Paclitaxel induces apoptosis via protein kinase A- and p38 mitogen-activated protein-dependent inhibition of the Na+/H+ exchanger (NHE) NHE isoform 1 in human breast cancer cells

Stephan J. Reshkin, Antonia Bellizzi, Rosa Angela Cardone, Massimo Tommasino, Valeria Casavola, Angelo Paradiso

Research output: Contribution to journalArticle

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Abstract

Purpose: The molecular signal components essential to paclitaxel-dependent apoptosis in breast cancers are potential targets for combined therapy. However, the signal mechanisms underlying paclitaxel action still need to be better defined. Experimental Design: In a breast cancer cell line, pharmacological agents and transient transfection with dominant interfering and constitutive active mutants were used to identify the signal transduction module involved in the regulation of paclitaxel-induced apoptosis and to evaluate its potential as a therapeutic target. Results: In MDA-MB-435 cells, paclitaxel treatment stimulated the activity of both protein kinase A and p38, and inhibited the activity of the Na+H+ exchanger isoform 1 (NHE1) with similar IC50 concentrations as for its activation of apoptosis. Activation and inhibition experiments demonstrated that protein kinase A and p38 participate sequentially upstream of the NHE1 in regulating the paclitaxel-induced apoptotic pathway. Importantly, concurrent specific inhibition of the NHE1 with paclitaxel treatment resulted in a synergistic induction of apoptosis and a reduction in the paclitaxel IC50 for apoptosis. This sensitization of paclitaxel apoptotic action by specific inhibition of NHE1 was verified in breast cancer cell lines with different paclitaxel sensitivity. Conclusions: We have, for the first time, identified NHE1 as an essential component of paclitaxel-induced apoptosis in breast cancer cells and, importantly, identified that simultaneous inhibition of the NHE1 results in a synergistic potentiation of low-dose paclitaxel apoptotic action. As specific NHE1 inhibitors have finished Phase II/Phase III clinical trials for myocardial protection, there is the possibility for a rapid biological translation of this novel therapeutic strategy to a clinical setting.

Original languageEnglish
Pages (from-to)2366-2373
Number of pages8
JournalClinical Cancer Research
Volume9
Issue number6
Publication statusPublished - Jun 1 2003

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Sodium-Hydrogen Antiporter
Cyclic AMP-Dependent Protein Kinases
Paclitaxel
Mitogens
Protein Isoforms
Apoptosis
Breast Neoplasms
Proteins
Inhibitory Concentration 50
Cell Line
Phase III Clinical Trials
Transfection
Signal Transduction
Research Design
Therapeutics
Pharmacology

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Paclitaxel induces apoptosis via protein kinase A- and p38 mitogen-activated protein-dependent inhibition of the Na+/H+ exchanger (NHE) NHE isoform 1 in human breast cancer cells. / Reshkin, Stephan J.; Bellizzi, Antonia; Cardone, Rosa Angela; Tommasino, Massimo; Casavola, Valeria; Paradiso, Angelo.

In: Clinical Cancer Research, Vol. 9, No. 6, 01.06.2003, p. 2366-2373.

Research output: Contribution to journalArticle

Reshkin, Stephan J. ; Bellizzi, Antonia ; Cardone, Rosa Angela ; Tommasino, Massimo ; Casavola, Valeria ; Paradiso, Angelo. / Paclitaxel induces apoptosis via protein kinase A- and p38 mitogen-activated protein-dependent inhibition of the Na+/H+ exchanger (NHE) NHE isoform 1 in human breast cancer cells. In: Clinical Cancer Research. 2003 ; Vol. 9, No. 6. pp. 2366-2373.
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