Abstract
Due to inadequate perfusion and oxygen supply, tumors force glycolytic metabolism leading to low glucose and high lactate levels combined with extracellular acidosis. The acidosis has been shown to increase the functional activity of the P-glycoprotein (Pgp), responsible for multidrug resistance. The aim of this study was to analyze whether other metabolic parameters such as glucose and lactate concentration or reactive oxygen species also affect Pgp activity and by the chemosensitivity. Pgp-positive R3327-AT cells were incubated either under complete glucose deprivation or with high lactate levels (10 and 20 mM) or with 50 μM H2O2. Glucose-free medium had almost no impact on the Pgp activity even though a reduction in the cellular ATP level by 45% was observed. However, the intracellular daunorubicin level was approximately 30% higher under these conditions leading to an increased cytotoxicity of the chemotherapy. High lactate levels increased the Pgp activity moderately by 40%. ROS finally reduced the Pgp transport rate by 15% but had no impact on the expression of the transporter. Compared to the impact of acidosis on Pgp activity, the parameters analyzed affect Pgp-mediated chemoresistance only marginally.
Keywords
- Reactive Oxygen Species Induction
- Intracellular Drug Concentration
- High Lactate Level
- Extracellular Acidosis
- Extracellular Lactate Concentration
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This study forms part of the doctoral thesis of Philipp Trach.
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References
Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49:6449–6465
Bussink J, Kaanders JH, Rijken PF et al (1998) Multiparameter analysis of vasculature, perfusion and proliferation in human tumour xenografts. Br J Cancer 77:57–64
Brown NS, Bicknell R (2001) Hypoxia and oxidative stress in breast cancer. Oxidative stress: its effects on the growth, metastatic potential and response to therapy of breast cancer. Breast Cancer Res 3:323–327
Higgins CF (2001) ABC transporters: physiology, structure and mechanism - an overview. Res Microbiol 152:205–210
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 8:143–152
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 123:2532–2542
Kunikane H, Zalupski MM, Ramachandran C et al (1997) Flow cytometric analysis of p-glycoprotein expression and drug efflux in human soft tissue and bone sarcomas. Cytometry 30:197–203
Xu RH, Pelicano H, Zhou Y et al (2005) Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res 65:613–621
Ledoux S, Yang R, Friedlander G et al (2003) Glucose depletion enhances P-glycoprotein expression in hepatoma cells: role of endoplasmic reticulum stress response. Cancer Res 63:7284–7290
Vaupel P, Schaefer C, Okunieff P (1994) Intracellular acidosis in murine fibrosarcomas coincides with ATP depletion, hypoxia, and high levels of lactate and total Pi. NMR Biomed 7:128–136
Thews O, Gassner B, Kelleher DK et al (2008) Activity of drug efflux transporters in tumor cells under hypoxic conditions. Adv Exp Med Biol 614:157–164
Wartenberg M, Gronczynska S, Bekhite MM et al (2005) Regulation of the multidrug resistance transporter P-glycoprotein in multicellular prostate tumor spheroids by hyperthermia and reactive oxygen species. Int J Cancer 113:229–240
Acknowledgments
This study was supported by Deutsche Krebshilfe (grants 106774/109136).
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Trach, P., Afahaene, N., Nowak, M., Thews, O. (2012). Impact of Environmental Parameters on the Activity of the P-Glycoprotein. In: Wolf, M., et al. Oxygen Transport to Tissue XXXIII. Advances in Experimental Medicine and Biology, vol 737. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-1566-4_24
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DOI: https://doi.org/10.1007/978-1-4614-1566-4_24
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