The antiproliferative effect of hexadecylphosphocholine toward HL60 cells is prevented by exogenous lysophosphatidylcholine.
The mechanisms that account for the anti-proliferative properties of the biologically active lysophospholipid analog hexadecylphosphocholine (HexPC) were investigated in HL60 cells. HexPC inhibited the incorporation of choline into phosphatidylcholine and the pattern of accumulation of soluble choline-derived metabolites pinpointed CTP:phosphocholine cytidylyltransferase (CT) as the inhibited step in vivo. HexPC also inhibited recombinant CT in vitro. HexPC treatment led to accumulation of cells in G2/M phase, triggered DNA fragmentation and caused morphological changes associated with apoptosis. The supplementation of HexPC-treated cells with exogenous lysophosphatidylcholine (LPC) completely reversed the cytotoxic effects of HexPC and restored HL60 cell proliferation in the presence of the drug. LPC provided an alternate pathway for phosphatidylcholine synthesis via the acylation of exogenous LPC. This result contrasted with the response of HL60 cells to 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3) where LPC overcame the cytotoxic effects but did not support continued cell proliferation. Morphological integrity, DNA stability and cell viability were maintained in cells treated with LPC plus either antineoplastic agent. Thus the inhibition of phosphatidylcholine biosynthesis at the CT step accounts for the cytotoxicity of both HexPC and ET-18-OCH3 which is overridden by providing an alternate pathway for phosphatidylcholine synthesis via the acylation of exogenous LPC.
Boggs
K
K
Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN 38101-3018, USA.
Rock
C O
CO
Jackowski
S
S
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002794:Choline / Q000378:metabolism; D019916:Choline-Phosphate Cytidylyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003566:Cytidine Diphosphate Choline / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D010713:Phosphatidylcholines / Q000096:biosynthesis; D010742:Phospholipid Ethers / Q000494:pharmacology; D010743:Phospholipids / Q000378:metabolism; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008244:Lysophosphatidylcholines; D010713:Phosphatidylcholines; D010742:Phospholipid Ethers; D010743:Phospholipids; D011994:Recombinant Proteins; D010767:Phosphorylcholine; C026659:edelfosine; D003566:Cytidine Diphosphate Choline; C039128:miltefosine; D019916:Choline-Phosphate Cytidylyltransferase; D002794:Choline