BACKGROUND: 26S proteasome inhibitors are a novel class of compounds entering clinical trials as a method to increase @entity5 sensitivity to standard chemotherapy. We determined the effect of alternate sequencing regimens of a proteasome inhibitor and @entity136 on molecular and cellular responses in @entity788 cells. MATERIALS AND METHODS: MIA-PaCa-2 @entity1 @entity788 cells were treated with the proteasome inhibitor @entity1749 either before, simultaneously or following exposure to @entity136 . Expression of the cell cycle proteins @entity994 ( @entity994 / @entity994 ) and @entity993 ( @entity13525 ), and the anti-apoptotic protein @entity588 were determined by Western blotting. Cell cycle changes and immediate or delayed induction of apoptosis were quantitated. RESULTS: @entity136 followed by @entity1749 induced the greatest induction of apoptosis and long-term inhibition of cell growth. @entity1749 treatment led to accumulation of @entity994 ( @entity994 / @entity994 ) and @entity993 ( @entity13525 ) and decreased @entity588 ; @entity136 decreased @entity993 ( @entity13525 ), induced @entity588 and had no effect on @entity994 ( @entity994 / @entity994 ). When these agents were given in combination or sequence, intermediate changes in these proteins were observed, and the alterations did not correlate with immediate or delayed induction of apoptosis. CONCLUSIONS: Inhibition of the 26S proteasome following chemotherapy appears to be the most effective regimen, though changes in @entity588 , @entity994 ( @entity994 / @entity994 ), @entity993 ( @entity13525 ) do not necessarily correlate with the cellular effects when various sequences are examined. Therefore, these proteins may not be the most appropriate surrogate markers of efficacy of this regimen. These data provide the background for the development of the optimal regimen to be used in clinical trials.

Schedule-dependent molecular effects of the proteasome inhibitor @entity1749 and XXXX in @entity788 .

@entity1 :: ('9606', 'Species') :: ['human'] @entity788 :: ('MESH:D010190', 'Disease') :: ['pancreatic cancer'] @entity588 :: ('596', 'Gene') :: ['BCL-2'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor'] @entity993 :: ('10671', 'Gene') :: ['p27'] @entity13525 :: ('1027', 'Gene') :: ['KIP1'] @entity1749 :: ('MESH:C400082', 'Chemical') :: ['bortezomib', 'Bortezomib'] @entity136 :: ('MESH:C056507', 'Chemical') :: ['Gemcitabine', 'gemcitabine'] @entity994 :: ('1026', 'Gene') :: ['CIP1', 'p21', 'WAF1']
@entity136 :: (MESH:C056507,Chemical) :: ['gemcitabine']
