Impact of Hypoxia-Related Tumor Acidosis on Cytotoxicity of Different Chemotherapeutic Drugs In Vitro and In Vivo

  • Oliver Thews
  • Anne Riemann
  • Martin Nowak
  • Michael Gekle
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 812)


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.


Multi-drug resistance Chemotherapy Acidosis p-Glycoprotein Pgp expression 



This study was supported by Deutsche Krebshilfe (grants 106774/106906).


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Copyright information

© Springer Science+Business Media, LLC 2014

Authors and Affiliations

  • Oliver Thews
    • 1
  • Anne Riemann
    • 1
  • Martin Nowak
    • 2
  • Michael Gekle
    • 1
  1. 1.Julius-Bernstein-Institute of PhysiologyUniversity of HalleHalle (Saale)Germany
  2. 2.Institute of Physiology and PathophysiologyUniversity of MainzMainzGermany

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