Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase-Akt/PKB survival pathway

Anticancer Drugs. 2003 Feb;14(2):167-73. doi: 10.1097/00001813-200302000-00011.

Abstract

Synthetic alkyl-lysophospholipids (ALPs) represent a new class of anti-tumor agents that target cell membranes and induce apoptosis. However, the exact mechanisms by which ALPs exert these effects remain unclear. Here, we investigated in the epithelial carcinoma cell lines A431 and HeLa the effect of three clinically relevant ALPs [Et-18-OCH3 (Edelfosine), HePC (Miltefosine) and D-21266 (Perifosine)] on the phosphatidylinositol 3-kinase (PI3K)-Akt/PKB survival pathway. We found that growth factor-induced Akt/PKB activation in these cells is dependent on PI3K and that all three ALPs inhibited this pathway in a dose-dependent manner. We further showed that inhibition of the PI3K-Akt/PKB pathway by wortmannin or ALPs is associated with activation of the pro-apoptotic SAPK/JNK pathway. Inhibition of the PI3K-Akt/PKB survival pathway represents a novel mode of action of ALPs that may significantly contribute to the induction of apoptosis.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Dose-Response Relationship, Drug
  • Growth Inhibitors / pharmacology*
  • HeLa Cells / drug effects
  • Humans
  • Mitogen-Activated Protein Kinase 12
  • Mitogen-Activated Protein Kinases / metabolism
  • Neoplasms, Glandular and Epithelial / enzymology
  • Neoplasms, Glandular and Epithelial / metabolism
  • Neoplasms, Glandular and Epithelial / pathology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phospholipid Ethers / pharmacology
  • Phosphorylation
  • Phosphorylcholine / analogs & derivatives*
  • Phosphorylcholine / pharmacology
  • Protein-Serine-Threonine Kinases*
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction / drug effects*

Substances

  • Antineoplastic Agents
  • Growth Inhibitors
  • Phospholipid Ethers
  • Proto-Oncogene Proteins
  • Phosphorylcholine
  • edelfosine
  • perifosine
  • miltefosine
  • Mitogen-Activated Protein Kinase 12
  • Phosphatidylinositol 3-Kinases
  • Protein-Tyrosine Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases