Hypoxia-induced p21waf and p27 regulation in c-myc immortalized cells

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21125-21125
Author(s):  
M. Rosati ◽  
C. Raimondi ◽  
M. Di Seri
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Kinase Inhibitors ◽  
Proteasome Inhibitors ◽  
Fibroblast Cell ◽  
Resistance Mechanisms ◽  
Assay Method ◽  
Induce Cell Cycle Arrest ◽  
Cycle Arrest

21125 Background: Hypoxia is an adaptative response to tissue damage whose mechanisms have not been yet characterized. From a clinical viewpoint, tumours with more necrosis, an indicator of severe hypoxic stress, are often resistant to conventional treatment. Moreover, numerous tumours overexpressed c-myc which strongly enforces proliferation in oxygen deprived conditions. Evidences showed that c-myc blocked cyclin-dependent kinase inhibitors (CDKI) through a complex network of interactions inducing proliferation and G0-S transition. We examined whether Rat-1 immortalized fibroblasts underwent cell cycle arrest p21waf- and p27- mediated in response to O2-deprivation. Materials and Methods: c-myc null cells (-/-) were derived by gene targeting from an immortalized but otherwise non- transformed Rat-1 fibroblast cell line. Oxygen deprivation conditions (0.2% and 1% O2) were achieved in a humidified anaerobic workstation at 37 °C for 6 or 24 hours. Protein concentration was determined by the Lawry assay method. Immunoblots for c-myc and p21waf and p27 were performed. Results: c-myc (+/+) samples collected after 6 hours of hypoxia, which were supposed to be slowly proliferating, showed lower p21waf and p27 levels than c-myc (-/-). Over 24 hours of hypoxia, cell cultures were supposed to be oxygen-dependent and we found higher CDKI levels in c-myc (+/+) cells. Discussion: Our data could explain same resistance mechanisms of tumours cells. In fact, 6 hours O2-deprived-cells, which are unable to supply autonomous O2 support (neo-angiogenesis, in vivo), downregulated p21waf and p27 expression to overcome CDKI cell-cycle arrest. When the cells acquired O2-dependent growth mechanism, low O2 level induced c-myc mediated p21waf and p27 up-regulation to induce cell cycle arrest. Despite the up-regulation of CDKI, PS 341 (a proteasome inhibitors) has been demonstrated to induce apoptosis. Our data kindly encouraging trials on the use of p21waf and p27 stabilizers (like PS 341) in those tumours which overexpressed c-myc. No significant financial relationships to disclose.

Sensory acceptable equivalent doses of β-phenylethyl isothiocyanate (PEITC) induce cell cycle arrest and retard the growth of p53 mutated oral cancer in vitro and in vivo

2018 ◽  
Vol 9 (7) ◽  
pp. 3640-3656 ◽  
Author(s):  
Aroonwan Lam-ubol ◽  
Alison Lea Fitzgerald ◽  
Arnat Ritdej ◽  
Tawaree Phonyiam ◽  
Hui Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Oral Cancer ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Induce Cell Cycle Arrest ◽  
Cycle Arrest ◽  
Oral Cancer Cells ◽  
Phenylethyl Isothiocyanate

Sensory acceptable doses of PEITC are selectively toxic to oral cancer cells via ROS-mediated cell cycle arrest.

scholarly journals miR-422a inhibits osteosarcoma proliferation by targeting BCL2L2 and KRAS

2018 ◽  
Vol 38 (2) ◽  
Author(s):  
Hao Zhang ◽  
Qian-Yun He ◽  
Guang-Chao Wang ◽  
Da-Ke Tong ◽  
Ren-Kai Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Underlying Mechanism ◽  
Clinical Samples ◽  
Osteosarcoma Cell ◽  
Osteosarcoma Cells ◽  
Induce Cell Cycle Arrest ◽  
Cycle Arrest

