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 language | English |
|---|---|
| Pages (from-to) | 2366-2373 |
| Number of pages | 8 |
| Journal | Clinical Cancer Research |
| Volume | 9 |
| Issue number | 6 |
| Publication status | Published - Jun 1 2003 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
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 journal › Article
}
TY - JOUR
T1 - 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
AU - Reshkin, Stephan J.
AU - Bellizzi, Antonia
AU - Cardone, Rosa Angela
AU - Tommasino, Massimo
AU - Casavola, Valeria
AU - Paradiso, Angelo
PY - 2003/6/1
Y1 - 2003/6/1
N2 - 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.
AB - 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.
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M3 - Article
VL - 9
SP - 2366
EP - 2373
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 6
ER -