Abstract/Details

The involvement of anti-apoptotic Bcl-2 family proteins in vinblastine-induced apoptosis


2009 2009

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Abstract (summary)

The efficacy of many chemotherapeutic agents can be attenuated by expression of the anti-apoptotic proteins Bcl-2, Bcl-X and Mcl-1. When ML-1 leukemia cells are incubated with vinblastine, they rapidly upregulate Mcl-1. Suppression of Mcl-1 with inhibitors of MEK-ERK signaling or by expression of shRNA dramatically accelerates the rate of apoptosis with cells dying in 4 hours. However, most leukemia cells appear to rely on Bcl-2 or Bcl-X rather than Mcl-1 to protect themselves from this acute vinblastine-mediated apoptosis. Small molecule inhibitors of Bcl-2 proteins were investigated for their ability to sensitize a range of leukemia cell lines to vinblastine. ABT-737, an inhibitor of Bcl-2 and Bcl-X, acutely sensitized only the NB4 cells which express only Bcl-2. Most of the other cell lines also expressed Mcl-1 which may provide resistance to ABT-737. However, GX15-070, which inhibits Mcl-1, Bcl-2 and Bcl-X only sensitized the ML-1 cells. This was attributed to its ability to inhibit MEK-ERK signaling and consequently suppress Mcl-1 protein levels. This is an off-target effect of this inhibitor, and no on-target effect was confirmed. As an alternative means to suppress Mcl-1, global transcription was suppressed with flavopiridol. Flavopiridol acutely sensitized most of the leukemia lines to vinblastine. Because flavopiridol-mediated sensitization did not correlate with expression of Mcl-1, these results suggest another short-lived protein suppresses this acute apoptosis. It is proposed that vinblastine primes the cells for apoptosis by activating a pro-apoptotic Bcl-2 protein while concurrent inhibition of anti-apoptotic proteins leads to rapid apoptosis. The rapid apoptosis is dependent on vinblastine-mediated activation of JNK which may cause concurrent inhibition of Bcl-2. One exception is the sensitization of NB4 cells to ABT-737, a situation where JNK-mediated inhibition of Bcl-2 would be redundant. Interestingly, OCI-AML1 cells were acutely sensitive to vinblastine alone, which was attributed to their expression of only Bcl-2 and at very low levels. The results have clinical significance as they show that brief administration of these drugs in combination can be sufficient to kill leukemia cells. A future challenge will be to determine which tumors will respond to each drug combination.

Indexing (details)


Subject
Molecular biology
Classification
0307: Molecular biology
Identifier / keyword
Biological sciences; Apoptosis; Bcl-2; Leukemia; Mcl-1
Title
The involvement of anti-apoptotic Bcl-2 family proteins in vinblastine-induced apoptosis
Author
Salerni, Bethany L.
Number of pages
129
Publication year
2009
Degree date
2009
School code
0059
Source
DAI-B 71/04, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9781109703504
Advisor
Eastman, Alan R.
Committee member
Cole, Michael; Lowrey, Christopher; Noelle, Randolph
University/institution
Dartmouth College
Department
Pharmacology and Toxicology
University location
United States -- New Hampshire
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3397933
ProQuest document ID
230876932
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/230876932
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