title: Interference of new alkylphospholipid analogues with mitogenic signal transduction.
abstract: 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)P3) formation and the subsequent Ca2+ release, on protein kinase C (PKC) in cell-free extracts, on the PKC-mediated activation of the Na+/H+ antiporter and on c-fos induction. The compounds investigated include hexadecylphosphocholine (HePC), octadecyl-[2-(N-methyl-piperidinio)-ethyl]-phosphate (D20133), octadecyl-(N,N-dimethyl-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-induced progression of growth-arrested NIH3T3 cells into S phase with similar IC50 values; (ii) the common denominator of all compounds is a reduction of Ins(1,4,5)P3 formation, resulting in an attenuation of Ca2+ release; (iii) the direct interaction with PKC does not significantly contribute 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 phospholipase C (PLC). The lower toxicities of these compounds cannot be explained by a less pronounced inhibition of PKC or PLC, respectively.
authors.affiliation: Institute of Medical Chemistry and Biochemistry, Medical School, University of Innsbruck, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Maly
authors.forename: F
authors.initials: F
authors.lastname: Uberall
authors.forename: C
authors.initials: C
authors.lastname: Schubert
authors.forename: E
authors.initials: E
authors.lastname: Kindler
authors.forename: J
authors.initials: J
authors.lastname: Stekar
authors.forename: H
authors.initials: H
authors.lastname: Brachwitz
authors.forename: H H
authors.initials: HH
authors.lastname: Grunicke
mesh_terms: D016475:3T3 Cells / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002474:Cell-Free System; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D051379:Mice; D010743:Phospholipids / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D018179:Receptors, Thrombin / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D017923:Sodium-Hydrogen Exchangers / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D010743:Phospholipids; D018179:Receptors, Thrombin; D017923:Sodium-Hydrogen Exchangers; D015544:Inositol 1,4,5-Trisphosphate; D011493:Protein Kinase C; D010738:Type C Phospholipases; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium