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.
This study forms part of the doctoral thesis of Philipp Trach.
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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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