Protein kinase C activation and lipid peroxidation by doxorubicin analogues

Several doxorubicin analogues have been tested for their capacity to activate protein kinase C (PKC) and to induce lipid peroxidation in intact human platelets. Only doxorubicin and 4'-iodo-doxorubicin were able to induce lipid peroxidation and PKC activation the first being the most effective. N-acetyldoxorubicin, N-trifluoroacetyl-doxorubicin-14-valerate (AD32) and doxorubicin-14-propionate were not effective on either event. This correlation supports that PKC activation in human platelets by doxorubicin is mediated by lipid peroxidation and suggests that the effect is specific for anthracyclines with a doxorubicin aglycone and a free charged amino group in the sugar moiety. The results stress the new action of anthracyclines, whose pharmacologic implications are presently under investigation on nucleated cells.