| The marine compound spongistatin 1 targets pancreatic tumor progression and metastasis. | |
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MedLine Citation:
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PMID: 20143389 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Treatment of pancreatic cancer remains a major challenge and new anticancer drugs are urgently required. Our study presents the marine natural compound spongistatin 1 as a promising experimental drug. Spongistatin 1 was applied in an orthotopic in vivo model of human pancreatic cancer. Spongistatin 1 significantly reduced tumor growth, which correlates with a strong apoptosis induction (DNA-fragmentation) and long-term effects on clonogenic survival of pancreatic tumor cells (L3.6pl) in vitro. In addition, the formation of metastasis was reduced in spongistatin 1-treated mice, which is in line with a diminished MMP-9 activity in tumor tissue determined by zymography. Based on the pronounced efficacy of spongistatin 1, the underlying mechanisms were studied in more detail. In vitro adhesion, as well as migration, and invasion assays showed spongistatin 1 to influence these critical steps in the metastatic cascade. Furthermore, spongistatin 1 induced anoikis in L3.6pl cells. Exposure to spongistatin 1 leads to phosphorylation, and thus inactivation of the antiapoptotic protein Bcl-2 in pancreatic tumor cells. siRNA experiments silencing Bcl-2 suggest a role of Bcl-2 in anoikis and cell migration. Taken together, spongistatin 1 not only proved to be a potent experimental drug but also served as a chemical tool to examine the role of the antiapoptotic protein Bcl-2 in pancreas carcinoma, thereby supporting the hypothesis of a link between apoptosis signaling and metastasis. |
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Authors:
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Andrea S Rothmeier; Uta M Schneiders; Romina M Wiedmann; Ivan Ischenko; Christiane J Bruns; Anita Rudy; Stefan Zahler; Angelika M Vollmar |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: International journal of cancer. Journal international du cancer Volume: 127 ISSN: 1097-0215 ISO Abbreviation: Int. J. Cancer Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-07-06 Completed Date: 2010-08-13 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0042124 Medline TA: Int J Cancer Country: United States |
Other Details:
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Languages: eng Pagination: 1096-105 Citation Subset: IM |
Affiliation:
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Department of Pharmacy, Center for Drug Research, University of Munich, Munich, Germany. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anoikis / drug effects Apoptosis / drug effects Blotting, Western Cell Adhesion / drug effects Cell Cycle / drug effects Cell Movement / drug effects Cell Proliferation / drug effects Colony-Forming Units Assay Female Humans Liver Neoplasms, Experimental / drug therapy*, metabolism, secondary Lymphatic Metastasis Macrolides / pharmacology* Mice Mice, Inbred BALB C Mice, Nude Pancreatic Neoplasms / drug therapy*, metabolism, pathology* Phosphorylation / drug effects Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors, genetics, metabolism* RNA, Messenger / genetics Reverse Transcriptase Polymerase Chain Reaction Tubulin Modulators / pharmacology* Xenograft Model Antitumor Assays |
| Chemical | |
Reg. No./Substance:
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0/Macrolides; 0/Proto-Oncogene Proteins c-bcl-2; 0/RNA, Messenger; 0/Tubulin Modulators; 148179-94-6/spongistatin 1 |
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