Schedule-dependent molecular effects of the proteasome inhibitor bortezomib and gemcitabine in pancreatic cancer

Bridget N. Fahy, Michael G. Schlieman, Subbulakshi Virudachalam, Richard J Bold

Research output: Contribution to journalArticle

46 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)88-95
Number of pages8
JournalJournal of Surgical Research
Volume113
Issue number1
DOIs
StatePublished - Jul 2003

Fingerprint

gemcitabine
Proteasome Inhibitors
Pancreatic Neoplasms
Appointments and Schedules
Apoptosis
Clinical Trials
Drug Therapy
Cell Cycle Proteins
Apoptosis Regulatory Proteins
Cell Cycle
Proteins
Biomarkers
Western Blotting
Bortezomib
Growth
Neoplasms

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 journalArticle

Fahy, Bridget N. ; Schlieman, Michael G. ; Virudachalam, Subbulakshi ; Bold, Richard J. / Schedule-dependent molecular effects of the proteasome inhibitor bortezomib and gemcitabine in pancreatic cancer. In: Journal of Surgical Research. 2003 ; Vol. 113, No. 1. pp. 88-95.
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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.",
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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.

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