Linked Life Data

20362557

Source:http://linkedlifedata.com/resource/pubmed/id/20362557

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2010-5-10
pubmed:abstractText
Syrbactins belong to a new class of proteasome inhibitors which include syringolins and glidobactins. These small molecules are structurally distinct from other, well-established proteasome inhibitors, and bind the eukaryotic 20S proteasome by a novel mechanism. In this study, we examined the effects of syringolin A (SylA) and glidobactin A (GlbA) as well as two synthetic SylA-analogs (SylA-PEG and SylA-LIP) in human neuroblastoma (SK-N-SH), human multiple myeloma (MM1.S, MM1.RL, and U266), and human ovarian cancer (SKOV-3) cells. While all four syrbactins inhibited cell proliferation in a dose-dependent manner, GlbA was most potent in both dexamethasone-sensitive MM1.S cells (IC(50): 0.004microM) and dexamethasone-resistant MM1.RL cells (IC(50): 0.005microM). Syrbactins also inhibited the chymotrypsin-like proteasome activity in a dose-dependent fashion, and GlbA was most effective in SK-N-SH cells (IC(50): 0.015microM). The GlbA-promoted inhibition of proteasomal activity in SK-N-SH cells resulted in the accumulation of ubiquitinated proteins and tumor suppressor protein p53 and led to apoptotic cell death in a time-dependent manner. GlbA treatment also promoted the activation of Akt/PKB via phosphorylation at residue Ser(473) and induced autophagy as judged by the presence of the lipidated form of microtubule-associated protein 1 light chain 3 (LC3) and autophagosomes. Collectively, our data suggest that syrbactins belong to a new and effective proteasome inhibitor class which promotes cell death. Proteasome inhibition is a promising strategy for targeted anticancer therapy and syrbactins are a new class of inhibitors which provide a structural platform for the development of novel, proteasome inhibitor-based drug therapeutics.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
1873-2968
pubmed:author
pubmed:copyrightInfo
2010 Elsevier Inc. All rights reserved.
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
80
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
170-8
pubmed:meshHeading
pubmed-meshheading:20362557-Antineoplastic Agents, pubmed-meshheading:20362557-Apoptosis, pubmed-meshheading:20362557-Autophagy, pubmed-meshheading:20362557-Cell Line, Tumor, pubmed-meshheading:20362557-Cell Proliferation, pubmed-meshheading:20362557-Cell Survival, pubmed-meshheading:20362557-Child, Preschool, pubmed-meshheading:20362557-Dose-Response Relationship, Drug, pubmed-meshheading:20362557-Drug Screening Assays, Antitumor, pubmed-meshheading:20362557-Female, pubmed-meshheading:20362557-Humans, pubmed-meshheading:20362557-Infant, pubmed-meshheading:20362557-Male, pubmed-meshheading:20362557-Multiple Myeloma, pubmed-meshheading:20362557-Neuroblastoma, pubmed-meshheading:20362557-Ovarian Neoplasms, pubmed-meshheading:20362557-Peptides, Cyclic, pubmed-meshheading:20362557-Protease Inhibitors, pubmed-meshheading:20362557-Proto-Oncogene Proteins c-akt, pubmed-meshheading:20362557-Tumor Suppressor Protein p53
pubmed:year
2010
pubmed:articleTitle
Syrbactin class proteasome inhibitor-induced apoptosis and autophagy occurs in association with p53 accumulation and Akt/PKB activation in neuroblastoma.
pubmed:affiliation
Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, 96813, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't