Cellular signalling as a target in cancer chemotherapy. Phospholipid analogues as inhibitors of mitogenic signal transduction.
Mitogenic signalling mechanisms emerged as novel targets for tumor chemotherapy. Current strategies for pharmacological interventions are briefly discussed. Phospholipid analogues are treated in greater detail. It is shown here that this new class of antitumor agents acts as inhibitors of mitogenic signal transduction. The common target of all phospholipid analogues studied so far is the phosphatidylinositol (PI)-specific phospholipase C (PLC). This results in an attenuated formation of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). The reduction in IP3-levels leads to a depressed release of Ca2+ from internal stores, and the reduced formation of DAG interferes with the growth factor-induced activation of protein-kinase C (PKC). In addition to the effect on PI-specific PLC, most phospholipid analogues inhibit PKC directly by interacting with the regulatory domain of the enzyme. This effect, however, is not observed with all phospholipid analogues. Some potent growth inhibitory representatives from this group like hexadecylphosphoserine or hexadecylphosphonoserine do not affect PKC in cell-free extracts. It is concluded, therefore, that the direct inhibition of PKC is not required for the growth-inhibitory activity of these agents. The ability of phospholipid analogues to interact with PKC was also not found to be correlated the occurrence of unwanted side effects. Phospholipid analogues have also been found to act as inhibitors of phospholipase D (PLD). However, in this case the correlation to the growth inhibitory potency of various phospholipid analogues was less clear, so that the contribution of the PLD inhibition to the growth inhibitory effect of these agents still remains to be established. The inhibition of the thrombin-induced rise in cytosolic free Ca2+ by phospholipid analogues is reversible by washing the cells in phospholipid-free medium. These findings suggest that phospholipid analogues do not cause persistent membrane damage and may act as cytostatic rather than cytotoxic agents.
Grunicke
H H
HH
Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
Maly
K
K
Uberall
F
F
Schubert
C
C
Kindler
E
E
Stekar
J
J
Brachwitz
H
H
D000970:Antineoplastic Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D009369:Neoplasms / Q000628:therapy*; D010739:Phospholipase D / Q000037:antagonists & inhibitors; D010743:Phospholipids / Q000494:pharmacology*; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D010768:Phosphoserine / Q000031:analogs & derivatives / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010743:Phospholipids; D017923:Sodium-Hydrogen Exchangers; D010767:Phosphorylcholine; C090561:hexadecylphosphoserine; D010768:Phosphoserine; C039128:miltefosine; D015544:Inositol 1,4,5-Trisphosphate; D011493:Protein Kinase C; D010738:Type C Phospholipases; D010739:Phospholipase D; D013917:Thrombin; D002118:Calcium