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

Abstract

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.

Growth arrest vs direct cytotoxicity and the importance of molecular structure for the in vitro anti-tumour activity of ether lipids

“…Testing a larger panel of agents, we have confirmed our earlier finding (Lohmeyer and Workman, 1992) (Munder and Westphal, 1990;Berdel, 1991) PI-3-kinase, the Na+/K+-ATPase, Ca2+ channels and the epidermal growth receptor (Oishi et al, 1988;Kosano and Takatani, 1989;Powis et al, 1992;Berggren et al, 1993 (Honma et al, 1981(Honma et al, , 1991Vallari et al, 1988;Maurer and Hilgard, 1992), but inhibition of differentiation has also been described in the same model system (Shoji et al, 1988;Kuo et al, 1990;Raynor et al, 1991). Apoptosis has been observed in some leukaemic cell lines, including HL60, in response to challenge with ATLs (Diomede et al, 1993(Diomede et al, , 1994, but this response is not universal (Morimoto et al, 1991). (3) As concentrations exceed 40 JAM, the detergent properties of the ATLs begin to induce direct lytic membrane damage.…”

A kinetic study of the lipase-catalyzed ethanolysis of two short-chain triradylglycerols: Alkylglycerols vs. triacylglycerols

“…Ether lipids have been used in the therapy of cancer [3], since they are potent antineoplastic agents which inhibit growth, show antimetastatic activity and induce differentiation and apoptosis in cancer cells [4,5]. Immune stimulators properties have also been attributed to dietary ingestion of these substances [6].…”

Phase I and Pharmacokinetic Study of the Cytotoxic Ether Lipid Ilmofosine Administered by Weekly Two-Hour Infusion in Patients with Advanced Solid Tumors

“…Several mechanisms of action for this class of agents have been proposed including the inhibition of protein kinase C membrane signal transduction (13)(14)(15)(16) and membrane disruption (17,18), and may also include induction of apoptosis (2,19) and immunomodulation (20,21).…”