Geldanamycin (GA), a benzoquinoid ansamycin antibiotic, has been used as a tyrosine kinase inhibitor and an anti-tumour agent and is known to bind to heat-shock protein 90. In the present study on human platelets we have found that GA inhibited platelet aggregation induced by ADP, thrombin and the thrombin-receptor-activating peptide and caused platelet plasma-membrane damage, detected by leakage of adenine nucleotides as well as serotonin. Scanning electron microscopy (SEM) revealed that platelet exposure to GA led to the formation of holes or fenestrations in the platelet plasma membrane, confirming GA's ability to initiate membrane damage. In addition, GA itself caused both the dephosphorylation and phosphorylation of proteins in resting platelets and prevented agonist-induced phosphorylation of pleckstrin, the 20-kDa myosin light chain and other proteins. Another ansamycin, herbimycin A, also inhibited platelet aggregation, but caused minimal membrane permeabilization, as detected by 3H release from platelets labelled previously with [3H]adenine, and much less membrane damage, revealed by SEM. Overall, GA is able to disrupt membrane structure and inhibit platelet aggregation, an ability which may be linked to alterations in the activity of protein kinases and phosphatases.
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Research Article|
January 10 2000
Geldanamycin disrupts platelet-membrane structure, leading to membrane permeabilization and inhibition of platelet aggregation
Sudawadee SUTTITANAMONGKOL;
Sudawadee SUTTITANAMONGKOL
1
1To whom correspondence should be addressed (e-mail ss2fn@;virginia.edu).
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Adrian R. L. GEAR;
Adrian R. L. GEAR
1Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, U.S.A.
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Renata POLANOWSKA-GRABOWSKA
Renata POLANOWSKA-GRABOWSKA
1Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, U.S.A.
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Publisher: Portland Press Ltd
Received:
April 14 1999
Revision Received:
October 13 1999
Accepted:
November 05 1999
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 2000
2000
Biochem J (2000) 345 (2): 307–314.
Article history
Received:
April 14 1999
Revision Received:
October 13 1999
Accepted:
November 05 1999
Citation
Sudawadee SUTTITANAMONGKOL, Adrian R. L. GEAR, Renata POLANOWSKA-GRABOWSKA; Geldanamycin disrupts platelet-membrane structure, leading to membrane permeabilization and inhibition of platelet aggregation. Biochem J 15 January 2000; 345 (2): 307–314. doi: https://doi.org/10.1042/bj3450307
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