scholarly journals The Anti-Tumor Activity of the NEDD8 Inhibitor Pevonedistat in Neuroblastoma

2021 ◽  
Vol 22 (12) ◽  
pp. 6565
Author(s):  
Jennifer H. Foster ◽  
Eveline Barbieri ◽  
Linna Zhang ◽  
Kathleen A. Scorsone ◽  
Myrthala Moreno-Smith ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Neuroblastoma Cell ◽  
Wild Type ◽  
Tumor Weight ◽  
Cycle Arrest ◽  
P53 Status ◽  
Neuroblastoma Cell Lines ◽  
Anti Tumor Activity

Pevonedistat is a neddylation inhibitor that blocks proteasomal degradation of cullin–RING ligase (CRL) proteins involved in the degradation of short-lived regulatory proteins, including those involved with cell-cycle regulation. We determined the sensitivity and mechanism of action of pevonedistat cytotoxicity in neuroblastoma. Pevonedistat cytotoxicity was assessed using cell viability assays and apoptosis. We examined mechanisms of action using flow cytometry, bromodeoxyuridine (BrDU) and immunoblots. Orthotopic mouse xenografts of human neuroblastoma were generated to assess in vivo anti-tumor activity. Neuroblastoma cell lines were very sensitive to pevonedistat (IC50 136–400 nM). The mechanism of pevonedistat cytotoxicity depended on p53 status. Neuroblastoma cells with mutant (p53MUT) or reduced levels of wild-type p53 (p53si-p53) underwent G2-M cell-cycle arrest with rereplication, whereas p53 wild-type (p53WT) cell lines underwent G0-G1 cell-cycle arrest and apoptosis. In orthotopic neuroblastoma models, pevonedistat decreased tumor weight independent of p53 status. Control mice had an average tumor weight of 1.6 mg + 0.8 mg versus 0.5 mg + 0.4 mg (p < 0.05) in mice treated with pevonedistat. The mechanism of action of pevonedistat in neuroblastoma cell lines in vitro appears p53 dependent. However, in vivo studies using mouse neuroblastoma orthotopic models showed a significant decrease in tumor weight following pevonedistat treatment independent of the p53 status. Novel chemotherapy agents, such as the NEDD8-activating enzyme (NAE) inhibitor pevonedistat, deserve further study in the treatment of neuroblastoma.

MCPIP1 overexpression in human neuroblastoma cell lines causes cell‐cycle arrest by G1/S checkpoint block

2020 ◽  
Vol 121 (5-6) ◽  
pp. 3406-3425 ◽  
Author(s):  
Elżbieta Boratyn ◽  
Iwona Nowak ◽  
Elżbieta Karnas ◽  
Damian Ryszawy ◽  
Dawid Wnuk ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Neuroblastoma Cell ◽  
Human Neuroblastoma Cell ◽  
Human Neuroblastoma ◽  
Cycle Arrest ◽  
Neuroblastoma Cell Lines

Guanine nucleotide depletion triggers cell cycle arrest and apoptosis in human neuroblastoma cell lines

2003 ◽  
Vol 108 (6) ◽  
pp. 812-817 ◽  
Author(s):  
Elisa Messina ◽  
Paola Gazzaniga ◽  
Vanna Micheli ◽  
Maria Rosaria Guaglianone ◽  
Silvia Barbato ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Neuroblastoma Cell ◽  
Human Neuroblastoma Cell ◽  
Guanine Nucleotide ◽  
Human Neuroblastoma ◽  
Cycle Arrest ◽  
Neuroblastoma Cell Lines

scholarly journals Menadione reduces CDC25B expression and promotes tumor shrinkage in gastric cancer

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.

scholarly journals Cyperus articulatus L. (Cyperaceae) Rhizome Essential Oil Causes Cell Cycle Arrest in the G2/M Phase and Cell Death in HepG2 Cells and Inhibits the Development of Tumors in a Xenograft Model

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2687
Author(s):  
Mateus L. Nogueira ◽  
Emilly J. S. P. de Lima ◽  
Asenate A. X. Adrião ◽  
Sheila S. Fontes ◽  
Valdenizia R. Silva ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Gas Chromatography ◽  
Cell Death ◽  
Liver Cancer ◽  
Essential Oil ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Hepg2 Cells ◽  
Cycle Arrest

