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Reduction of Intracellular pH as a Possible Mechanism for Killing Cells in Acidic Regions of Solid Tumors: Effects of Carbonylcyanide-3-chlorophenylhydrazone¹

Departments of Medicine [I. F. T.] and Medical Biophysics [K. J. N., I. F. T.], Ontario Cancer Institute and University of Toronto, Toronto, Ontario M4X 1K9, Canada

The environment of cells within solid tumors is known to be acidic relative to that in normal tissue, and the viability of tumor cells may depend on mechanisms which maintain intracellular pH (pH_i) above the extracellular pH (pH_e). We have assessed therefore the toxicity in vitro of the proton ionophore carbonylcyanide-3-chlorophenylhydrazone (CCCP), since this agent has been reported to be capable of transporting H⁺ equivalents through artificial lipid bilayers and mitochondrial membranes. CCCP was toxic to the human bladder carcinoma cell line MGH-U1 and to the murine mammary sarcoma cell line EMT-6 only at pH_e < 6.5. CCCP transported H⁺ equivalents through cell membranes at physiological (7.35) and low pH_e (6.20). Cell lines were found to have steady-state pH_i values approximately 0.1 to 0.2 pH units above pH_e at pH_e < 6.50. Addition of CCCP led to a decrease in steady-state pH_i values as compared to untreated cells at pH_e < 6.50, whereas there was no apparent effect of CCCP on steady-state pH_i values at pH_e > 6.50. The CCCP-induced reduction in steady-state pH_i combined with the uncoupling of oxidative phosphorylation by CCCP appeared to be the major mechanisms leading to cell death at pH_e < 6.50. The toxicity of CCCP under acidic conditions was enhanced by amiloride and 4,4'-diisothiocyanostilbene-2,2-disulfonic acid, agents which are known to inhibit membrane-based ion exchange mechanisms which regulate pH_i under acidic conditions. When both agents were combined with CCCP, cell killing was observed at pH_e < 7.30. Our results suggest that mechanisms which regulate pH_i under acidic conditions which occur in solid tumors may represent targets for new forms of tumor-specific therapy.

¹ This study was supported by a research grant from the Medical Research Council of Canada.

² To whom requests for reprints should be addressed.

Received 2/28/89. Revised 5/12/89. Accepted 5/18/89.

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