0000000000347172
AUTHOR
Birgit Gassner
Impact Of Hypoxic And Acidic Extracellular Conditions On Cytotoxicity Of Chemotherapeutic Drugs
In the microenvironment of solid growing tumors, pronounced hypoxia or extracellular acidosis is commonly found The aim of this study was the analysis of the cytotoxic effect of different chemotherapeutic agents (cisplatin, daunorubicin, docetaxel) under these conditions in vitro Prostate carcinoma cells (R3327-AT1) were exposed to hypoxia (pO 2 05 mmHg) or extracellular acidosis (pH=66) for 6h After 3h, cytotoxic drugs were added The cytotoxic effect was assessed by measuring caspase 3-activity (apoptosis), LDH release (necrosis) and repopulation of the cells after chemotherapy (cell death) Compared to aerobic control conditions, severe hypoxia over 6h per se led to a slight increase in ap…
Activity of Drug Efflux Transporters in Tumor Cells Under Hypoxic Conditions
Tumor cells exhibit mechanisms by which chemotherapeutic drugs can be actively pumped out of the cell (e.g., p-glycoprotein pGP, MRP1), resulting in a multidrug resistant phenotype. Many human tumors show pronounced hypoxia which can result in a local ATP depletion which in turn may compromise the efficacy of these transporters. The aim of this study was therefore to assess the transport activity and expression of drug transporters under hypoxic conditions. Prostate carcinoma cells (R3327-AT1) were exposed to hypoxia (pO2≶0.5 mmHg) for up to 24h and pump activity was determined by an efflux assay. The results showed that exposing cells to hypoxia for 3–6 h led to a moderate increase in pGP …
Impact of Extracellular Acidity on the Activity of P-glycoprotein and the Cytotoxicity of Chemotherapeutic Drugs
AbstractThe expression and activity of P-glycoprotein (pGP) play a role in the multidrug resistance of tumors. Because solid-growing tumors often show pronounced hypoxia or extracellular acidosis, this study attempted to analyze the impact of an acidic environment on the expression and activity of pGP and on the cytotoxicity of chemotherapeutic agents. For this, prostate carcinoma cells were exposed to an acidic extracellular environment (pH 6.6) for up to 24 hours. pGP activity was more than doubled after 3 to 6 hours of incubation in acidic medium, whereas cellular pGP expression remained constant, indicating that increased transport rate is the result of functional modulation. In paralle…
Role of the tumor microenvironment in the activity and expression of the p-glycoprotein in human colon carcinoma cells.
The metabolic microenvironment of solid tumors is characterized by an oxygen deficiency and increased anaerobic glycolysis leading to extracellular acidosis and ATP depletion, which in turn may affect other energy-dependent cellular pathways. Since many tumors overexpress active drug transporters (e.g. the p-glycoprotein) leading to a multidrug-resistant phenotype, this study analyzes the impact of the different aspects of the extracellular microenvironment (hypoxia and acidosis) on the activity and expression of the p-glycoprotein (pGP) in the human colon carcinoma cell line LS513. For up to 24 h cells were exposed to hypoxia (pO2<0.5 mmHg), an acidic extracellular environment (pH 6.6), or…