Adaptation to low pH modifies thermal and thermo-chemical responses of mammalian cells

Abstract

The thermal and thermochemical survival responses of mammalian cells growing routinely at pH 7.4 are affected by extracellular pH. The cells show an increase in sensitivity when heated at pH values below about pH 7 0. The possibility that this sensitivity at low pH can be modified by maintaining the cells at pH 6.8 (‘EP-2’ cells) or pH 6.5 (‘EP-1’ cells) was examined. When Chinese hamster cells (HA-1) were exposed to 42°C at pH 6.5, 6.8 and 7.4, a dramatic increase in sensitivity was seen at pH 6.5. EP-2 cells similarly exposed showed considerably less difference at the three pH values. Variations in survival due to these pH changes were almost eliminated when the EP-1 cells were exposed to 42°C. HA-1 cells tended to develop less thermotolerance rates and did so possibly at a reduced rate at pH 6.8 when compared to pH 7.4; the reduced pH had only a minor effect on the ability of EP-2 cells to develop thermotolerance. The effects of pH adaptation on the pH dependence of drug cytotoxicity at 37°C or at 43°C were also compared. Adaptation also modified drug cytotoxicity except that cell killing by BCNU (as a function of pH) was similar for both HA-1 and EP-2 cells at both temperatures. EP-2 cells were more sensitive to MMS treatment at 43°C and more resistant at 37°C than were HA-1 cells. EP-2 cells were consistently more resistant than HA-1 cells to the actions of bleomycin, amphotericin B and cis-platinum over the entire pH range examined; this was particularly true at 43°C. The data clearly show that the pH dependence of cytotoxicity at elevated temperatures is affected by pH history.