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Effects of Thioether Phospholipid BM 41.440 on Protein Kinase C and Phorbol Ester-induced Differentiation of Human Leukemia HL60 and KG-1 Cells¹

Departments of Medicine (Hematology/Oncology) [M. S., W. E. B., W. R. V.] and Pharmacology [R. L. R., J. F. K.], Emory University School of Medicine, Atlanta, Georgia 30322

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 K_i value of about 6.4 µM. 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.

¹ Supported by USPHS Research Grants CA-29850 (W. R. V.) and CA-36777, HL-15696, and NS-17608 (J. F. K.).

² Permanent address: Division of Hematology and Oncology, Department of Medicine 1, Technische Universität, Munich, Federal Republic of Germany.

Received 4/22/88. Revised 8/19/88. Accepted 8/26/88.

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