Potentiation of paclitaxel cytotoxicity in lung and esophageal cancer cells by pharmacologic inhibition of the phosphoinositide 3-kinase/protein kinase B (Akt)-mediated signaling pathway

Dao Nguyen, G. Aaron Chen, Rishindra Reddy, Wilson Tsai, William D. Schrump, George Cole, David S. Schrump, David A. Jones, Steven J. Mentzer, David H. Harpole

Research output: Contribution to journalArticle

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Abstract

Background: Constitutive activation of the phosphoinositide 3-kinase/protein kinase B survival signal transduction pathway influences the intrinsic chemoresistance of cancer cells. This study evaluates the effect of LY294002, a pharmacologic inhibitor of phosphoinositide 3-kinase, on the sensitivity of lung and esophageal cancer cells to paclitaxel (Taxol) in vitro. Materials and Methods: Cell viability and apoptosis of cancer cells treated with paclitaxel + LY294002 combinations were quantitated by methyl-thiazol-diphenyl-tetrazolium and terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling-based ApoBrdU assays, respectively. The effect of LY294002-mediated phosphoinositide 3-kinase inhibition on protein kinase B (Akt) activation and nuclear factor-κB signaling was determined by Western blot analysis. Nuclear factor-κB transcription activity in cultured cancer cells either at baseline or after treatments with LY294002 or BAY11-0782 (a pharmacologic inhibitor of nuclear factor-κB) was determined by the nuclear factor κB-Luciferase reporter system. Results: A 4- to more than 20-fold reduction of paclitaxel IC50 values was observed in cancer cells treated with paclitaxel + LY294002 combinations. This was paralleled with synergistic induction of apoptosis. LY294002 treatment caused a significant dose-dependent inhibition of protein kinase B (Akt) activation and suppression of nuclear factor-κB transcriptional activity that was accompanied by elevation of IκB, the intrinsic inhibitor of nuclear factor-κB, and concomitant reduction of nuclear factor-κB-regulated antiapoptotic proteins cIAP1, cIAP2, and BclXL. Direct inhibition of nuclear factor-κB activity by BAY11-0782 also resulted in profound enhancement of paclitaxel sensitivity and paclitaxel-mediated induction of apoptosis in lung and esophageal cancer cells. Conclusion: LY294002-mediated inhibition of the phosphoinositide 3-kinase/protein kinase B-dependent survival pathway with secondary suppression of nuclear factor-κB transcriptional activity was associated with enhancement of paclitaxel cytotoxicity in lung and esophageal cancer cells. Direct inhibition of nuclear factor-κB by BAY11-0782 also sensitized these cancer cells to paclitaxel, indicating that nuclear factor-κB may be the crucial intermediary step connecting phosphoinositide 3-kinase/protein kinase B (Akt) to the intrinsic susceptibility of cancer cells to chemotherapeutic agents.

Original languageEnglish
Pages (from-to)365-375
Number of pages11
JournalJournal of Thoracic and Cardiovascular Surgery
Volume127
Issue number2
DOIs
StatePublished - Feb 1 2004
Externally publishedYes

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Proto-Oncogene Proteins c-akt
1-Phosphatidylinositol 4-Kinase
Esophageal Neoplasms
Paclitaxel
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Lung Neoplasms
Neoplasms
Apoptosis
Inhibitor of Apoptosis Proteins
DNA Nucleotidylexotransferase
Luciferases
Inhibitory Concentration 50
Cultured Cells
Signal Transduction
Cell Survival
Western Blotting

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

Cite this

Potentiation of paclitaxel cytotoxicity in lung and esophageal cancer cells by pharmacologic inhibition of the phosphoinositide 3-kinase/protein kinase B (Akt)-mediated signaling pathway. / Nguyen, Dao; Chen, G. Aaron; Reddy, Rishindra; Tsai, Wilson; Schrump, William D.; Cole, George; Schrump, David S.; Jones, David A.; Mentzer, Steven J.; Harpole, David H.

In: Journal of Thoracic and Cardiovascular Surgery, Vol. 127, No. 2, 01.02.2004, p. 365-375.

