Abstract
Background. 26S proteasome inhibitors are a novel class of compounds entering clinical trials as a method to increase tumor sensitivity to standard chemotherapy. We determined the effect of alternate sequencing regimens of a proteasome inhibitor and gemcitabine on molecular and cellular responses in pancreatic cancer cells. Materials and methods. MIA-PaCa-2 human pancreatic cancer cells were treated with the proteasome inhibitor bortezomib either before, simultaneously or following exposure to gemcitabine. Expression of the cell cycle proteins p21WAF1/CIP1 and p27KIP1, and the anti-apoptotic protein BCL-2 were determined by Western blotting. Cell cycle changes and immediate or delayed induction of apoptosis were quantitated. Results. Gemcitabine followed by bortezomib induced the greatest induction of apoptosis and long-term inhibition of cell growth. Bortezomib treatment led to accumulation of p21WAF1/CIP1 and p27KIP1 and decreased BCL-2; gemcitabine decreased p27KIP1, induced BCL-2 and had no effect on p21WAF1/CIP1. 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 BCL-2, p21WAF1/CIP1, p27KIP1 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 88-95 |
| Number of pages | 8 |
| Journal | Journal of Surgical Research |
| Volume | 113 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 2003 |
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Keywords
- BCL-2
- NF-κB
- p21
- p27
ASJC Scopus subject areas
- Surgery
Cite this
Schedule-dependent molecular effects of the proteasome inhibitor bortezomib and gemcitabine in pancreatic cancer. / Fahy, Bridget N.; Schlieman, Michael G.; Virudachalam, Subbulakshi; Bold, Richard J.
In: Journal of Surgical Research, Vol. 113, No. 1, 07.2003, p. 88-95.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Schedule-dependent molecular effects of the proteasome inhibitor bortezomib and gemcitabine in pancreatic cancer
AU - Fahy, Bridget N.
AU - Schlieman, Michael G.
AU - Virudachalam, Subbulakshi
AU - Bold, Richard J
PY - 2003/7
Y1 - 2003/7
N2 - Background. 26S proteasome inhibitors are a novel class of compounds entering clinical trials as a method to increase tumor sensitivity to standard chemotherapy. We determined the effect of alternate sequencing regimens of a proteasome inhibitor and gemcitabine on molecular and cellular responses in pancreatic cancer cells. Materials and methods. MIA-PaCa-2 human pancreatic cancer cells were treated with the proteasome inhibitor bortezomib either before, simultaneously or following exposure to gemcitabine. Expression of the cell cycle proteins p21WAF1/CIP1 and p27KIP1, and the anti-apoptotic protein BCL-2 were determined by Western blotting. Cell cycle changes and immediate or delayed induction of apoptosis were quantitated. Results. Gemcitabine followed by bortezomib induced the greatest induction of apoptosis and long-term inhibition of cell growth. Bortezomib treatment led to accumulation of p21WAF1/CIP1 and p27KIP1 and decreased BCL-2; gemcitabine decreased p27KIP1, induced BCL-2 and had no effect on p21WAF1/CIP1. 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 BCL-2, p21WAF1/CIP1, p27KIP1 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.
AB - Background. 26S proteasome inhibitors are a novel class of compounds entering clinical trials as a method to increase tumor sensitivity to standard chemotherapy. We determined the effect of alternate sequencing regimens of a proteasome inhibitor and gemcitabine on molecular and cellular responses in pancreatic cancer cells. Materials and methods. MIA-PaCa-2 human pancreatic cancer cells were treated with the proteasome inhibitor bortezomib either before, simultaneously or following exposure to gemcitabine. Expression of the cell cycle proteins p21WAF1/CIP1 and p27KIP1, and the anti-apoptotic protein BCL-2 were determined by Western blotting. Cell cycle changes and immediate or delayed induction of apoptosis were quantitated. Results. Gemcitabine followed by bortezomib induced the greatest induction of apoptosis and long-term inhibition of cell growth. Bortezomib treatment led to accumulation of p21WAF1/CIP1 and p27KIP1 and decreased BCL-2; gemcitabine decreased p27KIP1, induced BCL-2 and had no effect on p21WAF1/CIP1. 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 BCL-2, p21WAF1/CIP1, p27KIP1 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.
KW - BCL-2
KW - NF-κB
KW - p21
KW - p27
UR - http://www.scopus.com/inward/record.url?scp=0042235056&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0042235056&partnerID=8YFLogxK
U2 - 10.1016/S0022-4804(03)00201-4
DO - 10.1016/S0022-4804(03)00201-4
M3 - Article
C2 - 12943815
AN - SCOPUS:0042235056
VL - 113
SP - 88
EP - 95
JO - Journal of Surgical Research
JF - Journal of Surgical Research
SN - 0022-4804
IS - 1
ER -