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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.

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Nguyen, DM; Chen, GA; Reddy, R; Tsai, W; Schrump, WD; Cole, G; Schrump, DS
Published in: J Thorac Cardiovasc Surg
February 2004

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-kappaB signaling was determined by Western blot analysis. Nuclear factor-kappaB transcription activity in cultured cancer cells either at baseline or after treatments with LY294002 or BAY11-0782 (a pharmacologic inhibitor of nuclear factor-kappaB) was determined by the nuclear factor-kappaB-Luciferase reporter system. RESULTS: A 4- to more than 20-fold reduction of paclitaxel IC(50) 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-kappaB transcriptional activity that was accompanied by elevation of IkappaB, the intrinsic inhibitor of nuclear factor-kappaB, and concomitant reduction of nuclear factor-kappaB-regulated antiapoptotic proteins cIAP1, cIAP2, and BclXL. Direct inhibition of nuclear factor-kappaB 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-kappaB transcriptional activity was associated with enhancement of paclitaxel cytotoxicity in lung and esophageal cancer cells. Direct inhibition of nuclear factor-kappaB by BAY11-0782 also sensitized these cancer cells to paclitaxel, indicating that nuclear factor-kappaB 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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Published In

J Thorac Cardiovasc Surg

DOI

ISSN

0022-5223

Publication Date

February 2004

Volume

127

Issue

2

Start / End Page

365 / 375

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Treatment Failure
  • Time Factors
  • Statistics as Topic
  • Signal Transduction
  • Respiratory System
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • Phosphorylation
 

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Nguyen, D. M., Chen, G. A., Reddy, R., Tsai, W., Schrump, W. D., Cole, G., & Schrump, D. S. (2004). 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. J Thorac Cardiovasc Surg. United States. https://doi.org/10.1016/j.jtcvs.2003.09.033
Nguyen, Dao M., G Aaron Chen, Rishindra Reddy, Wilson Tsai, William D. Schrump, George Cole, and David S. Schrump. “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.J Thorac Cardiovasc Surg, February 2004. https://doi.org/10.1016/j.jtcvs.2003.09.033.
Nguyen, Dao M., et al. “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.J Thorac Cardiovasc Surg, vol. 127, no. 2, Feb. 2004, pp. 365–75. Pubmed, doi:10.1016/j.jtcvs.2003.09.033.
Journal cover image

Published In

J Thorac Cardiovasc Surg

DOI

ISSN

0022-5223

Publication Date

February 2004

Volume

127

Issue

2

Start / End Page

365 / 375

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Treatment Failure
  • Time Factors
  • Statistics as Topic
  • Signal Transduction
  • Respiratory System
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • Phosphorylation