Killing tumour cells by alkylphosphocholines: evidence for involvement of CD95.
Many lipids act as cellular messengers and lead to a variety of different cellular responses. Out of the group of these compounds the ceramides are able to induce apoptosis, and some synthetic lipids can mimic this effect. Apoptosis is an important mechanism whereby chemotherapeutics exhibit their anti-oncogenic activity. Although, some lipid analogues were used in clinical trials, they exert severe side effects and their mechanism of action is widely unknown. We present here a new class of synthetic alkylphosphocholines (APC) that induce programmed cell death in leukaemia cells. The signs of apoptosis arise after 1 h of incubation with these compounds as shown by phosphatidylserine externalisation followed by caspase activation and DNA fragmentation. We demonstrate that the molecular target of these lipids is upstream of caspases and Bcl-2. Experiments with FADD dominant negative cells reveal that induction of apoptosis occurs on the level of CD95 and that these compounds can now be optimised for their capacity to activate the apoptosis-inducing receptor CD95.
Matzke
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A
Forschungszentrum Karlsruhe, Institute for Toxicology and Genetics, Germany.
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D000473:Alkanes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D002843:Chromatin / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation; D004789:Enzyme Activation; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000502:physiology; D015394:Molecular Structure; D010767:Phosphorylcholine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015843:Serpins / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D014764:Viral Proteins; D019014:fas Receptor / Q000378:metabolism*
D000473:Alkanes; D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D002843:Chromatin; D015853:Cysteine Proteinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D015843:Serpins; D014764:Viral Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; D010767:Phosphorylcholine; C074641:interleukin-1beta-converting enzyme inhibitor; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases