0000000000755980
AUTHOR
Anne Riemann
Acidosis induces multi-drug resistance in rat prostate cancer cells (AT1) in vitro and in vivo by increasing the activity of the p-glycoprotein via activation of p38.
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). Intracellul…
Impact of Hypoxia-Related Tumor Acidosis on Cytotoxicity of Different Chemotherapeutic Drugs In Vitro and In Vivo
Extracellular acidosis in tumors leads to an activation of the p-glycoprotein (Pgp) drug transporter. In the present study the cytotoxicity of different chemotherapeutic drugs and its dependence on the Pgp activity during acidosis were analyzed in vitro and in vivo. Treating R3327-AT1, Pgp-positive tumor cells at pH 7.4 with daunorubicin, cisplatin or docetaxel led to marked apoptosis induction and cell death. Under acidic (pH 6.6) conditions cytotoxicity of daunorubicin or docetaxel was significantly reduced whereas cisplatin-induced cell death was almost pH-independent. Inhibiting Pgp with verapamil reversed the acidosis-induced chemoresistance against daunorubicin and docetaxel. The Pgp …
Acidic Environment Leads to ROS-Induced MAPK Signaling in Cancer Cells
Tumor micromilieu often shows pronounced acidosis forcing cells to adapt their phenotype towards enhanced tumorigenesis induced by altered cellular signalling and transcriptional regulation. In the presents study mechanisms and potential consequences of the crosstalk between extra- and intracellular pH (pH(e), pH(i)) and mitogen-activated-protein-kinases (ERK1/2, p38) was analyzed. Data were obtained mainly in AT1 R-3327 prostate carcinoma cells, but the principle importance was confirmed in 5 other cell types. Extracellular acidosis leads to a rapid and sustained decrease of pH(i) in parallel to p38 phosphorylation in all cell types and to ERK1/2 phosphorylation in 3 of 6 cell types. Furth…