Induction of apoptosis in human leukemic cells by the ether lipid 1-octadecyl-2-methyl-rac-glycero-3-phosphocholine. A possible basis for its selective action.
Ether-linked glycerophospholipids (ether lipids, EL) are membrane-interactive drugs selectively cytotoxic toward neoplastic cells compared with normal cells. No conclusive explanation has yet been provided for this selectivity. We now present data indicating that the drug 1-octadecyl-2-methyl-rac-glycero-3-phosphocholine (ET-18-OMe) induces apoptosis, or programmed cell death, in human leukemic cells. Apoptotic death is induced selectively by ET-18-OMe in HL60 cells, which are sensitive to the drug's cytotoxic action, but not in the resistant K562 cell line. Enrichment of HL60 cells with cholesterol (HL60-CHOL cells) significantly protects the cells from the cytotoxic effect and from the induction of apoptosis by ET-18-OMe; the percentage of fragmented DNA is only 17% for HL60-CHOL, compared with 50% in native HL60 cells after exposure to 20 microns ET-18-OMe for 24 hr. Our study provides a possible explanation for differences in sensitivity to EL among different cell types and illustrates an indirect interaction of EL with cellular DNA.
Diomede
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Istituto di Ricerche Farmacologiche Mario Negri, Laboratory for Enzyme Research, Milan, Italy.
Colotta
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Piovani
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Re
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Modest
E J
EJ
Salmona
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M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002784:Cholesterol / Q000032:analysis; D004273:DNA, Neoplasm / Q000032:analysis / Q000187:drug effects; D004351:Drug Resistance; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000473:pathology; D008563:Membrane Lipids / Q000032:analysis; D010742:Phospholipid Ethers / Q000494:pharmacology*; D010743:Phospholipids / Q000032:analysis; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D008563:Membrane Lipids; D010742:Phospholipid Ethers; D010743:Phospholipids; C026659:edelfosine; D002784:Cholesterol