Intracellular pH and heat sensitivity in two human cancer cell lines.
OBJECTIVE
The majority of studies which have demonstrated a linear correlation between intracellular pH (pHi) and thermosensitivity have used rodent cell lines. In order to understand the therapeutic potential of this strategy, it is necessary to determine whether similar observations can be obtained with human cancer cells.


METHODS
Human breast cancer MCF-7, and nasopharyngeal carcinoma CNE-1 cell lines were heated at 43 degrees C under extracellular pH (pHe) conditions of 7.2 or 6.8, +/- NaHCO3. We studied the function of the Na+/H+ antiport, one of the primary membrane regulators of pHi, pHi level, and clonogenic survival after these treatments.


RESULTS
After 2-h exposure to 43 degrees C at pHe 7.2, antiport activity in MCF-7 cells was > 50% relative to that of unheated cells, in contrast to < 20% relative activity for CNE-1 cells. Respective survival levels under these conditions were 0.25 and 0.04. The addition of 5-(N-ethyl-N-isoproply) amiloride (EIPA), a potent inhibitor of Na+/H+ antiport, had no effect on MCF-7 cells, but enhanced cytotoxicity for CNE-1 cells, when heated at pHe 6.8 without NaHCO3. Analysis of the correlation between log surviving fraction and pHi demonstrated that this relationship was much steeper for CNE-1 compared to MCF-7 cells.


CONCLUSIONS
The relationship between pHi levels and thermosensitivity observed in rodent cells can also apply to two human cancer cell lines: MCF-7 and CNE-1, with the latter cells being apparently more amenable to manipulations of pHi regulation compared to the former.
Li
J H
JH
Department of Radiation Oncology, Princess Margaret Hospital/Ontario Cancer Institute, Toronto, Canada.
Liu
F F
FF
D000584:Amiloride / Q000031:analogs & derivatives / Q000633:toxicity; D017920:Antiporters / Q000187:drug effects / Q000502:physiology*; D001943:Breast Neoplasms / Q000503:physiopathology / Q000628:therapy; D002470:Cell Survival; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D006979:Hyperthermia, Induced; D017136:Ion Transport; D009303:Nasopharyngeal Neoplasms / Q000503:physiopathology / Q000628:therapy; D011522:Protons; D015222:Sodium Channels; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000502:physiology*
D017920:Antiporters; D011522:Protons; D015222:Sodium Channels; D000584:Amiloride; C039614:ethylisopropylamiloride