Shoji M, Raynor R L, Berdel W E, Vogler W R, Kuo J F
Department of Medicine (Hematology/Oncology), Emory University School of Medicine, Atlanta, Georgia 30322.
Cancer Res. 1988 Dec 1;48(23):6669-73.
The synthetic thioether phospholipid BM 41.440 (1-S-hexadecyl-2-methoxymethyl-rac-glycero-3-phosphocholine) was found to inhibit protein kinase C (PKC) activity competitively with respect to phosphatidylserine, with an apparent Ki value of about 6.4 microM. The agent also inhibited the enzyme activated by diolein or 12-O-tetradecanoylphorbol-13-acetate (TPA), without affecting binding of [3H]phorbol-12,13-dibutyrate to the enzyme. Myosin light chain kinase and cAMP-dependent protein kinase were not inhibited by BM 41.440, indicating a specificity of the action of the agent. BM 41.440 partly blocked the TPA-induced depletion of soluble PKC in HL60 and KG-1 cells (responsive to the differentiating effect of TPA) but not in K562 cells (resistant to the TPA effect). The thioether inhibited the phosphatidylserine/Ca2+-dependent phosphorylation of several common proteins in the solubilized homogenates of HL60 and KG-1 cells, and that of apparently distinct proteins in the preparation of K562 cells. The TPA-induced differentiation of HL60 and KG-1 cells was inhibited by BM 41.440 at a concentration inhibitory to PKC, but differentiation of HL60 cells promoted by dimethyl sulfoxide, retinoic acid, and 1,25-dihydroxyvitamin D3, on the other hand, was not affected. The present data suggested that PKC inhibition might partly account for the antineoplastic effect of BM 41.440, and that the agent could be useful in studying involvements of the PKC system in cellular processes.
合成硫醚磷脂BM 41.440（1-S-十六烷基-2-甲氧基甲基-外消旋甘油-3-磷酸胆碱）被发现相对于磷脂酰丝氨酸能竞争性抑制蛋白激酶C（PKC）活性，其表观Ki值约为6.4微摩尔。该试剂还能抑制由二油精或12-O-十四烷酰佛波醇-13-乙酸酯（TPA）激活的酶，而不影响[3H]佛波醇-12,13-二丁酸酯与该酶的结合。肌球蛋白轻链激酶和环磷酸腺苷依赖性蛋白激酶不受BM 41.440抑制，表明该试剂作用具有特异性。BM 41.440部分阻断了TPA诱导的HL60和KG-1细胞（对TPA的分化作用有反应）中可溶性PKC的消耗，但对K562细胞（对TPA作用有抗性）则无此作用。该硫醚抑制HL60和KG-1细胞溶解匀浆中几种常见蛋白质的磷脂酰丝氨酸/Ca2+依赖性磷酸化，以及K562细胞制剂中明显不同蛋白质的磷酸化。BM 41.440在抑制PKC的浓度下可抑制TPA诱导的HL60和KG-1细胞分化，但另一方面，二甲基亚砜、视黄酸和1,25-二羟基维生素D3促进的HL60细胞分化不受影响。目前的数据表明，PKC抑制可能部分解释了BM 41.440的抗肿瘤作用，并且该试剂可能有助于研究PKC系统在细胞过程中的参与情况。
