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J Thorac Cardiovasc Surg. 2004 Feb;127(2):365-75.

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.

Author information

1
Section of Throacic Oncology, Surgery Branch, Center for Cancer Research, National Cancer Center, National Institutes of Health, Bethesda, MD, USA. Dao_Nguyen@nih.gov

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-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.

PMID:
14762343
DOI:
10.1016/j.jtcvs.2003.09.033
[Indexed for MEDLINE]
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