Inhibition of cellular transport systems by alkyl phospholipid analogs in HL-60 human leukemia cells.
Specific non-metabolizable alkyl-phospholipids selectively kill neoplastic cells, yet normal and more differentiated cells are relatively resistant. Although these highly selective anticancer lipids appear to target the cell membrane, their mechanism of cytotoxic action remains to be defined. We report here that treatment of 'sensitive' HL-60 leukemia cells with one of the most potent lipid agents, 1-alkyl-2-methoxy-glycero-3-phosphocholine, inhibits the cellular transport of multiple essential nutrients including choline, amino acids, fatty acids, and the non-metabolizable carbohydrate, 2-deoxy-D-glucose. Minimal inhibitory responses of the varied transport systems were noted in HL-60 cells treated with the less potent, 2-lyso analog, and in 'resistant' K562 leukemia cells, treated with the 2-methoxy lipid. Although both the 2-methoxy lipid and 12-tetradacanoylphorbol 13-acetate induce differentiation in HL-60 cells, significant differences in the interactions of these lipids on cellular choline transport were found. Based on these results, we conclude that multiple nutrient deprivation induced by the detergent-like action of the methoxy-containing alkyl phospholipid results in the selective destruction of neoplastic cells that are sensitive to this membrane-targeted antitumor agent.
Hoffman
D R
DR
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas.
Thomas
V L
VL
Snyder
F
F
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002794:Choline / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism*; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D010713:Phosphatidylcholines / Q000096:biosynthesis; D010742:Phospholipid Ethers / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000970:Antineoplastic Agents; D009004:Monosaccharide Transport Proteins; D010713:Phosphatidylcholines; D010742:Phospholipid Ethers; C026659:edelfosine; D002794:Choline; D013755:Tetradecanoylphorbol Acetate