Cytotoxicity of weak electrolytes after the adaptation of cells to low pH: role of the transmembrane pH gradient

British Journal of Cancer
Sergey Kozin, Leo E Gerweck

Abstract

Theory suggests that the transmembrane pH gradient may be a major determinant of the distribution of lipophilic weak electrolytes across the cell membrane. The present study evaluates the extent to which this factor contributes to pH-dependent changes in the cytotoxicity of two such chemotherapeutic drugs: chlorambucil and mitoxantrone. Experiments were performed with two cell types of the same origin but exhibiting different pH gradients at the same extracellular pH (pHe): CHO cells cultured under normal physiological conditions (pH 7.4) and acid-adapted cells obtained by culturing under low pH conditions (6.8). Over the pHe range examined (6.0-7.6), the difference between intracellular pH (pHi) and pHe increased with decreasing pHe. Acid-adapted cells were more resistant to acute changes in pHi than normal cells, resulting in substantially larger gradients in these cells. Drug cell survival curves were performed at pHe values of 6.4, 6.8 and 7.4. The cytotoxicity of chlorambucil, a weak acid, increased with decreasing pHe, and low pH-adapted cells were more sensitive than normal cells at the same pHe. In contrast, for the weak base, mitoxantrone, cytotoxicity increased with pHe and was more pronounced in normal cells. As pred...Continue Reading

Citations

Jan 1, 2012·ISRN Otolaryngology·John Zenghong LiThian-Sze Wong
May 30, 2006·Molecular Cancer Therapeutics·Leo E GerweckSergey Kozin
Sep 2, 1999·Advances in Enzyme Regulation·M StubbsJ R Griffiths
Aug 11, 2001·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Natarajan Raghunand, Robert J. Gillies
Oct 31, 2003·Cancer Treatment Reviews·Hiroto IzumiKimitoshi Kohno
Apr 4, 2006·Biochemical and Biophysical Research Communications·Jiri NeuzilJean-Marc Zingg
Jul 9, 2020·Environmental Science & Technology·Markus BrinkmannMarkus Hecker

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