Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer.

Details

Serval ID
serval:BIB_E6413D3AF9DB
Type
Article: article from journal or magazin.
Collection
Publications
Title
Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer.
Journal
Cancer Research
Author(s)
Selzner M., Bielawska A., Morse M.A., Rüdiger H.A., Sindram D., Hannun Y.A., Clavien P.A.
ISSN
0008-5472 (Print)
ISSN-L
0008-5472
Publication state
Published
Issued date
2001
Volume
61
Number
3
Pages
1233-1240
Language
english
Notes
Publication types: Journal Article ; Research Support, U.S. Gov't, P.H.S.Publication Status: ppublish
Abstract
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.
Keywords
Amides/pharmacology, Amidohydrolases/antagonists & inhibitors, Animals, Apoptosis/drug effects, Ceramidases, Ceramides/metabolism, Ceramides/pharmacology, Colonic Neoplasms/drug therapy, Colonic Neoplasms/metabolism, Enzyme Inhibitors/pharmacology, Growth Inhibitors/pharmacology, Humans, Liver/cytology, Liver/drug effects, Liver Neoplasms, Experimental/prevention & control, Liver Neoplasms, Experimental/secondary, Male, Mice, Myristates/pharmacology, Propanolamines/pharmacology, Rats, Rats, Wistar, Sphingosine/analogs & derivatives, Sphingosine/pharmacology, Xenograft Model Antitumor Assays
Pubmed
Web of science
Create date
13/02/2012 9:36
Last modification date
20/08/2019 17:09
Usage data