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Reduction of tumour intracellular pH and enhancement of melphalan cytotoxicity by the ionophore nigericin
Author(s) -
Wood P. J.,
Sansom J. M.,
Nhweli K.,
Tannock F. F.,
Stratford I. J.
Publication year - 1995
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910600222
Subject(s) - nigericin , melphalan , ionophore , in vivo , extracellular , in vitro , intracellular , chemistry , cytotoxicity , biochemistry , biophysics , pharmacology , biology , chemotherapy , membrane , microbiology and biotechnology , genetics
Nigericin is an ionophore which permits the influx of H + ions into cells down a concentration gradient, thus reducing intracellular pH (pHi) when extracellular pH is low. The effects of nigericin on the pHi of solid murine tumours in vivo were examined using 31 P magnetic resonance spectroscopy. Nigericin at 2.5 mg/kg i.p. reduced pHi by 0.2–0.3 pH unit in the KHT and RIF‐1 tumours but had no effect on pHi in the SCCVII/Ha tumour. In vitro studies have shown that reduced pH can increase the toxicity of melphalan. Therefore, the anti‐tumour effect of combining nigericin with melphalan was also examined. Nigericin at 2.5 mg/kg i.p. given before various doses of melphalan resulted in substantial delay in growth of the RIF‐1 tumour over that induced by melphalan alone. This observation was confirmed by an in vivo/in vitro excision assay, where nigericin given before melphalan produced a 30‐fold increase in cell killing. By contrast, no enhancement of melphalan‐induced cell killing by nigericin was observed in the KHT and SCCVII/Ha tumours, using growth delay and in vivo/in vitro excision assays, respectively. © 1995 Wiley‐Liss, Inc.