Activation of P-glycoprotein (Pgp)-mediated drug efflux by extracellular acidosis: in vivo imaging with 68Ga-labelled PET tracer.
OBJECTIVE
In vitro it has been shown that the functional activity of P-glycoprotein (Pgp), an important drug transporter responsible for multidrug resistance, can be strongly increased by extracellular acidosis. Here mitogen-activated protein kinases (MAPK) (p38, ERK1/2) seem to play an important role for signal transduction. However, it is unclear whether these effects are also relevant in vivo.


METHODS
With the newly developed PET tracer Schiff base-based (68)Ga-MFL6.MZ the functional Pgp activity was visualized under acidic conditions and during inhibition of MAPKs non-invasively by means of microPET in rat tumours. Tumours were acidified either by inspiratory hypoxia (8% O(2)) or by injection of lactic acid. Inhibitors of the MAPK were injected intratumourally.


RESULTS
With increasing tumour volume the tumour pH changed from 7.0 to 6.7 and simultaneously the Pgp activity increased almost linearly. When the tumour was acidified by direct lactic acid injection the PET tracer uptake was reduced by 20% indicating a higher transport rate out of the cells. Changing the inspiratory O(2) fraction to 8% dynamically led to a reduction of extracellular pH and in parallel to a decrease of tracer concentration. While inhibition of the p38 pathway reduced the Pgp transport rate, inhibition of ERK1/2 had practically no impact.


CONCLUSIONS
An acidic extracellular environment significantly stimulates the Pgp activity. The p38 MAPK pathway plays an important role for Pgp regulation in vivo, whereas ERK1/2 is of minor importance. From these results new strategies for overcoming multidrug resistance (e.g. reducing tumour acidosis, inhibition of p38) may be developed.
Institute of Physiology and Pathophysiology, University Medicine Mainz, Duesbergweg 6, 55099 Mainz, Germany. OLTHEWS@uni-mainz.de
Oliver
O
Thews
Wolfgang
W
Dillenburg
Marco
M
Fellner
Hans-Georg
HG
Buchholz
Nicole
N
Bausbacher
Mathias
M
Schreckenberger
Frank
F
Rösch
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000138:Acidosis / Q000000981:diagnostic imaging* / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D005110:Extracellular Space / Q000000981:diagnostic imaging*; D005710:Gallium Radioisotopes; D006863:Hydrogen-Ion Concentration; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011849:Radioactive Tracers; D051381:Rats
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002070:Butadienes; D005710:Gallium Radioisotopes; D009570:Nitriles; D004364:Pharmaceutical Preparations; D047428:Protein Kinase Inhibitors; D011849:Radioactive Tracers; C113580:U 0126