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Tamoxifen stimulates ROS production in human platelets via activation of NADPH oxidase: relationship to tamoxifen‐induced thrombosis
Author(s) -
Dobrydneva Yuliya,
Shah Vidhi,
Vishneski Susan
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.593.8
Subject(s) - tamoxifen , apocynin , nadph oxidase , superoxide , pharmacology , wortmannin , platelet activation , medicine , chemistry , endocrinology , platelet , kinase , oxidative stress , cancer , biochemistry , phosphatidylinositol , breast cancer , enzyme
Tamoxifen is a widely prescribed drug for the treatment and prevention of breast cancer; however, thrombosis is a well‐known adverse effect of tamoxifen. Previously we established that tamoxifen promotes calcium influx into platelets, a critical step in platelet activation. In this study we sought to determine the mechanism of tamoxifen‐induced platelet activation. Experiments were conducted with freshly isolated human platelets from healthy volunteers. Tamoxifen increases binding of Annexin V and PAC‐1 antibody, surface markers of platelet activation. Tamoxifen promotes production of superoxide, as measured by lucigenin chemiluminescence; NADPH oxidase is likely the source of superoxide. Tempol and Tempo (ROS scavengers), apocynin and apocynin dimer (NADPH oxidase inhibitors) and Ly294002 and wortmannin, (inhibitors of PI3 kinase, upstream effector of NADPH oxidase) block tamoxifen effect. Raloxifene, a tamoxifen analog, does not cause platelet activation or superoxide production. This could explain lower incidence of thrombotic events in patients taking raloxifene compared to tamoxifen. Funded by Commonwealth Health Research Board, Cancer Research and Prevention Foundation, and American Heart Association.