Membrane damage in leukemic cells induced by ether and ester lipids: An electron microscopic study

Noseda, Alessandro; Jg, White; Godwin, Patrick L.; Jerome, W. Gray; Modest, Edward J.

doi:10.1016/0014-4800(89)90057-9

Cited by 66 publications

(27 citation statements)

References 17 publications

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“…The most striking observation was that ALP with an ether linkage in the sn-I position of the glycerol moiety and a metabolically stable substitution in the sn-2 position were directly antiproliferative and cytotoxic in vitro at micromolar concentrations towards cells of various types of leukaemia and a wide variety of lymphomas and solid tumours, when co-incubated with neoplastic cells for more than 24 h. However, sn-I ester analogs were ineffective within this dose range, regardless of changes made in the sn-2 position of the molecule (Andreesen et al, 1978;Berdel et al, 1985). Scanning electron microscopy revealed that destruction of the outer cell membrane occurs during incubation with the lipids (Berdel et al, 1983;Noseda et al, 1989). For the purging approach in the setting of ABMT it might be of interest that cell lines selected for resistance towards different cytotoxic drugs do not develop major cross-resistance to the cytotoxicity of ether lipids (Himmelmann et al, 1990 (Hoffman et al, 1986).…”

Section: Precfinical Studiesmentioning

confidence: 99%

Membrane-interactive lipids as experimental anticancer drugs

Berdel¹

1991

Br J Cancer

109

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Section: Precfinical Studiesmentioning

confidence: 99%

Membrane-interactive lipids as experimental anticancer drugs

Berdel¹

1991

Br J Cancer

109

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“…ATLs also interfere with cellular phospholipid metabolism (Modolell et al, 1979;Berkovic et al, 1992). In addition, they alter membrane fluidity, effect cell shape changes and permeabilise cells by membrane pore formation (Noseda et al, 1989a;Dive et al, 1991). However, direct permeabilisation and lysis may not be the key cytotoxic lesion at lower, pharmacological doses of ATLs (Lohmeyer and Workman, 1992).…”

mentioning

confidence: 99%

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

Lohmeyer

Workman²

1995

Br J Cancer

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Summary A panel of 25 different lipid agents was evaluated for in vitro activity against HT29 human colon carcinoma and HL60 promyelocytic leukaemia cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The structure-activity relationships seen with this series, including those for four sets of positional or stereoisomers, indicate that specific receptor proteins are unlikely as targets for anti-tumour lipid (ATL) action. Additional data confirm the lack of involvement of the platelet-activating factor receptor in particular and suggest that metabolic stability is a most important determinant of ATL activity. More detailed studies, with 1-O-octadecyl-2-0-methyl-rac-glycero-3-phosphocholine (ET18-OCH3) and (±)-2-{Hydroxy[tetrahydro-2-(octadecyloxy)methylfuran-2-yl]methoxylphosphinyloxy)-N,N,N,-trimethylethaniminium hydroxide (SRI 62-834), suggest three different modes of activity, depending on drug concentration and exposure time. Low doses of up to 5 jiM in standard serum-containing medium cause population growth arrest after prolonged exposure. Growth arrest was associated with a leaky G2/M block as determined by flow cytometry. These effects are reversible. Intermediate concentrations (5-40 M) were cytotoxic, causing a net reduction in cell numbers after 2-3 days. At even higher concentrations, all lipids caused rapid, direct membrane lysis. When the clonogenic assay was used to assess the effects of ATLs, most agents reduced colony formation at concentrations above 5 jIM. However, some compounds proved stimulatory at nanomolar concentrations, suggesting that they might possess mitogenic properties. These results, particularly those concerning the concentration and time dependence, may be relevant to current clinical trials with ether lipids.

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“…In the last decade, cellular membranes have been identified as novel targets for antineoplastic drugs (Noseda et al, 1989). Alkylphosphocholines (APC) have been proposed as promising membrane targeted antineoplastic drugs, exerting cytotoxic effects in cell culture as well as in animal models (Berger et al, 1993;Clive et al, 1999;Konstantinov and Berger, 1999;Smorenburg et al, 2000;Ruiter et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Intracellular mediators of erucylphosphocholine-induced apoptosis

et al. 2003

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Induction of apoptosis contributes to the cytotoxic action of the intravenously applicable alkylphosphocholine erucylphosphocholine (ErPC). To define molecular requirements for ErPC-induced apoptosis, activation of caspases-8, -9 and -3 and cleavage of the caspase-3 substrates PARP and ICAD were tested in normal Jurkat T cells, Jurkat cells resistant to death receptor (CD95 or TNFarelated apoptosis inducing ligand (TRAIL)-induced apoptosis, Jurkat cells lacking caspase-8 or Fas-associated death domain (FADD) Jurkat cells expressing a dominant-negative caspase-9 or overexpressing Bcl-2 as well as BJAB B-lymphoma cells expressing a dominantnegative FADD (FADD-DN). ErPC induced a time-and dose-dependent apoptotic cell death in Jurkat and BJAB cells, which was characterized by breakdown of the phosphatidylserine asymmetry, depolarization of the mitochondrial membrane potential, release of cytochrome c, activation of caspases-9, -8 and -3, cleavage of PARP and ICAD, as well as chromatin condensation. ErPCinduced apoptosis was independent from CD95-receptor signaling and FADD since CD95-and TRAIL-resistant, caspase-8-and FADD-negative Jurkat cells, as well as BJAB cells expressing FADD-DN were sensitive to ErPC-induced apoptosis. In contrast, inhibition of caspase-9 and overexpression of Bcl-2 significantly reduced ErPC-induced caspase activation and apoptosis. Thus, ErPC triggers apoptosis via a Bcl-2-dependent mitochondrial but death receptor-independent pathway.

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Membrane damage in leukemic cells induced by ether and ester lipids: An electron microscopic study

Cited by 66 publications

References 17 publications

Membrane-interactive lipids as experimental anticancer drugs

Membrane-interactive lipids as experimental anticancer drugs

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

Intracellular mediators of erucylphosphocholine-induced apoptosis

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