Hypoxia-induced extracellular acidosis increases p-glycoprotein activity and chemoresistance in tumors in vivo via p38 signaling pathway.

Due to inadequate perfusion, tumors develop hypoxia and extracellular acidosis. In vitro, this acidic environment (pH=6.6) has a strong impact on the activity of the p-glycoprotein (pGP) drug transporter responsible for multidrug resistance. This effect is most probably mediated via p38 and/or ERK1/2 signalling pathways. The aim of the study was to analyze whether these findings also play a role for chemosensitivity in solid growing tumors in vivo. Therefore, experimental R3327-AT1 tumors of the rat were exposed to an acidifying treatment leading to forced glycolysis. The intratumoral pO(2)1 was determined polarographically and the extracellular pH was measured with needle electrodes. In addition the cytotoxicity of daunorubicin chemotherapy was assessed. Tumor oxygenation was markedly worsened by the acidosis treatment leading to a mean tumor pO(2) of 1 mmHg. This hypoxia resulted in a pronounced acidification of the tumor tissue from pH 7.04 down to 6.65. Extracellular acidosis in vivo decreased caspase 3-activity after daunorubicin treatment by 30%indicating a reduced chemosensitivity. Inhibition of the p38 signalling pathway restored the reduced chemosensitivity at least partially. However, in contrast to the in vitro findings inhibition of ERK1/2 had practically no impact in vivo.