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Influence of Hypoxia and an Acidic Environment on the Metabolism and Viability of Cultured Cells: Potential Implications for Cell Death in Tumors¹

Departments of Medical Biophysics [D. R., I. F. T.] and Biochemistry [B. R.], University of Toronto, and Division of Physics [D. R., I. F. T.] and Department of Medicine [I. F. T.], Ontario Cancer Institute, 500 Sherbourne Street, Toronto, Ontario, Canada M4X 1K9

Hypoxia and an acidic environment are known to occur in regions of solid tumors and might be involved in the causation of necrosis. The viability and energy metabolism of cells in tissue culture were therefore investigated under hypoxic and/or acidic conditions. Acute exposure of Chinese hamster ovary (CHO) cells or human bladder cancer MGH-U1 cells to hypoxia plus low pH (6.5 to 6.0) was cytotoxic in a time- and pH-dependent manner; surviving fraction was reduced to 10^-4 following a 6-h exposure to hypoxia at pH 6.0. There was no effect on viability when aerobic CHO cells were exposed for 6 h at pH 6.0, or when either cell line was rendered hypoxic for 6 h at pH 7.0; MGH-U1 cells showed slight sensitivity to acidic pH in air. Decrease in viability of CHO cells incubated under acid conditions was observed over the range of oxygen concentrations from 0.2 to 0.05%, similar to the range which causes change in cellular sensitivity to radiation. Glucose consumption and lactate production by both cell lines were inhibited at low pH under both aerobic and hypoxic conditions. Cellular adenosine triphosphate (ATP) levels and the energy charge [(ATP + adenosine diphosphate)/(adenosine monophosphate + adenosine diphosphate + ATP)] of CHO cells were reduced by about 85 and 25%, respectively, after a 6-h exposure to hypoxia at pH 6.0 but were not influenced by hypoxia or acid pH alone. Inhibition of glycolysis by incubation of CHO cells under hypoxic conditions in the absence of glucose (at pH 7.0) led to a larger fall in cellular ATP and energy charge, but cell survival fell to only 10^-2 at 6 h. These results demonstrate that hypoxia and an acid environment interact to cause marked toxicity. A decrease in energy charge of the cells may contribute to loss of viability, but additional mechanisms appear to be involved.

¹ This study was supported by a research grant from the National Cancer Institute of Canada and by Grant CA 36913 from the National Cancer Institute, NIH.

² Recipient of a research studentship from the National Cancer Institute of Canada.

³ To whom requests for reprints should be addressed.

Received 8/ 6/85. Revised 12/ 9/85. Revised 2/24/86. Accepted 2/27/86.

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