Linked Life Data

15291360

Source:http://linkedlifedata.com/resource/pubmed/id/15291360

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2004-8-4
pubmed:abstractText
Bryostatin, a macrocyclic lactone and protein kinase C (PKC) modulator, has been shown to have differentiation and anti-tumor activity against several leukemia cell lines in vitro. In this study, we demonstrated Bryostatin-induced differentiation in B-cell chronic lymphocytic leukemia (B-CLL) cells, characterized by an increase in cell size and a marked up-regulation of CD11c expression. The specific inhibitors of the extracellular signal-regulated kinase (ERK) and protein kinase C pathways, PD98059 and GF 109203X respectively, each completely blocked Bryostatin-induced differentiation of B-CLL cells, suggesting that activation of the ERK pathway plays a direct role in this process in a PKC-dependent manner. Furthermore, Bryostatin reduced both spontaneous and drug-induced apoptosis with chlorambucil, fludarabine and 2-chloro-2'-deoxyadenosine (2-Cda) in B-CLL cells. This resistance was associated with an early up-regulation of the anti-apoptotic protein Mcl-1 and post-translational phosphorylation of Bcl-2 at serine 70. The anti-apoptotic effects of Bryostatin were abrogated by GF 109203X, and to a lesser extent by the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, LY294002. Interestingly, the ERK inhibitor, PD98059 inhibited Mcl-1 expression but had little effect on Bryostatin-induced survival suggesting that the ERK pathway predominantly affects differentiation. Taken together these results present an explanation for Bryostatin-induced B-CLL cell survival in which modulation of the PKC pathway couples differentiation with an increase in antiapoptotic protein expression and calls into question the rationale for its use in the treatment of B-CLL.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
1042-8194
pubmed:author
pubmed:issnType
Print
pubmed:volume
45
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
997-1008
pubmed:dateRevised
2008-7-9
pubmed:meshHeading
pubmed:year
2004
pubmed:articleTitle
Bryostatin induces protein kinase C modulation, Mcl-1 up-regulation and phosphorylation of Bcl-2 resulting in cellular differentiation and resistance to drug-induced apoptosis in B-cell chronic lymphocytic leukemia cells.
pubmed:affiliation
Department of Haematology, Llandough Hospital, Penlan Road, Penarth, Vale of Glamorgan, CF64 2XX, UK. alunt@llanhaem.demon.co.uk
pubmed:publicationType
Journal Article