Linked Life Data

17541428

Source:http://linkedlifedata.com/resource/pubmed/id/17541428

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2007-8-17
pubmed:abstractText
Melanoma cells depend on sustained proteasomal function for survival. However, bortezomib, the first proteasome inhibitor in clinical use, is not sufficient to improve the poor prognosis of metastatic melanoma patients. Since the proteasome is also expressed in all normal cell compartments, it is unclear how to enhance the efficacy of bortezomib without exacerbating secondary toxicities. Here, we present pharmacological and genetic analyses of mechanisms of resistance to proteasome inhibition. We focused on Bcl-2, Bcl-x(L) and Mcl-1 as main antiapoptotic factors associated with melanoma progression. Despite an efficient blockage of the proteasome, bortezomib could not counteract the intrinsically high levels of Bcl-2 and Bcl-x(L) in melanoma cells. Moreover, Mcl-1 was only downregulated at late time points after treatment. Based on these results, a combination treatment including (-)-gossypol, an inhibitor of Mcl-1/Bcl-2/Bcl-x(L), was designed and proven effective in vivo. Using a specific RNA interference approach, the survival of bortezomib-treated melanoma cells was found to rely primarily on Mcl-1, and to a lesser extent on Bcl-x(L) (but not on Bcl-2). Importantly, neither Mcl-1 nor Bcl-x(L) inactivation affected the viability of normal melanocytes. This hierarchical requirement of Bcl-2 family members for the maintenance of normal and malignant cells offers a therapeutic window to overcome melanoma chemoresistance in a tumor cell-selective manner.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
1350-9047
pubmed:author
pubmed:issnType
Print
pubmed:volume
14
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1605-16
pubmed:meshHeading
pubmed-meshheading:17541428-Animals, pubmed-meshheading:17541428-Antineoplastic Agents, pubmed-meshheading:17541428-Antineoplastic Combined Chemotherapy Protocols, pubmed-meshheading:17541428-Apoptosis, pubmed-meshheading:17541428-Boronic Acids, pubmed-meshheading:17541428-Caspases, pubmed-meshheading:17541428-Cell Line, Tumor, pubmed-meshheading:17541428-Gossypol, pubmed-meshheading:17541428-Humans, pubmed-meshheading:17541428-Melanoma, Experimental, pubmed-meshheading:17541428-Mice, pubmed-meshheading:17541428-Neoplasm Transplantation, pubmed-meshheading:17541428-Protease Inhibitors, pubmed-meshheading:17541428-Proteasome Endopeptidase Complex, pubmed-meshheading:17541428-Proto-Oncogene Proteins c-bcl-2, pubmed-meshheading:17541428-Pyrazines, pubmed-meshheading:17541428-Transplantation, Heterologous
pubmed:year
2007
pubmed:articleTitle
Therapeutic window for melanoma treatment provided by selective effects of the proteasome on Bcl-2 proteins.
pubmed:affiliation
Department of Dermatology, University of Michigan, Comprehensive Cancer Center, Ann Arbor, MI 48109, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural