression Levels ◽  
Cycle Arrest

The main chemical component of cannabis, cannabidiol (CBD), has been shown to have antitumor properties. The present study examined the in vitro effects of CBD on human gastric cancer SGC-7901 cells. We found that CBD significantly inhibited the proliferation and colony formation of SGC-7901 cells. Further investigation showed that CBD significantly upregulated ataxia telangiectasia-mutated gene (ATM) and p53 protein expression and downregulated p21 protein expression in SGC-7901 cells, which subsequently inhibited the levels of CDK2 and cyclin E, thereby resulting in cell cycle arrest at the G0–G1 phase. In addition, CBD significantly increased Bax expression levels, decreased Bcl-2 expression levels and mitochondrial membrane potential, and then upregulated the levels of cleaved caspase-3 and cleaved caspase-9, thereby inducing apoptosis in SGC-7901 cells. Finally, we found that intracellular reactive oxygen species (ROS) increased after CBD treatment. These results indicated that CBD could induce G0–G1 phase cell cycle arrest and apoptosis by increasing ROS production, leading to the inhibition of SGC-7901 cell proliferation, thereby suggesting that CBD may have therapeutic effects on gastric cancer.

scholarly journals Aqueous Extracts of the Edible Gracilaria tenuistipitata are Protective Against H2O2-Induced DNA Damage, Growth Inhibition, and Cell Cycle Arrest

Molecules ◽  
2012 ◽  
Vol 17 (6) ◽  
pp. 7241-7254 ◽  
Author(s):  
Jing-Iong Yang ◽  
Chi-Chen Yeh ◽  
Jin-Ching Lee ◽  
Szu-Cheng Yi ◽  
Hurng-Wern Huang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Growth Inhibition ◽  
Cell Cycle Arrest ◽  
Aqueous Extracts ◽  
Damage Growth ◽  
Gracilaria Tenuistipitata ◽  
Cycle Arrest

Mollugin induced oxidative DNA damage via up-regulating ROS that caused cell cycle arrest in hepatoma cells

2022 ◽  
pp. 109805
Author(s):  
Xin-ge Ke ◽  
Yi-yi Xiong ◽  
Bing Yu ◽  
Chong Yuan ◽  
Peng-yu Chen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Oxidative Dna Damage ◽  
Hepatoma Cells ◽  
Cycle Arrest

Octadecyloxyethyl Adefovir Exhibits Potent in vitro and in vivo Cytotoxic Activity and Has Synergistic Effects with Ara-C in Acute Myeloid Leukemia

Chemotherapy ◽  
2018 ◽  
Vol 63 (4) ◽  
pp. 225-237 ◽  
Author(s):  
Haytham Khoury ◽  
Ruijuan He ◽  
Aaron Schimmer ◽  
James R. Beadle ◽  
Karl Y. Hostetler ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Acute Myeloid Leukemia ◽  
Cell Cycle Arrest ◽  
Clinical Benefit ◽  
Myeloid Leukemia ◽  
Mouse Bone Marrow ◽  
Medical Needs ◽  
Cycle Arrest ◽  
Acute Myeloid

Acute myeloid leukemia (AML) continues to be a deadly disease, with only 50–70% of patients achieving complete remission and less than 30% of adults having sustained long-term remissions. In order to address these unmet medical needs, we carried out a high-throughput screen of an in-house library of on- and off-patent drugs with the OCI/AML-2 cell line. Through this screen, we discovered adefovir dipi­voxil (adefovir-DP) as being active against human AML. In addition to adefovir-DP, there are second-generation formulations of adefovir, including octadecyloxyethyl adefovir (ODE-adefovir) and hexadecyloxypropyl adefovir (HDP-adefovir), which were designed to overcome the pharmacokinetic problems of the parent compound adefovir. Given the known clinical benefit of nucleoside analogs for the treatment of AML, we undertook studies to evaluate the potential benefit of adefovir-based molecules. In AML cell lines and patient samples, adefovir-DP and ODE-adefovir were highly potent, whereas HDP-adefovir was significantly less active. Interestingly, ODE-adefovir was remarkably less toxic than adefovir-DP towards normal hematopoietic cells. In addition, ODE-adefovir at a dose of 15 mg/kg/day showed potent activity against human AML in a NOD/SCID mouse model, with a reduction of human leukemia in mouse bone marrow of > 40% in all mice tested within 20 days of treatment. Based on its chemical structure, we hypothesized that the cytotoxicity of ODE-adefovir toward AML was through cell cycle arrest and DNA damage. Indeed, ODE-adefovir treatment induced cell cycle arrest in the S phase and increased levels of pH2Ax, indicating the induction of DNA damage. Furthermore, there was an increase in phospho-p53, transactivation of proapoptotic genes and activation of the intrinsic apoptotic pathway. Subsequent investigation unveiled strong synergism between ODE-adefovir and ara-C, making their coadministration of potential clinical benefit. Expression of MRP4, a nucleoside transporter, appeared to influence the response of AML cells to ODE-adefovir, as its inhibition potentiated ODE-adefovir killing. Taken together, our findings indicate that clinical development of ODE-adefovir or related compounds for the treatment of AML is warranted.

scholarly journals RUNX Family Participates in the Regulation of p53-Dependent DNA Damage Response

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Toshinori Ozaki ◽  
Akira Nakagawara ◽  
Hiroki Nagase
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Dna Damage Response ◽  
Apoptotic Cell ◽  
Genetic Alterations ◽  
Apoptotic Cell Death ◽  
Cycle Arrest ◽  
Damage Response

A proper DNA damage response (DDR), which monitors and maintains the genomic integrity, has been considered to be a critical barrier against genetic alterations to prevent tumor initiation and progression. The representative tumor suppressor p53 plays an important role in the regulation of DNA damage response. When cells receive DNA damage, p53 is quickly activated and induces cell cycle arrest and/or apoptotic cell death through transactivating its target genes implicated in the promotion of cell cycle arrest and/or apoptotic cell death such asp21WAF1,BAX, andPUMA. Accumulating evidence strongly suggests that DNA damage-mediated activation as well as induction of p53 is regulated by posttranslational modifications and also by protein-protein interaction. Loss of p53 activity confers growth advantage and ensures survival in cancer cells by inhibiting apoptotic response required for tumor suppression. RUNX family, which is composed of RUNX1, RUNX2, and RUNX3, is a sequence-specific transcription factor and is closely involved in a variety of cellular processes including development, differentiation, and/or tumorigenesis. In this review, we describe a background of p53 and a functional collaboration between p53 and RUNX family in response to DNA damage.

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