Linked Life Data

15930315

Source:http://linkedlifedata.com/resource/pubmed/id/15930315

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
2005-6-2
pubmed:abstractText
Breast cancer metastasis to the bone occurs frequently, causing numerous complications including severe pain, fracture, hypercalcemia, and paralysis. Despite its prevalence and severity, few effective therapies exist. To address this, we examined whether the heat shock protein 90 (Hsp90) inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), would be efficacious in inhibiting breast cancer metastasis to bone. Utilizing the human breast cancer subline, MDA-MB-231SA, previously in vivo selected for its enhanced ability to generate osteolytic bone lesions, we determined that 17-AAG potently inhibited its in vitro proliferation and migration. Moreover, 17-AAG significantly reduced MDA-MB-231SA tumor growth in the mammary-fat pad of nude mice. Despite these findings, 17-AAG enhanced the incidence of bone metastasis and osteolytic lesions following intracardiac inoculation in the nude mouse. Consistent with these findings, 17-AAG enhanced osteoclast formation 2- to 4-fold in mouse bone marrow/osteoblast cocultures, receptor activator of nuclear factor kappaB ligand (RANKL)-stimulated bone marrow, and RAW264.7 cell models of in vitro osteoclastogenesis. Moreover, the drug enhanced osteoclastogenesis in human cord blood progenitor cells, demonstrating that its effects were not limited to mouse models. In addition to 17-AAG, other Hsp90 inhibitors, such as radicicol and herbimycin A, also enhanced osteoclastogenesis. A pro-osteolytic action of 17-AAG independent of tumor presence was also determined in vivo, in which 17-AAG-treated tumor-naive mice had reduced trabecular bone volume with an associated increase in osteoclast number. Thus, HSP90 inhibitors can stimulate osteoclast formation, which may underlie the increased incidence of osteolysis and skeletal tumor incidence caused by 17-AAG in vivo. These data suggest an important contraindication to the Hsp90 targeted cancer therapy currently undergoing clinical trial.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
65
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4929-38
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:15930315-Animals, pubmed-meshheading:15930315-Benzoquinones, pubmed-meshheading:15930315-Bone Neoplasms, pubmed-meshheading:15930315-Breast Neoplasms, pubmed-meshheading:15930315-Cell Growth Processes, pubmed-meshheading:15930315-Cell Line, Tumor, pubmed-meshheading:15930315-Cell Movement, pubmed-meshheading:15930315-Chemotaxis, pubmed-meshheading:15930315-Disease Models, Animal, pubmed-meshheading:15930315-Female, pubmed-meshheading:15930315-HSP90 Heat-Shock Proteins, pubmed-meshheading:15930315-Humans, pubmed-meshheading:15930315-Lactams, Macrocyclic, pubmed-meshheading:15930315-Mice, pubmed-meshheading:15930315-Mice, Inbred BALB C, pubmed-meshheading:15930315-Mice, Nude, pubmed-meshheading:15930315-Neoplasm Transplantation, pubmed-meshheading:15930315-Osteoclasts, pubmed-meshheading:15930315-Rifabutin, pubmed-meshheading:15930315-Transplantation, Heterologous
pubmed:year
2005
pubmed:articleTitle
The heat shock protein 90 inhibitor, 17-allylamino-17-demethoxygeldanamycin, enhances osteoclast formation and potentiates bone metastasis of a human breast cancer cell line.
pubmed:affiliation
Tumour Cell Migration and Metastasis Laboratory, St. Vincent's Institute, Melbourne, Vistoria, Australia. jprice@svi.edu.au
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't