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J Thorac Cardiovasc Surg 2004;127:365-375
© 2004 The American Association for Thoracic Surgery

General thoracic surgery

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 M. Nguyen, MD, MSc, FRCSC, FACSa,*, G. Aaron Chen, MSa, Rishindra Reddy, MDa, Wilson Tsai, MDa, William D. Schrumpa, George Cole, Jr, MDa, David S. Schrump, MD, FACSa

a Section of Thoracic Oncology, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md, USA

Read at the Eighty-third Annual Meeting of The American Association for Thoracic Surgery, Boston, Mass, May 4-7, 2003.

Received for publication May 2, 2003; revisions received August 28, 2003; accepted for publication September 9, 2003.

* Address for reprints: Dao M. Nguyen, MD, MSc, FRCSC, FACS, Section of Thoracic Oncology, Room 2B07, Building 10, 10 Center Drive, Bethesda, MD, USA
Dao_Nguyen{at}nih.gov

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-{kappa}B signaling was determined by Western blot analysis. Nuclear factor-{kappa}B transcription activity in cultured cancer cells either at baseline or after treatments with LY294002 or BAY11-0782 (a pharmacologic inhibitor of nuclear factor-{kappa}B) was determined by the nuclear factor-{kappa}B-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-{kappa}B transcriptional activity that was accompanied by elevation of I{kappa}B, the intrinsic inhibitor of nuclear factor-{kappa}B, and concomitant reduction of nuclear factor-{kappa}B–regulated antiapoptotic proteins cIAP1, cIAP2, and BclXL. Direct inhibition of nuclear factor-{kappa}B 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-{kappa}B transcriptional activity was associated with enhancement of paclitaxel cytotoxicity in lung and esophageal cancer cells. Direct inhibition of nuclear factor-{kappa}B by BAY11-0782 also sensitized these cancer cells to paclitaxel, indicating that nuclear factor-{kappa}B 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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