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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.
- Source :
-
The Journal of thoracic and cardiovascular surgery [J Thorac Cardiovasc Surg] 2004 Feb; Vol. 127 (2), pp. 365-75. - Publication Year :
- 2004
-
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.<br />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.<br />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.
- Subjects :
- Antineoplastic Agents, Phytogenic administration & dosage
Apoptosis drug effects
Carcinoma, Non-Small-Cell Lung enzymology
Cell Survival drug effects
Chromones administration & dosage
Dose-Response Relationship, Drug
Down-Regulation drug effects
Drug Therapy, Combination
Enzyme Activation drug effects
Enzyme Inhibitors administration & dosage
Esophageal Neoplasms enzymology
Humans
Lung Neoplasms enzymology
Morpholines administration & dosage
NF-kappa B drug effects
NF-kappa B metabolism
Paclitaxel administration & dosage
Phosphatidylinositol 3-Kinases metabolism
Phosphorylation drug effects
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins c-akt
Statistics as Topic
Time Factors
Treatment Failure
Tumor Cells, Cultured
Antineoplastic Agents, Phytogenic toxicity
Carcinoma, Non-Small-Cell Lung drug therapy
Esophageal Neoplasms drug therapy
Lung Neoplasms drug therapy
Paclitaxel toxicity
Phosphatidylinositol 3-Kinases drug effects
Phosphoinositide-3 Kinase Inhibitors
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins antagonists & inhibitors
Proto-Oncogene Proteins drug effects
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0022-5223
- Volume :
- 127
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Journal of thoracic and cardiovascular surgery
- Publication Type :
- Academic Journal
- Accession number :
- 14762343
- Full Text :
- https://doi.org/10.1016/j.jtcvs.2003.09.033