p53 status, cellular recovery and cell cycle arrest as prognosticators of in vitro radiosensitivity in human pancreatic adenocarcinoma cell lines

Oleiferasaponin C6 was isolated from Camellia oleifera Abel. and inhibits proliferation through inducing cell-cycle arrest and apoptosis on cancer cell lines in vitro.

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Menadione reduces CDC25B expression and promotes tumor shrinkage in gastric cancer

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284819895435 ◽

2020 ◽

Vol 13 ◽

pp. 175628481989543

Author(s):

Amanda Braga Bona ◽

Danielle Queiroz Calcagno ◽

Helem Ferreira Ribeiro ◽

José Augusto Pereira Carneiro Muniz ◽

Giovanny Rebouças Pinto ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cell Lines ◽

Specific Inhibitor ◽

Gastric Carcinogenesis ◽

In Vivo Experiments ◽

Cycle Arrest

Background: Gastric cancer is one of the most incident types of cancer worldwide and presents high mortality rates and poor prognosis. MYC oncogene overexpression is a key event in gastric carcinogenesis and it is known that its protein positively regulates CDC25B expression which, in turn, plays an essential role in the cell division cycle progression. Menadione is a synthetic form of vitamin K that acts as a specific inhibitor of the CDC25 family of phosphatases. Methods: To better understand the menadione mechanism of action in gastric cancer, we evaluated its molecular and cellular effects in cell lines and in Sapajus apella, nonhuman primates from the new world which had gastric carcinogenesis induced by N-Methyl-N-nitrosourea. We tested CDC25B expression by western blot and RT-qPCR. In-vitro assays include proliferation, migration, invasion and flow cytometry to analyze cell cycle arrest. In in-vivo experiments, in addition to the expression analyses, we followed the preneoplastic lesions and the tumor progression by ultrasonography, endoscopy, biopsies, histopathology and immunohistochemistry. Results: Our tests demonstrated menadione reducing CDC25B expression in vivo and in vitro. It was able to reduce migration, invasion and proliferation rates, and induce cell cycle arrest in gastric cancer cell lines. Moreover, our in-vivo experiments demonstrated menadione inhibiting tumor development and progression. Conclusions: We suggest this compound may be an important ally of chemotherapeutics in the treatment of gastric cancer. In addition, CDC25B has proven to be an effective target for investigation and development of new therapeutic strategies for this malignancy.

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Cell Cycle Arrest by the Isoprenoids Perillyl Alcohol, Geraniol, and Farnesol Is Mediated by p21Cip1and p27Kip1in Human Pancreatic Adenocarcinoma Cells

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.106.111666 ◽

2006 ◽

Vol 320 (3) ◽

pp. 1163-1170 ◽

Cited By ~ 93

Author(s):

Dean A. Wiseman ◽

Sean R. Werner ◽

Pamela L. Crowell

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Pancreatic Adenocarcinoma ◽

Perillyl Alcohol ◽

Human Pancreatic Adenocarcinoma ◽

Cycle Arrest ◽

Adenocarcinoma Cells

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MKC-1 Is a Novel Agent That Induces Cell Cycle Arrest and Disrupts Multiple Survival Pathways in Hematologic Cancers.

Blood ◽

10.1182/blood.v108.11.4390.4390 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4390-4390

Author(s):

Trisha A. Denny ◽

Xiaoru Chen ◽

Cassandra L. Waters ◽

Patricia A. Burke ◽

Graham C. Fletcher ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Cell Lines ◽

Solid Tumor ◽

Hematopoietic Cell ◽

Cycle Arrest ◽

Survival Pathways ◽

Dose Dependent ◽

Hematopoietic Cell Lines

Abstract MKC-1 is a novel, orally active cell cycle inhibitor with in vitro and in vivo activity against a wide range of human solid tumor cell lines, including multi-drug resistant cell lines. MKC-1 has been tested in over 270 patients to date and is currently in Phase II clinical trials. The strong pre-clinical activity of MKC-1 towards solid tumor lines and signs of efficacy in the initial clinical evaluation with lack of neuropathy and cardiotoxicity suggests that MKC-1 may also be of clinical benefit in the treatment of hematopoietic cancers. The antiproliferative activity of MKC-1 was examined against a panel of hematopoietic cell lines including HL-60, U937, MV4;11, THP-1, Jurkat, and OCI-AML 1–5. MKC-1 showed potent and dose-dependent activity towards these cell lines, with IC50 values in the range of 20 – 400 nM. MKC-1 also inhibited in vitro growth of primary cells derived from AML and CML patients. Additionally, MKC-1 showed enhanced activity with Ara-C in combination studies in vitro when added either simultaneously or sequentially using the cell line OCI-AML 4. Binding studies have shown that MKC-1 binds to the colchicine binding site of tubulin and to members of the importin beta family of proteins. Consistent with these results, cell cycle arrest in the G2/M phase of the cell cycle followed by apoptosis was observed in cell lines and patient samples treated with MKC-1. Immunofluorescence analysis of cells treated with MKC-1 revealed that the drug induced a disruption of the microtubule network and the formation of aberrant mitotic spindles. Furthermore, MKC-1 was also shown to induce a dose-dependent reduction in the levels of both phospho-Akt and phospho-p70S6K kinases through Western blot analysis of treated THP-1 cells. In conclusion, our results indicate MKC-1 arrests the cell cycle and disrupts multiple survival pathways to induce apoptosis in hematopoietic cell lines and patient samples. These results suggest that MKC-1 may have clinical potential in the treatment of leukemia either alone or in combination with other agents. Phase I trials in hematological cancers are currently being explored.

