Inhibitors of coenzyme A-independent transacylase induce apoptosis in human HL-60 cells.
ET-18-O-CH3 (1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine) is an antiproliferative agent, blocking the growth of cancer cells both in vitro and in vivo. However, there is controversy regarding the mechanism leading to its antiproliferative effects. CoA-independent transacylase (CoA-IT) is an enzyme that remodels arachidonate between specific phospholipid donor and acceptor molecules in a variety of mammalian cells. ET-18-O-CH3 was found to be a potent inhibitor of CoA-IT (IC50, 0.5 microM), and kinetic analysis revealed that its inhibition was competitive with the lyso-phospholipid substrate. The goal of the current study was to explore the connection between inhibition of CoA-IT and antiproliferative effects using several structurally distinct inhibitors of CoA-IT. ET-18-O-CH3 and other inhibitors of CoA-IT were found to inhibit cell proliferation and thymidine incorporation into the DNA, as well as to induce apoptosis in human HL-60 monocytic leukemia cells. The mechanism of apoptosis induced by ET-18-O-CH3 appeared to be different from that induced by tumor necrosis factor; the former failed to activate NF-kappa B, whereas tumor necrosis factor did. Closer examination of the pharmacology of apoptosis in this model revealed that compounds that were structurally related to CoA-IT inhibitors, but lacked CoA-IT inhibitory activity, also failed to induce apoptosis. In addition, compounds that inhibited other enzymes that participate in arachidonic acid metabolism, cyclooxygenase, 5-lipoxygenase and phospholipase A2, did not induce apoptosis. Taken together, these results demonstrate that inhibition of CoA-IT can be linked to blockade of proliferation and the induction of apoptosis in HL-60 cells.
Winkler
J D
JD
Department of Immunopharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Eris
T
T
Sung
C M
CM
Chabot-Fletcher
M
M
Mayer
R J
RJ
Surette
M E
ME
Chilton
F H
FH
D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016718:Arachidonic Acid / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003065:Coenzyme A / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D050356:Lipid Metabolism; D016328:NF-kappa B / Q000378:metabolism; D010742:Phospholipid Ethers / Q000494:pharmacology*; D010743:Phospholipids / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D010742:Phospholipid Ethers; D010743:Phospholipids; C026659:edelfosine; D016718:Arachidonic Acid; D000217:Acyltransferases; C039766:arachidonyl transacylase; D003065:Coenzyme A