Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer.
Dysfunction in the physiological pathways of programmed cell death may promote proliferation of malignant cells, and correction of such defects may selectively induce apoptosis in cancer cells. We measured the levels of ceramide, a candidate lipid mediator of apoptosis, in human metastatic colorectal cancer and tested in vitro and in vivo effects of various ceramide analogues in inducing apoptosis in metastatic colon cancer. Human colon cancer showed a > 50% decrease in the cellular content of ceramide when compared with normal colon mucosa. Application of ceramide analogues and ceramidase inhibitors induced rapid cell death through activation of various proapoptotic molecules, such as caspases and release of cytochrome c. Ceramidase inhibition increases the ceramide content of tumor cells, resulting in maximum activation of the apoptotic cascade. Normal liver cells were completely resistant to inhibitors of ceramidases. Treatment of nude mice with B13, the most potent ceramidase inhibitor, completely prevented tumor growth using two different aggressive human colon cancer cell lines metastatic to the liver. Therefore, B13 and related analogues of ceramide and inhibitors of ceramidases offer a promising therapeutic strategy with selective toxicity toward malignant but not normal cells. These studies also suggest that the ceramide content in cancer cells might be involved in the pathogenesis of tumor growth in vitro and in vivo.
Selzner
M
M
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Bielawska
A
A
Morse
M A
MA
Rüdiger
H A
HA
Sindram
D
D
Hannun
Y A
YA
Clavien
P A
PA
D000577:Amides / Q000494:pharmacology; D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D055572:Ceramidases; D002518:Ceramides / Q000378:metabolism / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008114:Liver Neoplasms, Experimental / Q000517:prevention & control / Q000556:secondary; D008297:Male; D051379:Mice; D009226:Myristates / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000577:Amides; D002518:Ceramides; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D009226:Myristates; C421619:N-(1-(4-nitrophenyl)-1,3-dihydroxyprop-2-yl)tetradecanamide; C064769:N-acetylsphingosine; D011412:Propanolamines; C101954:N-caproylsphingosine; C099657:2-(N-myristoylamino)-1-phenyl-1-propanol; D000581:Amidohydrolases; D055572:Ceramidases; D013110:Sphingosine