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 activity. After 24 h pGP activity was reduced by 44% compared to control levels. Hypoxia reduced the MRPI activity to a lesser extent (by 25%). However, the expression of pGP and MRP1 was almost independent of the medium pO2. In conclusion, pronounced hypoxia had only minor effects on the activity of drug transporters with the activity decreasing only after 12-24 h under hypoxia, possibly as a result of ATP depletion. Instead, indirect effects of hypoxia leading to extracellular acidosis seem to have a much more pronounced effect on pGP activity.
Thews
Oliver
O
Institute of Physiology and Pathophysiology, University of Mainz, 55099 Mainz, Germany.
Gassner
Birgit
B
Kelleher
Debra K
DK
Gekle
Michael
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000138:Acidosis / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D005452:Fluoresceins / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D007552:Isotonic Solutions; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D020112:Rhodamine 123 / Q000378:metabolism; D000077331:Ringer's Solution; D013997:Time Factors; D014700:Verapamil / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005452:Fluoresceins; D005456:Fluorescent Dyes; D007552:Isotonic Solutions; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020112:Rhodamine 123; D000077331:Ringer's Solution; D014700:Verapamil; C085925:calcein AM; C421109:multidrug resistance-associated protein 1