Cancer cells maintain low intracellular pH [pHi]; therefore, it is likely that resveratrol [RSVL] inhibits cell growth through interference with regulation of pHi. Na-H exchanger [NHE] regulates pHi and NaCl uptake. In this study, we investigated a putative role of NHE-1 and NHE-3 isoforms in the RSVL-induced cell death using MDA-MB-231 estrogen receptor-negative [ER-] and MCF-7 [ER+] human breast cancer cell lines. ECL Western blot analysis and fluorescence morphometeric analysis were used. Cell viability and counting were performed using standard procedures. RSVL caused a dose- and time-dependent induction of NHE-1 and NHE-3 proteins in both cancer cell lines as shown by ECL Western blot analysis and fluorescence measurement. Interestingly, the level of actin, an internal control, remains unaltered. Thus, it is concluded that RSVL-inhibited cell growth and viability, increased cell size, and volume along with an increased apoptotic activity are due to the induction of NHE-1 and NHE-3 isoforms in the present breast cancer cell lines. Induction of NHE will increase the uptake of NaCl and decrease pHi leading to disturbance in Ca(2+) homeostasis, which is responsible for cell death.