title: Lipid peroxidation, phosphoinositide turnover and protein kinase C activation in human platelets treated with anthracyclines and their complexes with Fe(III).
abstract: The effects of the antitumor drugs daunorubicin, doxorubicin and their complexes with Fe(III) on phosphoinositide hydrolysis, lipid peroxidation and protein kinase C (PKC) activation were measured in intact human platelets. Doxorubicin and the Fe(III) complexes of both doxorubicin and daunorubicin quickly induced lipid peroxidation [as measured by the thiobarbituric acid (TBA) assay], phosphorylation of the 40 K substance of PKC, and increased levels of phosphatidic acid and inositol phosphates. Fe(III) alone or complexed to acetohydroxamic acid induced high levels of TBA-reactive material but did not affect either PKC activation or phosphoinositide turnover. In contrast, daunorubicin, which was ineffective per se, inhibited all these doxorubicin- and anthracyclines/Fe(III)-induced biochemical events. We suggest that phosphoinositide hydrolysis determined by anthracyclines, and consequently PKC activation, could be due to lipid peroxidation, thus triggering the activity of phospholipase C.
authors.affiliation: Division of Experimental Oncology B, Istituto Nazionale Tumori, Milano, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Banfi
authors.forename: O
authors.initials: O
authors.lastname: Parolini
authors.forename: C
authors.initials: C
authors.lastname: Lanzi
authors.forename: R A
authors.initials: RA
authors.lastname: Gambetta
mesh_terms: D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D003630:Daunorubicin / Q000494:pharmacology; D004075:Diglycerides / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005290:Ferric Compounds / Q000494:pharmacology*; D006801:Humans; D007295:Inositol Phosphates / Q000032:analysis; D015227:Lipid Peroxidation / Q000187:drug effects*; D009355:Neomycin / Q000494:pharmacology; D010712:Phosphatidic Acids / Q000032:analysis; D010716:Phosphatidylinositols / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*
chemical_list: C011439:1,2-diacylglycerol; D004075:Diglycerides; D005290:Ferric Compounds; D007295:Inositol Phosphates; D010712:Phosphatidic Acids; D010716:Phosphatidylinositols; D004317:Doxorubicin; D011493:Protein Kinase C; D009355:Neomycin; D003630:Daunorubicin