Because solid growing tumors often show hypoxia and pronounced extracellular acidosis, the aim of this study was to analyze the impact of an acidotic environment on the activity of the p-glycoprotein (pGP) and on the cellular content and cytotoxicity of the chemotherapeutic drug daunorubicin in the AT1 R-3327 Dunning prostate carcinoma cell line cultured in vitro and in vivo. In vitro, extracellular acidosis (pH 6.6) activated p38 and ERK1/2 and thereby induced daunorubicin resistance via a pronounced activation of pGP. De-novo protein synthesis was not necessary and analysis of transport kinetics indicated a fast and persistent pGP activation at pH 6.6 (when compared with 7.4). Intracellular acidification also induced daunorubicin resistance via activation of pGP, which was mediated by activation of p38 alone. In vivo, tumors were implanted subcutaneously, and the tumor pH was artificially lowered by forcing anaerobic metabolism. In vivo, the reduced extracellular pH of 6.6 was also able to induce daunorubicin resistance, which was abolished by inhibition of p38. These results suggest that pGP activity is dependent on extracellular pH in vitro and in vivo. Moreover, there is strong indication that this effect is mediated via activation of p38 in vivo. Activation of ERK is also suitable to induce pGP activity. Therefore, inhibition of p38 (and ERK) may be used to prevent acidosis induced increase in pGP activity and thereby attenuate multidrug resistance. In addition, supportive treatments reducing tumor acidosis may improve the cytotoxic effect of chemotherapeutic drugs.
(c) 2008 Wiley-Liss, Inc.