Interference of new alkylphospholipid analogues 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)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.
Maly
K
K
Institute of Medical Chemistry and Biochemistry, Medical School, University of Innsbruck, Austria.
Uberall
F
F
Schubert
C
C
Kindler
E
E
Stekar
J
J
Brachwitz
H
H
Grunicke
H H
HH
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
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