Neddylation inhibitor MLN4924 induces G2 cell cycle arrest, DNA damage and sensitizes esophageal squamous cell carcinoma cells to cisplatin

Lin, Shan; Shang, Zhaoyang; Li, Shuo; Gao, Peng; Zhang, Yi; Hou, Shuaiheng; Qin, Peng; Dong, Ziming; Hu, Tao; Chen, Ping

doi:10.3892/ol.2017.7616

Cited by 19 publications

(25 citation statements)

References 34 publications

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“…As MLN4924 and cisplatin are both known to induce DNA damage and are used in clinical practice for the treatment of specific malignancies, the effects of combined MLN4924 and cisplatin treatment on pancreatic cancer cells were investigated in the present study. This hypothesis was verified in esophageal squamous cell carcinoma (24). The results demonstrated that MLN4924 + cisplatin treatment significantly suppressed pancreatic cancer growth both in vitro and in vivo, and that combined treatment was well tolerated by the mice.…”

Section: Discussionmentioning

confidence: 60%

An overactive neddylation pathway serves as a therapeutic target and MLN4924 enhances the anticancer activity of cisplatin in pancreatic cancer

Zeng

Pan

et al. 2019

Oncol Lett

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The survival rate of patients with pancreatic cancer is between 3 and 5%. The neddylation pathway is overactive in multiple cancer types and is associated with poor prognosis. In recent years, the neddylation process has become a popular research target for the development of novel cancer therapies. However, the activation level of the pathway, and whether its targeting sensitizes pancreatic cancer cells to cisplatin treatment is currently unclear. In the present study, using reverse transcription-quantitative PCR and western blot analyses, the neddylation pathway was observed to be overactivated at the protein, but not the mRNA level. In addition, by analyzing The Cancer Genome Atlas data, it was demonstrated that high expression levels of NEDD8 activating enzyme E1 subunit 1 were observed to be a predictor of poor prognosis for patients with pancreatic cancer. Cisplatin enhanced the cytotoxic effects of MLN4924 both in vitro and in vivo according to Cell Counting kit-8 assays and an in vivo tumor model. Further mechanistic studies, including western blotting and immunohistochemistry assays, revealed that combined MLN4924 and cisplatin treatment induced higher levels of DNA damage by increasing the accumulation of well-defined cullin-ring ligase substrates, such as chromatin licensing and DNA replication factor 1, origin recognition complex subunit 1, p21, p27 and phosphorylated IκBα. The results of the present study support the clinical use of combined neddylation inhibitor and cisplatin treatment, which may improve the survival of, and impart other benefits for patients with pancreatic cancer.

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Section: Discussionmentioning

confidence: 60%

An overactive neddylation pathway serves as a therapeutic target and MLN4924 enhances the anticancer activity of cisplatin in pancreatic cancer

Zeng

Pan

et al. 2019

Oncol Lett

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“…Evasion of cell cycle arrest is most frequently observed in tumor development [ 34 , 35 ]. One of the anticancer mechanisms of chemotherapeutic agents is the induction of cell cycle arrest in cancer cells [ 36 , 37 ]. It has been reported that the combination of other agents with DDP significantly induces various levels of cell cycle arrest in OS cells [ 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

Synergistic inhibitory effects of capsaicin combined with cisplatin on human osteosarcoma in culture and in xenografts

Wang

Deng

Chang

et al. 2018

J Exp Clin Cancer Res

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BackgroundThe combination of phytochemicals with chemotherapy drugs is an emerging new strategy for cancer therapy to increase antitumor responses.MethodsThe present study investigates the effect of the combination of capsaicin (CAP) with cisplatin (DDP) and the potential underlying anticancer mechanisms in osteosarcoma (OS) cells in vitro and in vivo.ResultsCell viability assays and isobolographic analyses demonstrated that the combination of CAP and DDP showed synergistic cytotoxic effects on OS cells. We chose relatively low concentrations of CAP (100 μM) and DDP (16.7 μM) for subsequent experiments. Generally, the combination of CAP and DDP had significant effects on apoptosis induction, cell cycle arrest and cell invasion inhibition in OS cells compared with the individual-treatment groups and the control group. Moreover, cotreatment with CAP and DDP triggered prosurvival autophagy through reactive oxygen species (ROS)/JNK and p-AKT/mTOR signaling in OS cells. The combination regimen of CAP and DDP also inhibited tumor growth in an OS xenograft model.ConclusionThese results suggest that the combination of CAP and DDP has strong inhibitory effects on OS cells and identify CAP as a promising agent for supplementing standard chemotherapy and possible future targeted therapy in OS.

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“…The CCK-8 and colony-forming experiments performed in the present study demonstrated that simvastatin significantly inhibited the proliferation of SACC-83 cells in a time- and concentration-dependent manner. Cancer cell proliferation is usually accompanied by cell cycle arrest, and cell cycle progression is modulated by cyclin-dependent kinase inhibitors ( 41 , 42 ). In the present study, an increased number of SACC-83 cells were arrested at the G 1 phase following simvastatin treatment; however, further investigation is required to elucidate the underlying mechanisms involved.…”

Section: Discussionmentioning

confidence: 99%

Effect of survivin downregulation by simvastatin on the growth and invasion of salivary adenoid cystic carcinoma

et al. 2018

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Simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, is been used in the clinic due to its pleiotropic effects, such as breast cancer, prostate cancer, pancreatic cancer. Simvastatin has recently been demonstrated to serve a potential role in the prophylaxis and therapeutics of a number of human cancers. The majority of reports concerning simvastatin treatment in the majority of human cancers have demonstrated that survivin is significantly decreased as a result and has been implicated in tumorigenesis. However, only a limited number of studies have investigated the use of simvastatin for the treatment of salivary gland adenoid cystic carcinoma (SACC). Therefore, this agent is a candidate for further investigation. The aim of the present study was to investigate the effects of simvastatin on the proliferation, invasion and apoptosis of the human salivary adenoid cystic carcinoma cell line, SACC-83, as well as survivin expression in the cells. The Cell Counting kit-8 assay results revealed that simvastatin inhibited the proliferation of SACC-83 cells in a dose-dependent (10 to 50 µM) and time-dependent (24 to 48 h) manner when compared with the untreated cells. Flow cytometry analysis indicated that simvastatin increased the percentage of cells in early and late apoptosis. Invasion assays revealed that simvastatin treatment inhibited the invasiveness of SACC-83 cells in a dose-dependent manner. In addition, simvastatin downregulated survivin expression in SACC-83 cells. In conclusion, simvastatin significantly inhibited the proliferation and invasion of SACC-83 cells, induced apoptosis, and reduced the expression of survivin, which suggests that simvastatin may be a novel target for SACC therapy.

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Neddylation inhibitor MLN4924 induces G2 cell cycle arrest, DNA damage and sensitizes esophageal squamous cell carcinoma cells to cisplatin

Cited by 19 publications

References 34 publications

An overactive neddylation pathway serves as a therapeutic target and MLN4924 enhances the anticancer activity of cisplatin in pancreatic cancer

An overactive neddylation pathway serves as a therapeutic target and MLN4924 enhances the anticancer activity of cisplatin in pancreatic cancer

Synergistic inhibitory effects of capsaicin combined with cisplatin on human osteosarcoma in culture and in xenografts

Effect of survivin downregulation by simvastatin on the growth and invasion of salivary adenoid cystic carcinoma

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