Novel proteasome inhibitor ixazomib sensitizes neuroblastoma cells to doxorubicin treatment

Li, Haoyu; Chen, Zhenghu; Hu, Tian; Wang, Long; Ye, Yu; Zhao, Yanling; Sun, Wenijing; Guan, Shan; Pang, Ji‐Jie; Woodfield, Sarah E.; Liu, Qing; Yang, Jianhua

doi:10.1038/srep34397

Cited by 21 publications

(19 citation statements)

References 47 publications

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“…The experiments were performed as described previously4647. Briefly, after each treatment, cells were washed twice with ice cold PBS and then lysed on a rotator at 4 °C for 30 min in cooled RIPA buffer (50 mM Tris-HCl at pH 7.4, 150 mM NaCl, 1 mM EDTA, 1% NP-40, 0.25% sodium deoxycholate, 1 mM phenylmethylsulfonyl fluoride, 1 mM benzamidine, 10 μg/mL leupeptin, 1 mM dithiothreitol, 50 mM sodium fluoride, 0.1 mM sodium orthovanadate, and phosphatase inhibitor cocktail 2 and 3 (p5726 and p0044, Sigma)).…”

Section: Methodsmentioning

confidence: 99%

Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis

Chen

Wang

Yao

et al. 2016

Sci Rep

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Neuroblastoma (NB) is the most common extracranial tumor in children. Unlike in most adult tumors, tumor suppressor protein 53 (p53) mutations occur with a relatively low frequency in NB and the downstream function of p53 is intact in NB cell lines. Wip1 is a negative regulator of p53 and hindrance of Wip1 activity by novel inhibitor GSK2830371 is a potential strategy to activate p53’s tumor suppressing function in NB. Yet, the in vivo efficacy and the possible mechanisms of GSK2830371 in NB have not yet been elucidated. Here we report that novel Wip1 inhibitor GSK2830371 induced Chk2/p53-mediated apoptosis in NB cells in a p53-dependent manner. In addition, GSK2830371 suppressed the colony-formation potential of p53 wild-type NB cell lines. Furthermore, GSK2830371 enhanced doxorubicin- (Dox) and etoposide- (VP-16) induced cytotoxicity in a subset of NB cell lines, including the chemoresistant LA-N-6 cell line. More importantly, GSK2830371 significantly inhibited tumor growth in an orthotopic xenograft NB mouse model by inducing Chk2/p53-mediated apoptosis in vivo. Taken together, this study suggests that GSK2830371 induces Chk2/p53-mediated apoptosis both in vitro and in vivo in a p53 dependent manner.

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Section: Methodsmentioning

confidence: 99%

Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis

Chen

Wang

Yao

et al. 2016

Sci Rep

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“…Ixazomib is a selective second-generation proteasome inhibitor able to enhance the Dox cytotoxicity (Figure 4) and capable to inhibit Dox-induced NF-κB activation [59]. Li and colleagues demonstrated the anti-tumor efficacy of Ixazomib in combination with Dox corroborating the hypothesis that combination therapies of proteasome inhibitors and chemotherapeutic agents will achieve better outcomes in neuroblastoma therapy.…”

Section: Combined Therapy With Proteasome Inhibitormentioning

confidence: 62%

Epigenetic Approaches in Neuroblastoma Disease Pathogenesis

Caputi¹,

Candeletti²,

Romualdi³

2017

Neuroblastoma - Current State and Recent Updates

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Neuroblastoma is an embryonal extracranial solid tumor originating from undifferentiated neural crest cell and it is the most common among children. Neuroblastoma is highly heterogeneous, and on these bases different outcomes are observed across the subtypes. Its clinical impact (~13% of all pediatric cancer mortality) has made this aggressive malignancy the focus of a considerable translational research effort. New insights into tumor biology are leading to the development of novel therapeutic approaches, which include small-molecule inhibitors as well as epigenetic approaches, noncoding-RNA, and cell-based immunologic therapies. Recently, chromatin immunoprecipitation with high-throughput sequencing and RNA-sequencing studies have demonstrated that epigenetic changes contribute to the aggressive pathophysiology of pediatric neuroblastoma disease. Epigenetic abnormalities are feature of human cancer cells and the epigenetic alterations may be the key toward tumorigenesis. In particular, the increase of deacetylation has been involved in epigenetically mediated tumor-suppressor gene silencing. In addition, several studies evaluated the 5-methylcytosine (5 mC) distribution patterns, which distinguish cancer cells from normal cells, and how CpG methylation contributes to the oncogenic phenotype.In particular, histone changes and DNA methylation are fundamental biological processes representing versatile candidates for pharmacological manipulation with important therapeutic advantages.

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“… 15 It not only achieved satisfactory clinical outcomes in MM patients but also showed obvious anticancer effects against multiple tumors including chronic lymphocytic leukemia, prostate cancer, breast cancer, and neuroblastoma. 16 – 19 However, researches focusing on the antitumor effects of ixazomib on CRC are limited, and the anti-CRC mechanisms of ixazomib remain far more to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Identification of the anticancer effects of a novel proteasome inhibitor, ixazomib, on colorectal cancer using a combined method of microarray and bioinformatics analysis

Fan¹,

Liu²

2017

OTT

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PurposeThe study aimed to explore the anticancer effects of a novel proteasome inhibitor, ixazomib, on colorectal cancer (CRC) using a combined method of microarray and bioinformatics analysis.Materials and methodsCell proliferation was tested by Cell Counting Kit-8 (CCK-8) assay for SW620 cells treated with different concentrations of ixazomib and different treatment times. The microarray analysis was conducted for six samples, including three samples of SW620 cells untreated with ixazomib and three samples of SW620 cells treated with ixazomib. The differentially expressed genes (DEGs) between untreated and treated samples were identified by the Linear Models for Microarray data (LIMMA) package in R language. The Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed for the DEGs using the Database for Annotation, Visualization and Integrated Discovery (DAVID) and KEGG Orthology-Based Annotation System (KOBAS) online tool. The protein–protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and module analysis was performed for the PPI network.ResultsIxazomib could inhibit the proliferation of SW620 cells in a dose-dependent and time-dependent manner. A total of 743 DEGs, including 203 upregulated DEGs such as HSPA6 and 540 downregulated DEGs such as APCDD1, were identified. Eighty-three GO terms were enriched for DEGs, which were mainly related to protein folding, apoptotic process, transcription factor activity, and proteasome. Thirty-seven KEGG pathways were perturbed, including pathway of apoptosis and cell cycle. Forty-six hub genes, such as TP53, JUN, and ITGA2, were screened out, and three modules with important functions were mined from the PPI network.ConclusionThe novel proteasome inhibitor ixazomib significantly inhibited the proliferation of human CRC SW620 cells. It exerted anticancer effects through targeting the expression of DEGs, such as HSPA6, APCDD1, TP53, and JUN, and affecting the signaling pathways including apoptosis and cell cycle pathway, which demonstrated the promising potential of ixazomib for CRC therapy.

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Novel proteasome inhibitor ixazomib sensitizes neuroblastoma cells to doxorubicin treatment

Cited by 21 publications

References 47 publications

Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis

Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis

Epigenetic Approaches in Neuroblastoma Disease Pathogenesis

Identification of the anticancer effects of a novel proteasome inhibitor, ixazomib, on colorectal cancer using a combined method of microarray and bioinformatics analysis

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