Advertisement

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)

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.

Keywords

Multi-drug resistance Chemotherapy Acidosis p-Glycoprotein Pgp expression 

Notes

Acknowledgments

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

References

  1. 1.
    Teicher BA, Holden SA, al Achi A et al (1990) Classification of antineoplastic treatments by their differential toxicity toward putative oxygenated and hypoxic tumor subpopulations in vivo in the FSaIIC murine fibrosarcoma. Cancer Res 50:3339–3344PubMedGoogle Scholar
  2. 2.
    Fang J, Nakamura H, Iyer AK (2007) Tumor-targeted induction of oxystress for cancer therapy. J Drug Target 15:475–486CrossRefPubMedGoogle Scholar
  3. 3.
    Chaplin DJ, Horsman MR, Trotter MJ et al (1998) Therapeutic significance of microenvironmental factors. In: Molls M, Vaupel P (eds) Blood perfusion and microenvironment of human tumors. Springer, Berlin, pp 131–143Google Scholar
  4. 4.
    Teicher BA (1994) Hypoxia and drug resistance. Cancer Metastasis Rev 13:139–168CrossRefPubMedGoogle Scholar
  5. 5.
    Sauvant C, Nowak M, Wirth C et al (2008) 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. Int J Cancer 123:2532–2542CrossRefPubMedGoogle Scholar
  6. 6.
    Thews O, Gassner B, Kelleher DK et al (2006) Impact of extracellular acidity on the activity of p-glycoprotein and the cytotoxicity of chemotherapeutic drugs. Neoplasia 8:143–152CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Di Marco A, Casazza AM, Dasdia T et al (1977) Changes of activity of daunorubicin, adriamycin and stereoisomers following the introduction or removal of hydroxyl groups in the amino sugar moiety. ChemBiol Interact 19:291–302CrossRefGoogle Scholar
  8. 8.
    Chan LM, Lowes S, Hirst BH (2004) The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability. Eur J Pharm Sci 21:25–51CrossRefPubMedGoogle Scholar
  9. 9.
    Workman P, Aboagye EO, Balkwill F et al (2010) Guidelines for the welfare and use of animals in cancer research. Br J Cancer 102:1555–1577CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Kalliomäki T, Hill RP (2004) Effects of tumour acidification with glucose + MIBG on the spontaneous metastatic potential of two murine cell lines. Br J Cancer 90:1842–1849CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Schwerdt G, Freudinger R, Schuster C et al (2003) Inhibition of mitochondria prevents cell death in kidney epithelial cells by intra- and extracellular acidification. Kidney Int 63:1725–1735CrossRefPubMedGoogle Scholar
  12. 12.
    Thews O, Dillenburg W, Fellner M et al (2010) Activation of P-glycoprotein (Pgp)-mediated drug efflux by extracellular acidosis: in vivo imaging with 68Ga-labelled PET tracer. Eur J Nucl Med Mol Imaging 37:1935–1942CrossRefPubMedGoogle Scholar
  13. 13.
    Reichert M, Steinbach JP, Supra P et al (2002) Modulation of growth and radiochemosensitivity of human malignant glioma cells by acidosis. Cancer 95:1113–1119CrossRefPubMedGoogle Scholar
  14. 14.
    Atema A, Buurman KJ, Noteboom E et al (1993) Potentiation of DNA-adduct formation and cytotoxicity of platinum-containing drugs by low pH. Int J Cancer 54:166–172CrossRefPubMedGoogle Scholar

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

Personalised recommendations