title: Impact of hypoxia-related tumor acidosis on cytotoxicity of different chemotherapeutic drugs in vitro and in vivo.
abstract: 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 expression was unaffected by pH. In vivo the cytotoxicity of daunorubicin and docetaxel was also pH dependent. When acidifying the tumors by forcing glycolytic metabolism, apoptosis induction decreased significantly indicating a reduced chemosensitivity. The cytotoxic effect of cisplatin in vivo was unaffected by the tumor pH. Since daunorubicin and docetaxel (but not cisplatin) are substrates of the Pgp, these results underline the influence of the tumor acidosis on the Pgp-mediated chemoresistance which can be counteracted by inhibition of the drug transporter.
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle, Halle (Saale), Germany. oliver.thews@medizin.uni-halle.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Thews
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle, Halle (Saale), Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Riemann
authors.affiliation: Institute of Physiology and Pathophysiology, University of Mainz, Mainz, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Nowak
authors.affiliation: Julius-Bernstein-Institute of Physiology, University of Halle, Halle (Saale), Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gekle
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051381:Rats
chemical_list: D000970:Antineoplastic Agents