Lipid peroxidation, phosphoinositide turnover and protein kinase C activation in human platelets treated with anthracyclines and their complexes with Fe(III).
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.
Banfi
P
P
Division of Experimental Oncology B, Istituto Nazionale Tumori, Milano, Italy.
Parolini
O
O
Lanzi
C
C
Gambetta
R A
RA
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*
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