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Selective Loss of TGFβ Smad-Dependent Signalling Prevents Cell Cycle Arrest and Promotes Invasion in Oesophageal Adenocarcinoma Cell Lines

PLoS ONE ◽

10.1371/journal.pone.0000177 ◽

2007 ◽

Vol 2 (1) ◽

pp. e177 ◽

Cited By ~ 22

Author(s):

Benjamin A. Onwuegbusi ◽

Jonathan R.E. Rees ◽

Pierre Lao-Sirieix ◽

Rebecca C. Fitzgerald

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Cell Lines ◽

Oesophageal Adenocarcinoma ◽

Adenocarcinoma Cell ◽

Selective Loss ◽

Cycle Arrest

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Optimized anti–tumor effects of anthracyclines plus Vinca alkaloids using a novel, mechanism-based application schedule

Blood ◽

10.1182/blood-2010-02-269811 ◽

2011 ◽

Vol 118 (23) ◽

pp. 6123-6131 ◽

Cited By ~ 18

Author(s):

Harald Ehrhardt ◽

David Schrembs ◽

Christian Moritz ◽

Franziska Wachter ◽

Subrata Haldar ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Cell Lines ◽

Childhood Leukemia ◽

Underlying Mechanism ◽

Dependent Manner ◽

Vinca Alkaloids ◽

Cycle Arrest ◽

Induced Apoptosis

Abstract Application of anthracyclines and Vinca alkaloids on the same day represents a hallmark of polychemotherapy protocols for hematopoietic malignancies. Here we show, for the first time, that both drugs might act most efficiently if they are applied on different days. Proof-of-concept studies in 18 cell lines revealed that anthracyclines inhibited cell death by Vinca alkaloids in 83% of cell lines. Importantly, in a preclinical mouse model, doxorubicin reduced the anti–tumor effect of vincristine. Both drugs acted in a sequence-dependent manner and the strongest anti–tumor effect was obtained if both drugs were applied on different days. Most notably for clinical relevance, in 34% of 35 fresh primary childhood leukemia cells tested in vitro, doxorubicin reduced the anti–tumor effect of vincristine. As underlying mechanism, doxorubicin activated p53, p53 induced cell-cycle arrest, and cell-cycle arrest disabled inactivation of antiapoptotic Bcl-2 family members by vincristine; therefore, vincristine was unable to activate downstream apoptosis signaling. As molecular proof, antagonism was rescued by knockdown of p53, whereas knockdown of cyclin A inhibited vincristine-induced apoptosis. Our data suggest evaluating anthracyclines and Vinca alkaloids on different days in future trials. Selecting drug combinations based on mechanistic understanding represents a novel conceptional strategy for potent polychemotherapy protocols.

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Cell-cycle arrest and senescence in TP53-wild type renal carcinoma by enhancer RNA-P53-bound enhancer regions 2 (p53BER2) in a p53-dependent pathway

Cell Death and Disease ◽

10.1038/s41419-020-03229-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Haibiao Xie ◽

Kaifang Ma ◽

Kenan Zhang ◽

Jingcheng Zhou ◽

Lei Li ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Cell Lines ◽

Kidney Cancer ◽

Renal Cancer ◽

Wild Type ◽

Enhancer Rna ◽

Cycle Arrest

AbstractTP53 is a classic tumor suppressor, but its role in kidney cancer remains unclear. In our study, we tried to explain the role of p53 in kidney cancer through the p53-related enhancer RNA pathway. Functional experiments were used to explore whether P53-bound enhancer regions 2 (p53BER2) has a role in the cell cycle and senescence response of TP53-wild type (WT) renal cancer cells in vitro or vivo. RNA-sequencing was used to identify the potential target of p53BER2. The results showed that the expression level of P53BER2 was downregulated in renal cancer tissues and cell lines, further dual-luciferase experiments and APR-256-reactivated experiments showed p53BER2 expresses in a p53-dependent way. Moreover, knockdown p53BER2 could reverse nutlin-3-induced cytotoxic effect in TP53-WT cell lines. Further exploration showed the downregulation of p53BER2 could reverse nutlin-3-induced G1-arrest and senescence in TP53-WT cell lines. What is more, the knockdown of p53BER2 showed resistance to nutlin-3 treatment in vivo. Additionally, we found BRCA2 could be regulated by p53BER2 in vitro and vivo; further experiment showed p53BER2 could induce cell-cycle arrest and DNA repair by mediating BRCA2. In summary, the p53-associated enhancer RNA-p53BER2 mediates the cell cycle and senescence of p53 in TP53-WT renal cancer cells.

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