Cyperus articulatus L. (Cyperaceae), popularly known in Brazil as “priprioca” or “piriprioca”, is a tropical and subtropical plant used in popular medical practices to treat many diseases, including cancer. In this study, C. articulatus rhizome essential oil (EO), collected from the Brazilian Amazon rainforest, was addressed in relation to its chemical composition, induction of cell death in vitro and inhibition of tumor development in vivo, using human hepatocellular carcinoma HepG2 cells as a cell model. EO was obtained by hydrodistillation using a Clevenger-type apparatus and characterized qualitatively and quantitatively by gas chromatography coupled to mass spectrometry (GC-MS) and gas chromatography with flame ionization detection (GC-FID), respectively. The cytotoxic activity of EO was examined against five cancer cell lines (HepG2, HCT116, MCF-7, HL-60 and B16-F10) and one non-cancerous one (MRC-5) using the Alamar blue assay. Cell cycle distribution and cell death were investigated using flow cytometry in HepG2 cells treated with EO after 24, 48 and 72 h of incubation. The cells were also stained with May–Grunwald–Giemsa to analyze the morphological changes. The anti-liver-cancer activity of EO in vivo was evaluated in C.B-17 severe combined immunodeficient (SCID) mice with HepG2 cell xenografts. The main representative substances of this EO sample were muskatone (11.6%), cyclocolorenone (10.3%), α-pinene (8.26%), pogostol (6.36%), α-copaene (4.83%) and caryophyllene oxide (4.82%). EO showed IC50 values for cancer cell lines ranging from 28.5 µg/mL for HepG2 to >50 µg/mL for HCT116, and an IC50 value for non-cancerous of 46.0 µg/mL (MRC-5), showing selectivity indices below 2-fold for all cancer cells tested. HepG2 cells treated with EO showed cell cycle arrest at G2/M along with internucleosomal DNA fragmentation. The morphological alterations included cell shrinkage and chromatin condensation. Treatment with EO also increased the percentage of apoptotic-like cells. The in vivo tumor mass inhibition rates of EO were 46.5–50.0%. The results obtained indicate the anti-liver-cancer potential of C. articulatus rhizome EO.

scholarly journals Effect of Piceatannol on Cell Cycle Progression in Prostate Cancer Cells (P05-005-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Larissa Kido ◽  
Eun-Ryeong Hahm ◽  
Valeria Cagnon ◽  
Mário Maróstica ◽  
Shivendra Singh
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Cell Cycle Distribution ◽  
Mutant P53 ◽  
Wild Type ◽  
Cycle Progression ◽  
Cycle Arrest

Abstract Objectives Piceatannol (PIC) is a polyphenolic and resveratrol analog that is found in many vegetables consumed by humans. Like resveratrol, PIC has beneficial effects on health due to its anti-inflammatory, anti-oxidative and anti-proliferative features. However, the molecular targets of PIC in prostate cancer (PCa), which is the second most common cancer in men worldwide, are still poorly understood. Preventing cancer through dietary sources is a promising strategy to control diseases. Therefore, the aim of present study was to investigate the molecular mechanistic of actions of PIC in PCa cell lines with different genetic background common to human prostate cancer. Methods Human PCa cell lines (PC-3, 22Rv1, LNCaP, and VCaP) were treated with different doses of PIC (5–40 µM) and used for cell viability assay, measurement of total free fatty acids (FFA) and lactate, and cell cycle distribution. Results PIC treatment dose- and time-dependently reduced viability in PC-3 (androgen-independent, PTEN null, p53 null) and VCaP cells (androgen-responsive, wild-type PTEN, mutant p53). Because metabolic alterations, such as increased glucose and lipid metabolism are implicated in pathogenesis of in PCa, we tested if PIC could affect these pathways. Results from lactate and total free fatty acid assays in VCaP, 22Rv1 (castration-resistant, wild-type PTEN, mutant p53), and LNCaP (androgen-responsive, PTEN null, wild-type p53) revealed no effect of PIC on these metabolisms. However, PIC treatment delayed cell cycle progression in G0/G1 phase concomitant with the induction of apoptosis in both LNCaP and 22Rv1 cells, suggesting that growth inhibitory effect of PIC in PCa is associated with cell cycle arrest and apoptotic cell death at least LNCaP and 22Rv1 cells. Conclusions While PIC treatment does not alter lipid or glucose metabolism, cell cycle arrest and apoptosis induction are likely important in anti-cancer effects of PIC. Funding Sources São Paulo Research Foundation (2018/09793-7).

