Pancreatic cancer cell genetics and signaling response to treatment correlate with efficacy of gemcitabine-based molecular targeting strategies

Bryan Holcomb, Michele Yip-Schneider, Jesus M. Matos, Jennifer Dixon, Jason Kennard, Julie Mahomed, Rajasubramaniam Shanmugam, Judith Sebolt-Leopold, C. Schmidt

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Introduction Pancreatic cancer is a deadly cancer with limited sensitivity to gemcitabine. Molecular targeting of critical signaling pathways [nuclear factor kappa-B (NF-κB), PI3K/AKT, and mutagen-activated protein kinas (MAPK)] in combination with gemcitabine may improve sensitivity. We hypothesize that pancreatic cancer cell genetics and signaling response to treatment correlate with efficacy of gemcitabine-based molecular targeting strategies. Materials and Methods PANC-1, PaCa-2, and BxPC-3 cells were treated with cur cumin, LY294002, or PD325901 alone or in combination with gemcitabine. Proliferation was measured by cell counts and enzyme activity by Western blot and electro phonetic mobility shift assay. Results each agent dose-dependently decreased proliferation. All cells decreased NF-κB activity with cur cumin (24 h) except PaCa-2, MEK activity with PD325901 (24 h), and PI3Kinase with LY294002 (3 h). However, PI3K rebounded to (PaCa-2) or above (Panc-1, BxPC-3) basal in LY294002-treated cells (24 h). Combinations with gemcitabine resulted in at least additive effects on proliferate inhibition. For PANC-1, cur cumin + gemcitabine were nearly synergistic, correlating with gemcitabine-induced NF-κB activity. LY294002 + gemcitabine were nearly synergistic in PaCa-2 cells, which showed a lower induction of PI3Kinase activity with LY294002. Finally, gemcitabine + PD325901 were only effective in BxPC-3, which exhibited increased MEK activity with gemcitabine. Conclusions these results demonstrate differences in treatment efficacy, which correlate with the cell's signaling response to treatment. Signaling profiles of each tumor may be necessary to determine an optimal chemotherapy for pancreatic cancer.

Original languageEnglish
Pages (from-to)288-296
Number of pages9
JournalJournal of Gastrointestinal Surgery
Volume12
Issue number2
DOIs
StatePublished - 2008

Fingerprint

gemcitabine
Pancreatic Neoplasms
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Cuminum
NF-kappa B
Mitogen-Activated Protein Kinase Kinases
Phosphatidylinositol 3-Kinases
Phonetics
Critical Pathways
Mutagens
Electrophoretic Mobility Shift Assay

Keywords

  • Gemcitabine
  • MAP kinase
  • NF-κB
  • Pancreatic cancer
  • PI3 kinas

ASJC Scopus subject areas

  • Surgery
  • Gastroenterology

Cite this

Pancreatic cancer cell genetics and signaling response to treatment correlate with efficacy of gemcitabine-based molecular targeting strategies. / Holcomb, Bryan; Yip-Schneider, Michele; Matos, Jesus M.; Dixon, Jennifer; Kennard, Jason; Mahomed, Julie; Shanmugam, Rajasubramaniam; Sebolt-Leopold, Judith; Schmidt, C.

In: Journal of Gastrointestinal Surgery, Vol. 12, No. 2, 2008, p. 288-296.

Research output: Contribution to journalArticle

Holcomb, Bryan ; Yip-Schneider, Michele ; Matos, Jesus M. ; Dixon, Jennifer ; Kennard, Jason ; Mahomed, Julie ; Shanmugam, Rajasubramaniam ; Sebolt-Leopold, Judith ; Schmidt, C. / Pancreatic cancer cell genetics and signaling response to treatment correlate with efficacy of gemcitabine-based molecular targeting strategies. In: Journal of Gastrointestinal Surgery. 2008 ; Vol. 12, No. 2. pp. 288-296.
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abstract = "Introduction Pancreatic cancer is a deadly cancer with limited sensitivity to gemcitabine. Molecular targeting of critical signaling pathways [nuclear factor kappa-B (NF-κB), PI3K/AKT, and mutagen-activated protein kinas (MAPK)] in combination with gemcitabine may improve sensitivity. We hypothesize that pancreatic cancer cell genetics and signaling response to treatment correlate with efficacy of gemcitabine-based molecular targeting strategies. Materials and Methods PANC-1, PaCa-2, and BxPC-3 cells were treated with cur cumin, LY294002, or PD325901 alone or in combination with gemcitabine. Proliferation was measured by cell counts and enzyme activity by Western blot and electro phonetic mobility shift assay. Results each agent dose-dependently decreased proliferation. All cells decreased NF-κB activity with cur cumin (24 h) except PaCa-2, MEK activity with PD325901 (24 h), and PI3Kinase with LY294002 (3 h). However, PI3K rebounded to (PaCa-2) or above (Panc-1, BxPC-3) basal in LY294002-treated cells (24 h). Combinations with gemcitabine resulted in at least additive effects on proliferate inhibition. For PANC-1, cur cumin + gemcitabine were nearly synergistic, correlating with gemcitabine-induced NF-κB activity. LY294002 + gemcitabine were nearly synergistic in PaCa-2 cells, which showed a lower induction of PI3Kinase activity with LY294002. Finally, gemcitabine + PD325901 were only effective in BxPC-3, which exhibited increased MEK activity with gemcitabine. Conclusions these results demonstrate differences in treatment efficacy, which correlate with the cell's signaling response to treatment. Signaling profiles of each tumor may be necessary to determine an optimal chemotherapy for pancreatic cancer.",
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T1 - Pancreatic cancer cell genetics and signaling response to treatment correlate with efficacy of gemcitabine-based molecular targeting strategies

