| Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389. | |
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MedLine Citation:
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PMID: 15313917 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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E7389, a macrocyclic ketone analog of the marine natural product halichondrin B, currently is undergoing clinical trials for cancer. This fully synthetic agent exerts its highly potent in vitro and in vivo anticancer effects via tubulin-based antimitotic mechanisms, which are similar or identical to those of parental halichondrin B. In an attempt to understand the impressive potency of E7389 in animal models of human cancer, its ability to induce apoptosis following prolonged mitotic blockage was evaluated. Treatment of U937 human histiocytic lymphoma cells with E7389 led to time-dependent collection of cells in the G2-M phase of the cell cycle, beginning as early as 2 h and becoming maximal by 12 h. Increased numbers of hypodiploid events were seen beginning at 12 h, suggesting initiation of apoptosis after prolonged E7389-induced mitotic blockage. The identity of hypodiploid events as apoptotic cells under these conditions was confirmed by two additional morphologic criteria: green to orange/yellow shifts on acridine orange/ethidium bromide staining, and cell surface annexin V binding as assessed by flow cytometry. Several biochemical correlates of apoptosis also were seen following E7389 treatment, including phosphorylation of the antiapoptotic protein Bcl-2, cytochrome c release from mitochondria, proteolytic activation of caspase-3 and -9, and cleavage of the caspase-3 substrate poly(ADP-ribose) polymerase (PARP). In LNCaP human prostate cancer cells, treatment with E7389 also led to generation of hypodiploid cells, activation of caspase-3 and -9, and appearance of cleaved PARP, indicating that E7389 can activate cellular apoptosis pathways under anchorage-independent and -dependent cell culture conditions. These results show that prolonged mitotic blockage by E7389 can lead to apoptotic cell death of human cancer cells in vitro and can provide a mechanistic basis for the significant in vivo anticancer efficacy of E7389. |
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Authors:
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Galina Kuznetsov; Murray J Towle; Hongsheng Cheng; Takanori Kawamura; Karen TenDyke; Diana Liu; Yoshito Kishi; Melvin J Yu; Bruce A Littlefield |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Cancer research Volume: 64 ISSN: 0008-5472 ISO Abbreviation: Cancer Res. Publication Date: 2004 Aug |
Date Detail:
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Created Date: 2004-08-17 Completed Date: 2004-09-30 Revised Date: 2012-02-01 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 5760-6 Citation Subset: IM |
Affiliation:
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Department of Candidate Assessment and In Vitro Technologies, Eisai Research Institute, Andover, Massachusetts 01810, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects* Caspase 3 Caspase 9 Caspases / metabolism Cell Line, Tumor Cell Membrane / drug effects, physiology Cell Polarity / drug effects Cytochromes c / secretion Diploidy Enzyme Activation / drug effects Ethers, Cyclic / pharmacology* Furans / pharmacology* G2 Phase / drug effects Humans Ketones / pharmacology* Male Mitochondria / drug effects, secretion Mitosis / drug effects* Phosphorylation / drug effects Poly(ADP-ribose) Polymerases / metabolism Prostatic Neoplasms / drug therapy*, genetics, pathology* Proto-Oncogene Proteins c-bcl-2 / metabolism U937 Cells |
| Chemical | |
Reg. No./Substance:
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0/Ethers, Cyclic; 0/Furans; 0/Ketones; 0/Proto-Oncogene Proteins c-bcl-2; 0/eribulin; 9007-43-6/Cytochromes c; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/CASP9 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 9; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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