Effect of the specific P53 stabilizer CBS9106 on multiple myeloma (MM)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8601-8601
Author(s):  
H. Ikeda ◽  
T. Hideshima ◽  
G. Perrone ◽  
Y. Okawa ◽  
N. Raje ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Protein Expression ◽  
Tumor Cells ◽  
Cell Lines ◽  
Primary Tumor ◽  
P53 Protein ◽  
Wild Type ◽  
Cycle Arrest ◽  
P53 Protein Expression

8601 Background: The mutations of P53 tumor suppressor protein are associated with progressive in Multiple Myeloma (MM), conversely, stabilization of P53 leads to cell cycle arrest and apoptosis. In this study, we examined p53 protein expression and demonstrated the effect of P53 stabilization using a novel specific P53 stabilizer CBS9106 in MM. Method: We examined P53 protein expression using Immunoblot analysis, as well as the growth inhibitory effect of CBS9106 in MM cell lines and primary tumor cells from MM patients. We also defined whether CBS9106 can overcome the growth promoting effect of exogenous cytokines and bone marrow stroma cells (BMSCs) using [3H]-thymidine uptake assay. Results: Expression of P53 protein was observed in 3/3 primary tumor cells from MM patients and 6/6 MM cell lines. CBS9106 at low nM levels triggered cytotoxicity against p53 wild type MM cell lines and primary tumor cells from MM patients, associated with phosphorylation of P53 (serine15 and 20). In contrast, CBS9106 did not affect the survival of normal peripheral blood mononuclear cells from healthy volunteers at concentrations as high as 10 μM. This agent also induced G1 cell cycle arrest, followed by apoptosis associated with cleavage of caspase-3, -8, -9 and PARP. Neither growth stimulating cytokines (IL-6 and IGF-1) nor BMSCs protected against apoptotic effect of CBS9106. Moreover, we demonstrate that combination of CBS9106 with MDM2 inhibitor Nutrin3 or proteasome inhibitor bortezomib induces synergistic anti-MM activity in both P53 wild type MM cell lines and primary tumor cells from MM patients. Conclusions: Stabilizing P53 by CBS9106 represents a novel promising p53-based therapy in MM. These results provide the preclinical framework supporting evaluation of CBS9106 in clinical trials to improve patient outcome in MM. No significant financial relationships to disclose.

scholarly journals ALT Neuroblastoma Chemoresistance due to ATM Activation by Telomere Dysfunction is Reversible with the ATM Inhibitor AZD0156

2021 ◽  
Author(s):  
Balakrishna Koneru ◽  
Ahsan Farooqi ◽  
Thinhh H. Nguyen ◽  
Wan Hsi Chen ◽  
Ashly Hindle ◽  
...  
Keyword(s):  
Cell Lines ◽  
De Novo ◽  
Clinical Stage ◽  
Neuroblastoma Cell ◽  
Telomere Dysfunction ◽  
Atm Kinase ◽  
Kinase Activation ◽  
Neuroblastoma Cell Lines

AbstractCancers overcome replicative immortality by activating either telomerase or an alternative lengthening of telomeres (ALT) mechanism. ALT occurs in ∼ 25% of high-risk neuroblastomas and relapse or progression in ALT neuroblastoma patients during or after front-line therapy is frequent and almost uniformly fatal. Temozolomide + irinotecan is commonly used as salvage therapy for neuroblastoma. Patient-derived cell-lines and xenografts established from relapsed ALT neuroblastoma patients demonstrated de novo resistance to temozolomide + irinotecan (as SN-38 in vitro, P<0.05) and in vivo (mouse event-free survival (EFS) P<0.0001) relative to telomerase-positive neuroblastomas. We observed that ALT neuroblastoma cells manifest constitutive ATM kinase activation due to spontaneous telomere dysfunction while telomerase- positive tumors lacked constitutive ATM activation or spontaneous telomere DNA damage. We demonstrated that induction of telomere dysfunction resulted in ATM activation that in turn conferred resistance to temozolomide + SN-38 (4.2 fold-change in IC50, P<0.001). ATM kinase shRNA knock-down or inhibition using a clinical-stage small molecule inhibitor (AZD0156) reversed resistance to temozolomide + irinotecan in ALT neuroblastoma cell-lines in vitro (P<0.001) and in 4 ALT xenografts in vivo (EFS P<0.0001). AZD0156 showed modest to no enhancement of temozolomide + irinotecan activity in telomerase-positive neuroblastoma cell lines and xenografts. ATR inhibition using AZD6738 did not enhance temozolomide + SN-38 activity in ALT neuroblastoma cell lines. Thus, resistance to chemotherapy in ALT neuroblastoma occurs via ATM kinase activation and was reversed with the ATM inhibitor AZD0156. Combining AZD0156 with temozolomide + irinotecan warrants clinical testing in neuroblastoma.One Statement SummaryATM activation at telomeres confers resistance to DNA damaging chemotherapy in ALT neuroblastoma that was reversed with ATM knockdown or inhibition.

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