Research output: Contribution to journalArticle

Nguyen, Dao ; Chen, G. Aaron ; Reddy, Rishindra ; Tsai, Wilson ; Schrump, William D. ; Cole, George ; Schrump, David S. ; Jones, David A. ; Mentzer, Steven J. ; Harpole, David H. / Potentiation of paclitaxel cytotoxicity in lung and esophageal cancer cells by pharmacologic inhibition of the phosphoinositide 3-kinase/protein kinase B (Akt)-mediated signaling pathway. In: Journal of Thoracic and Cardiovascular Surgery. 2004 ; Vol. 127, No. 2. pp. 365-375.
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abstract = "Background: Constitutive activation of the phosphoinositide 3-kinase/protein kinase B survival signal transduction pathway influences the intrinsic chemoresistance of cancer cells. This study evaluates the effect of LY294002, a pharmacologic inhibitor of phosphoinositide 3-kinase, on the sensitivity of lung and esophageal cancer cells to paclitaxel (Taxol) in vitro. Materials and Methods: Cell viability and apoptosis of cancer cells treated with paclitaxel + LY294002 combinations were quantitated by methyl-thiazol-diphenyl-tetrazolium and terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling-based ApoBrdU assays, respectively. The effect of LY294002-mediated phosphoinositide 3-kinase inhibition on protein kinase B (Akt) activation and nuclear factor-κB signaling was determined by Western blot analysis. Nuclear factor-κB transcription activity in cultured cancer cells either at baseline or after treatments with LY294002 or BAY11-0782 (a pharmacologic inhibitor of nuclear factor-κB) was determined by the nuclear factor κB-Luciferase reporter system. Results: A 4- to more than 20-fold reduction of paclitaxel IC50 values was observed in cancer cells treated with paclitaxel + LY294002 combinations. This was paralleled with synergistic induction of apoptosis. LY294002 treatment caused a significant dose-dependent inhibition of protein kinase B (Akt) activation and suppression of nuclear factor-κB transcriptional activity that was accompanied by elevation of IκB, the intrinsic inhibitor of nuclear factor-κB, and concomitant reduction of nuclear factor-κB-regulated antiapoptotic proteins cIAP1, cIAP2, and BclXL. Direct inhibition of nuclear factor-κB activity by BAY11-0782 also resulted in profound enhancement of paclitaxel sensitivity and paclitaxel-mediated induction of apoptosis in lung and esophageal cancer cells. Conclusion: LY294002-mediated inhibition of the phosphoinositide 3-kinase/protein kinase B-dependent survival pathway with secondary suppression of nuclear factor-κB transcriptional activity was associated with enhancement of paclitaxel cytotoxicity in lung and esophageal cancer cells. Direct inhibition of nuclear factor-κB by BAY11-0782 also sensitized these cancer cells to paclitaxel, indicating that nuclear factor-κB may be the crucial intermediary step connecting phosphoinositide 3-kinase/protein kinase B (Akt) to the intrinsic susceptibility of cancer cells to chemotherapeutic agents.",
author = "Dao Nguyen and Chen, {G. Aaron} and Rishindra Reddy and Wilson Tsai and Schrump, {William D.} and George Cole and Schrump, {David S.} and Jones, {David A.} and Mentzer, {Steven J.} and Harpole, {David H.}",
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T1 - Potentiation of paclitaxel cytotoxicity in lung and esophageal cancer cells by pharmacologic inhibition of the phosphoinositide 3-kinase/protein kinase B (Akt)-mediated signaling pathway

AU - Nguyen, Dao

AU - Chen, G. Aaron

AU - Reddy, Rishindra

AU - Tsai, Wilson

AU - Schrump, William D.

AU - Cole, George

AU - Schrump, David S.

AU - Jones, David A.

AU - Mentzer, Steven J.

AU - Harpole, David H.

