Linked Life Data

9354463

Source:http://linkedlifedata.com/resource/pubmed/id/9354463

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
21
pubmed:dateCreated
1997-11-20
pubmed:abstractText
Betulinic acid (BA), a melanoma-specific cytotoxic agent, induced apoptosis in neuroectodermal tumors, such as neuroblastoma, medulloblastoma, and Ewing's sarcoma, representing the most common solid tumors of childhood. BA triggered an apoptosis pathway different from the one previously identified for standard chemotherapeutic drugs. BA-induced apoptosis was independent of CD95-ligand/receptor interaction and accumulation of wild-type p53 protein, but it critically depended on activation of caspases (interleukin 1beta-converting enzyme/Ced-3-like proteases). FLICE/MACH (caspase-8), considered to be an upstream protease in the caspase cascade, and the downstream caspase CPP32/YAMA/Apopain (caspase-3) were activated, resulting in cleavage of the prototype substrate of caspases PARP. The broad-spectrum peptide inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, which blocked cleavage of FLICE and PARP, also completely abrogated BA-triggered apoptosis. Cleavage of caspases was preceded by disturbance of mitochondrial membrane potential and by generation of reactive oxygen species. Overexpression of Bcl-2 and Bcl-XL conferred resistance to BA at the level of mitochondrial dysfunction, protease activation, and nuclear fragmentation. This suggested that mitochondrial alterations were involved in BA-induced activation of caspases. Furthermore, Bax and Bcl-xs, two death-promoting proteins of the Bcl-2 family, were up-regulated following BA treatment. Most importantly, neuroblastoma cells resistant to CD95- and doxorubicin-mediated apoptosis were sensitive to treatment with BA, suggesting that BA may bypass some forms of drug resistance. Because BA exhibited significant antitumor activity on patients' derived neuroblastoma cells ex vivo, BA may be a promising new agent for the treatment of neuroectodermal tumors in vivo.
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Antibiotics, Antineoplastic, http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD95, http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, Phytogenic, http://linkedlifedata.com/resource/pubmed/chemical/Caspase 1, http://linkedlifedata.com/resource/pubmed/chemical/Cysteine Endopeptidases, http://linkedlifedata.com/resource/pubmed/chemical/DNA, Neoplasm, http://linkedlifedata.com/resource/pubmed/chemical/Doxorubicin, http://linkedlifedata.com/resource/pubmed/chemical/Neoplasm Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-bcl-2, http://linkedlifedata.com/resource/pubmed/chemical/Triterpenes, http://linkedlifedata.com/resource/pubmed/chemical/Tumor Suppressor Protein p53, http://linkedlifedata.com/resource/pubmed/chemical/betulinic acid
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
57
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4956-64
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1997
pubmed:articleTitle
Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors.
pubmed:affiliation
Division of Hematology/Oncology, University Children's Hospital, German Cancer Research Center, Heidelberg.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't