INTERFERENCE OF NEW ALKYLPHOSPHOLIPID ANALOGS WITH MITOGENIC SIGNAL-TRANSDUCTION

The interference of several new hexadecylphosphocholine analogues with mitogenic signal transduction was investigated in NIH3T3 fibroblasts by studying the effects of these agents on thrombin-induced inositol 1 ,4,5-trisphosphate (Ins(1,4,5)P-3) formation and the subsequent Ca2+ r elease, on protein kinase C (PKC) in cell-free extracts, on the PKC-me diated activation of the Na+/H+ antiporter and on c-fos induction. The compounds investigated include hexadecylphosphocholine (HePC), ctadec yl-[2-(N-methyl-piperidinio)-ethy]-phosphate (D20133), octadecyl(N,N-d imethyl-piperidinio-4-yl)-phosphate (D21266); octadecyl-[2-(trimethyl- arsonio)ethyl]-phosphate (D21805) and hexadecylphospho-L-serine (HePS) . The data indicate that (i) all compounds inhibit the thrombin-induce d progression of growth-arrested NIH3T3 cells into S phase with simila r IC50 values; (ii) the common denominator of all compounds is a reduc tion of Ins(1,4,5)P-3 formation, resulting in an attenuation of Ca2+ r elease; (iii) the direct interaction with PKC does not significantly c ontribute to the antitumor activity of these agents; (iv) the new HePC congeners D21266; D21133 and D21805 affect the same targets as HePC, i.e. PKC and phosphatidylinositol 4,5-bisphosphate-specific phospholip ase C (PLC). The lower toxicities of these compounds cannot be explain ed by a less pronounced inhibition of PKC or PLC, respectively.