AU - Holcomb, Bryan

AU - Yip-Schneider, Michele

AU - Matos, Jesus M.

AU - Dixon, Jennifer

AU - Kennard, Jason

AU - Mahomed, Julie

AU - Shanmugam, Rajasubramaniam

AU - Sebolt-Leopold, Judith

AU - Schmidt, C.

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N2 - Introduction Pancreatic cancer is a deadly cancer with limited sensitivity to gemcitabine. Molecular targeting of critical signaling pathways [nuclear factor kappa-B (NF-κB), PI3K/AKT, and mutagen-activated protein kinas (MAPK)] in combination with gemcitabine may improve sensitivity. We hypothesize that pancreatic cancer cell genetics and signaling response to treatment correlate with efficacy of gemcitabine-based molecular targeting strategies. Materials and Methods PANC-1, PaCa-2, and BxPC-3 cells were treated with cur cumin, LY294002, or PD325901 alone or in combination with gemcitabine. Proliferation was measured by cell counts and enzyme activity by Western blot and electro phonetic mobility shift assay. Results each agent dose-dependently decreased proliferation. All cells decreased NF-κB activity with cur cumin (24 h) except PaCa-2, MEK activity with PD325901 (24 h), and PI3Kinase with LY294002 (3 h). However, PI3K rebounded to (PaCa-2) or above (Panc-1, BxPC-3) basal in LY294002-treated cells (24 h). Combinations with gemcitabine resulted in at least additive effects on proliferate inhibition. For PANC-1, cur cumin + gemcitabine were nearly synergistic, correlating with gemcitabine-induced NF-κB activity. LY294002 + gemcitabine were nearly synergistic in PaCa-2 cells, which showed a lower induction of PI3Kinase activity with LY294002. Finally, gemcitabine + PD325901 were only effective in BxPC-3, which exhibited increased MEK activity with gemcitabine. Conclusions these results demonstrate differences in treatment efficacy, which correlate with the cell's signaling response to treatment. Signaling profiles of each tumor may be necessary to determine an optimal chemotherapy for pancreatic cancer.

AB - Introduction Pancreatic cancer is a deadly cancer with limited sensitivity to gemcitabine. Molecular targeting of critical signaling pathways [nuclear factor kappa-B (NF-κB), PI3K/AKT, and mutagen-activated protein kinas (MAPK)] in combination with gemcitabine may improve sensitivity. We hypothesize that pancreatic cancer cell genetics and signaling response to treatment correlate with efficacy of gemcitabine-based molecular targeting strategies. Materials and Methods PANC-1, PaCa-2, and BxPC-3 cells were treated with cur cumin, LY294002, or PD325901 alone or in combination with gemcitabine. Proliferation was measured by cell counts and enzyme activity by Western blot and electro phonetic mobility shift assay. Results each agent dose-dependently decreased proliferation. All cells decreased NF-κB activity with cur cumin (24 h) except PaCa-2, MEK activity with PD325901 (24 h), and PI3Kinase with LY294002 (3 h). However, PI3K rebounded to (PaCa-2) or above (Panc-1, BxPC-3) basal in LY294002-treated cells (24 h). Combinations with gemcitabine resulted in at least additive effects on proliferate inhibition. For PANC-1, cur cumin + gemcitabine were nearly synergistic, correlating with gemcitabine-induced NF-κB activity. LY294002 + gemcitabine were nearly synergistic in PaCa-2 cells, which showed a lower induction of PI3Kinase activity with LY294002. Finally, gemcitabine + PD325901 were only effective in BxPC-3, which exhibited increased MEK activity with gemcitabine. Conclusions these results demonstrate differences in treatment efficacy, which correlate with the cell's signaling response to treatment. Signaling profiles of each tumor may be necessary to determine an optimal chemotherapy for pancreatic cancer.

KW - Gemcitabine

KW - MAP kinase

KW - NF-κB

KW - Pancreatic cancer

KW - PI3 kinas

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