INHIBITION OF MYOSIN LIGHT CHAIN KINASE, CAMP-DEPENDENT PROTEIN-KINASE, PROTEIN-KINASE-C AND OF PLANT CA2-CIRCLE-PLUS-DEPENDENT PROTEIN-KINASE BY ANTHRAQUINONES

A variety of anthraquinone (anthracene-9,10-dione) derivatives inhibits rat brain Ca2+- and phospholipid-activated protein kinase C (PKC) of which the most potent inhibitors are mitoxantrone (1,4-dihydroxy-5,8-bis[2-(hydroxyethylamino)-ethyl-amino]-9,10-anthracenedione) (IC50 4muM) and quinalizarin (1,2,5,8-tetrahydroxy-anthraquinone (IC50 4muM). Anthraquinone derivatives with less polar substitution in positions 1 to 4 and 5 to 8 are less effective as inhibitors of PKC. Wheat germ Ca2+-dependent protein kinase (CDPK) assayed with a myosin light chain-based peptide substrate is much less sensitive to inhibition by anthraquinones, the most effective anthraquinone inhibitors being the 1,2,4-trihydroxy (IC50 14muM), 1,8-dihydroxy-3-methyl (IC50 56muM) and 1,2,5,8-tetrahydroxy (IC50 65muM) derivatives. Ca2+-calmodulin-dependent myosin light chain kinase (MLCK) is inhibited by a range of di-, tri- and tetrahydroxylated anthraquinones (IC50 values 2 to 53muM), the most potent inhibitors being the more polar compounds, namely mitoxantrone (IC50 2muM) and emodin (1,3,8-trihydroxy-6-methylanthraquinone) (IC50 8muM). Mitoxantrone interacts with calmodulin as determined from abolition of Ca2+-dependent fluorescence enhancement of dansyl-calmodulin (IC50 4muM). A range of anthraquinone derivatives inhibits the catalytic subunit of cAMP-dependent protein kinase (cAK). In a number of cases compounds acting as potent inhibitors of MLCK (such as mitoxantrone and emodin) are very poor inhibitors of cAK and vice versa.