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Y1 - 2004/2/1

N2 - Background: Constitutive activation of the phosphoinositide 3-kinase/protein kinase B survival signal transduction pathway influences the intrinsic chemoresistance of cancer cells. This study evaluates the effect of LY294002, a pharmacologic inhibitor of phosphoinositide 3-kinase, on the sensitivity of lung and esophageal cancer cells to paclitaxel (Taxol) in vitro. Materials and Methods: Cell viability and apoptosis of cancer cells treated with paclitaxel + LY294002 combinations were quantitated by methyl-thiazol-diphenyl-tetrazolium and terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling-based ApoBrdU assays, respectively. The effect of LY294002-mediated phosphoinositide 3-kinase inhibition on protein kinase B (Akt) activation and nuclear factor-κB signaling was determined by Western blot analysis. Nuclear factor-κB transcription activity in cultured cancer cells either at baseline or after treatments with LY294002 or BAY11-0782 (a pharmacologic inhibitor of nuclear factor-κB) was determined by the nuclear factor κB-Luciferase reporter system. Results: A 4- to more than 20-fold reduction of paclitaxel IC50 values was observed in cancer cells treated with paclitaxel + LY294002 combinations. This was paralleled with synergistic induction of apoptosis. LY294002 treatment caused a significant dose-dependent inhibition of protein kinase B (Akt) activation and suppression of nuclear factor-κB transcriptional activity that was accompanied by elevation of IκB, the intrinsic inhibitor of nuclear factor-κB, and concomitant reduction of nuclear factor-κB-regulated antiapoptotic proteins cIAP1, cIAP2, and BclXL. Direct inhibition of nuclear factor-κB activity by BAY11-0782 also resulted in profound enhancement of paclitaxel sensitivity and paclitaxel-mediated induction of apoptosis in lung and esophageal cancer cells. Conclusion: LY294002-mediated inhibition of the phosphoinositide 3-kinase/protein kinase B-dependent survival pathway with secondary suppression of nuclear factor-κB transcriptional activity was associated with enhancement of paclitaxel cytotoxicity in lung and esophageal cancer cells. Direct inhibition of nuclear factor-κB by BAY11-0782 also sensitized these cancer cells to paclitaxel, indicating that nuclear factor-κB may be the crucial intermediary step connecting phosphoinositide 3-kinase/protein kinase B (Akt) to the intrinsic susceptibility of cancer cells to chemotherapeutic agents.

AB - Background: Constitutive activation of the phosphoinositide 3-kinase/protein kinase B survival signal transduction pathway influences the intrinsic chemoresistance of cancer cells. This study evaluates the effect of LY294002, a pharmacologic inhibitor of phosphoinositide 3-kinase, on the sensitivity of lung and esophageal cancer cells to paclitaxel (Taxol) in vitro. Materials and Methods: Cell viability and apoptosis of cancer cells treated with paclitaxel + LY294002 combinations were quantitated by methyl-thiazol-diphenyl-tetrazolium and terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling-based ApoBrdU assays, respectively. The effect of LY294002-mediated phosphoinositide 3-kinase inhibition on protein kinase B (Akt) activation and nuclear factor-κB signaling was determined by Western blot analysis. Nuclear factor-κB transcription activity in cultured cancer cells either at baseline or after treatments with LY294002 or BAY11-0782 (a pharmacologic inhibitor of nuclear factor-κB) was determined by the nuclear factor κB-Luciferase reporter system. Results: A 4- to more than 20-fold reduction of paclitaxel IC50 values was observed in cancer cells treated with paclitaxel + LY294002 combinations. This was paralleled with synergistic induction of apoptosis. LY294002 treatment caused a significant dose-dependent inhibition of protein kinase B (Akt) activation and suppression of nuclear factor-κB transcriptional activity that was accompanied by elevation of IκB, the intrinsic inhibitor of nuclear factor-κB, and concomitant reduction of nuclear factor-κB-regulated antiapoptotic proteins cIAP1, cIAP2, and BclXL. Direct inhibition of nuclear factor-κB activity by BAY11-0782 also resulted in profound enhancement of paclitaxel sensitivity and paclitaxel-mediated induction of apoptosis in lung and esophageal cancer cells. Conclusion: LY294002-mediated inhibition of the phosphoinositide 3-kinase/protein kinase B-dependent survival pathway with secondary suppression of nuclear factor-κB transcriptional activity was associated with enhancement of paclitaxel cytotoxicity in lung and esophageal cancer cells. Direct inhibition of nuclear factor-κB by BAY11-0782 also sensitized these cancer cells to paclitaxel, indicating that nuclear factor-κB may be the crucial intermediary step connecting phosphoinositide 3-kinase/protein kinase B (Akt) to the intrinsic susceptibility of cancer cells to chemotherapeutic agents.

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