Quaternary ammonium analogs of ether lipids inhibit the activation of protein kinase C and the growth of human leukemia cell lines.

Abstract

PURPOSE:

ET-18-OCH3 (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) is a representative of the first generation of antitumor ether lipids and is a model in the development of new compounds including a series of quaternary ammonium analogs (QAA). In the present study, we evaluated the QAA as inhibitors of cell growth and studied their mechanism of action.

METHODS:

We compared the effects of the QAA on the proliferation of human leukemia cell lines which are sensitive (HL-60) or resistant to ET-18-OCH3 (HL-60R and K562). In addition we used cell fractionation and enzymatic assays to determine the effects of QAA on protein kinase C (PKC) translocation in response to 12-O-tetradecanoyl-phorbol-13-acetate (TPA).

RESULTS:

The QAA and ET-18-OCH3 were approximately equally effective inhibitors of HL-60 cell growth. However, the QAA were more effective inhibitors of K562 and HL-60R cell proliferation. The HL-60R cells, which were selected for resistance to ET-18-OCH3, were also resistant to BM 41.440 which is structurally similar. In serum-free medium, the phosphorus-containing compounds (ET-18-OCH3, BM 41.440 and He-PC) were much more effective inhibitors (8-20-fold) of the K562 cell line while the activities of the QAA were only moderately increased (1.2-2.3-fold). When serum albumin was added to the serum-free medium, the K562 cells became resistant to ET-18-OCH3, suggesting that albumin is responsible for the differential sensitivity. The QAA compounds, which inhibit PKC activity in vitro, inhibited cell proliferation. However, a QAA which did not inhibit PKC did not inhibit cell proliferation. The phorbol ester TPA stimulates PKC translocation and causes HL-60 cell differentiation to adherent macrophage-type cells. The QAA inhibited TPA-induced cell differentiation and PKC translocation indicating that they also inhibit PKC in intact cells.

CONCLUSIONS:

The cellular effects of the QAA appear to be due to inhibition of PKC. In addition, these data indicate that albumin, which is important as a mediator of the uptake of ET-18-OCH3, has only a small effect on the uptake of QAA. Together these data indicate that the QAA are potential anticancer agents, showing a significant ability to inhibit growth of leukemia cell lines that are resistant to ET-18-OCH3.

• Authors: F Civoli, L W Daniel
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 42 Issue 4 Pg. 319-26 ( 1998) ISSN: 0344-5704 [Print] Germany
• PMID: 9744778 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Culture Media, Serum-Free
• Furans
• Phospholipid Ethers
• Quaternary Ammonium Compounds
• Phosphorylcholine
• SRI 62-834
• edelfosine
• miltefosine
• ilmofosine
• Protein Kinase C
• Tetradecanoylphorbol Acetate

Topics

• Antineoplastic Agents (pharmacology)
• Cell Differentiation (drug effects)
• Cell Division (drug effects)
• Cell Survival (drug effects)
• Culture Media, Serum-Free
• Drug Resistance
• Enzyme Activation (drug effects)
• Furans (pharmacology)
• HL-60 Cells
• Humans
• Phospholipid Ethers (pharmacology)
• Phosphorylcholine (analogs & derivatives, pharmacology)
• Protein Kinase C (antagonists & inhibitors)
• Quaternary Ammonium Compounds (pharmacology)
• Structure-Activity Relationship
• Tetradecanoylphorbol Acetate