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. However, the underlying mechanism of osteosarcoma carcinogenesis and progression remains unknown. In the present study, we evaluated the expression profile of miRNAs in osteosarcoma tissues and the adjacent normal tissues. We found that the expression of miR-422a was down-regulated in osteosarcoma tissues and cell lines. In addition, we observed significantly elevated levels of repressive H3K9me3 and H3K27me3 and decreased active H3K4me3 on the promote region of miR-422a in osteosarcoma cells and clinical samples. Furthermore, up-regulation of miR-422a exhibited both in vitro and in vivo anti-tumor effects by inhibiting osteosarcoma cell growth and inducing apoptosis and cell cycle arrest. We also found that miR-422a targeted BCL2L2 and KRAS and negatively regulated their protein expression. Furthermore, restoration of miR-422a and knockdown of BCL2L2 and KRAS promoted apoptosis and induce cell cycle arrest in osteosarcoma cells. Taken together, the present study demonstrates that miR-422a may serve as a tumor suppressor in osteosarcoma via inhibiting BCL2L2 and KRAS translation both in vitro and in vivo. Therefore, miR-422a could be developed as a novel therapeutic target in osteosarcoma.

scholarly journals A Marine Alkaloid, Ascomylactam A, Suppresses Lung Tumorigenesis via Inducing Cell Cycle G1/S Arrest through ROS/Akt/Rb Pathway

Marine Drugs ◽  
2020 ◽  
Vol 18 (10) ◽  
pp. 494
Author(s):  
Lan Wang ◽  
Yun Huang ◽  
Cui-hong Huang ◽  
Jian-chen Yu ◽  
Ying-chun Zheng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Molecular Mechanisms ◽  
Soft Agar ◽  
Ros Generation ◽  
Induce Cell Cycle Arrest ◽  
Cycle Arrest

Ascomylactam A was reported for the first time as a new 13-membered-ring macrocyclic alkaloid in 2019 from the mangrove endophytic fungus Didymella sp. CYSK-4 from the South China Sea. The aim of our study was to delineate the effects of ascomylactam A (AsA) on lung cancer cells and explore the antitumor molecular mechanisms underlying of AsA. In vitro, AsA markedly inhibited the cell proliferation with half-maximal inhibitory concentration (IC50) values from 4 to 8 μM on six lung cancer cell lines, respectively. In vivo, AsA suppressed the tumor growth of A549, NCI-H460 and NCI-H1975 xenografts significantly in mice. Furthermore, by analyses of the soft agar colony formation, 5-ethynyl-20-deoxyuridine (EdU) assay, reactive oxygen species (ROS) imaging, flow cytometry and Western blotting, AsA demonstrated the ability to induce cell cycle arrest in G1 and G1/S phases by increasing ROS generation and decreasing of Akt activity. Conversely, ROS inhibitors and overexpression of Akt could decrease cell growth inhibition and cell cycle arrest induced by AsA. Therefore, we believe that AsA blocks the cell cycle via an ROS-dependent Akt/Cyclin D1/Rb signaling pathway, which consequently leads to the observed antitumor effect both in vitro and in vivo. Our results suggest a novel leading compound for antitumor drug development.

N6-Isopentenyladenosine and its Analogue N6-Benzyladenosine Induce Cell Cycle Arrest and Apoptosis in Bladder Carcinoma T24 Cells

2013 ◽  
Vol 13 (4) ◽  
pp. 672-678 ◽  
Author(s):  
Sara Castiglioni ◽  
Silvana Casati ◽  
Roberta Ottria ◽  
Pierangela Ciuffreda ◽  
Jeanette A.M. Maier
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Bladder Carcinoma ◽  
Induce Cell Cycle Arrest ◽  
Cycle Arrest ◽  
T24 Cells

Trichosanthes dioica seed lectin inhibits Ehrlich ascites carcinoma cells growth in vivo in mice by inducing G 0 /G 1 cell cycle arrest

2021 ◽  
Author(s):  
Shaikh Shohidul Islam ◽  
Md. Rezaul Karim ◽  
A. K. M. Asaduzzaman ◽  
A. H. M. Khurshid Alam ◽  
Zahid Hayat Mahmud ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Ehrlich Ascites Carcinoma ◽  
Carcinoma Cells ◽  
Cycle Arrest ◽  
Ehrlich Ascites ◽  
Trichosanthes Dioica

scholarly journals Selective Inhibition of Aurora Kinase A by AK-01/LY3295668 Attenuates MCC Tumor Growth by Inducing MCC Cell Cycle Arrest and Apoptosis

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3708
Author(s):  
Bhaba K. Das ◽  
Aarthi Kannan ◽  
Quy Nguyen ◽  
Jyoti Gogoi ◽  
Haibo Zhao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Standard Of Care ◽  
Aurora Kinase ◽  
Selective Inhibition ◽  
Potential Candidate ◽  
Cycle Arrest

Merkel cell carcinoma (MCC) is an often-lethal skin cancer with increasing incidence and limited treatment options. Although immune checkpoint inhibitors (ICI) have become the standard of care in advanced MCC, 50% of all MCC patients are ineligible for ICIs, and amongst those treated, many patients develop resistance. There is no therapeutic alternative for these patients, highlighting the urgent clinical need for alternative therapeutic strategies. Using patient-derived genetic insights and data generated in our lab, we identified aurora kinase as a promising therapeutic target for MCC. In this study, we examined the efficacy of the recently developed and highly selective AURKA inhibitor, AK-01 (LY3295668), in six patient-derived MCC cell lines and two MCC cell-line-derived xenograft mouse models. We found that AK-01 potently suppresses MCC survival through apoptosis and cell cycle arrest, particularly in MCPyV-negative MCC cells without RB expression. Despite the challenge posed by its short in vivo durability upon discontinuation, the swift and substantial tumor suppression with low toxicity makes AK-01 a strong potential candidate for MCC management, particularly in combination with existing regimens.

scholarly journals Novel Benzenesulfonate Scaffolds with a High Anticancer Activity and G2/M Cell Cycle Arrest

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1790
Author(s):  
Katarzyna Malarz ◽  
Jacek Mularski ◽  
Michał Kuczak ◽  
Anna Mrozek-Wilczkiewicz ◽  
Robert Musiol
Keyword(s):  
Cell Cycle ◽  
Anticancer Activity ◽  
Cell Cycle Arrest ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
P53 Protein ◽  
Structural Similarity ◽  
M Cell ◽  
Cycle Arrest ◽  
Small Series

Sulfonates, unlike their derivatives, sulphonamides, have rarely been investigated for their anticancer activity. Unlike the well-known sulphonamides, esters are mainly used as convenient intermediates in a synthesis. Here, we present the first in-depth investigation of quinazoline sulfonates. A small series of derivatives were synthesized and tested for their anticancer activity. Based on their structural similarity, these compounds resemble tyrosine kinase inhibitors and the p53 reactivator CP-31398. Their biological activity profile, however, was more related to sulphonamides because there was a strong cell cycle arrest in the G2/M phase. Further investigation revealed a multitargeted mechanism of the action that corresponded to the p53 protein status in the cell. Although the compounds expressed a high submicromolar activity against leukemia and colon cancers, pancreatic cancer and glioblastoma were also susceptible. Apoptosis and autophagy were confirmed as the cell death modes that corresponded with the inhibition of metabolic activity and the activation of the p53-dependent and p53-independent pathways. Namely, there was a strong activation of the p62 protein and GADD44. Other proteins such as cdc2 were also expressed at a higher level. Moreover, the classical caspase-dependent pathway in leukemia was observed at a lower concentration, which again confirmed a multitargeted mechanism. It can therefore be concluded that the sulfonates of quinazolines can be regarded as promising scaffolds for developing anticancer agents.

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