Glycolysis in P-glycoprotein-overexpressing human tumor cell lines. Effects of resistance-modifying agents.
We show that drugs, such as verapamil, which reverse multidrug resistance (MDR), in P-glycoprotein-overexpressing tumor cells, increased the rate of lactate production in four human MDR cell lines, but not in the parent, sensitive cell lines. The effect on glycolytic rate was maximal at a medium concentration of 2 microM verapamil. The glycolytic rate in sensitive (A2780) and MDR 2780AD) cells showed the same pH dependence, but the effect of verapamil was seen only in 2780AD cells at all pH values investigated (6.6, 7.4 and 8.2). A series of drugs such as nigericin, oligomycin, amiloride and monensin had similar effects in the two cells. Phorbol myristate acetate increased lactate formation in neither cell line. Verapamil induced an extra amount of ATP consumption in P-glycoprotein-expressing 2780AD cells of approx. 25 pmol/s per 10(6) cells, which was estimated to be about 10% of cellular energy turnover.
Broxterman
H J
HJ
Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands.
Pinedo
H M
HM
Kuiper
C M
CM
Schuurhuis
G J
GJ
Lankelma
J
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000255:Adenosine Triphosphate / Q000378:metabolism; D000584:Amiloride / Q000494:pharmacology; D001798:Blood Proteins; D002738:Chloroquine / Q000494:pharmacology; D003571:Cytochalasin B / Q000494:pharmacology; D004351:Drug Resistance; D004734:Energy Metabolism / Q000187:drug effects; D005982:Glutathione Transferase / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007773:Lactates / Q000096:biosynthesis; D019344:Lactic Acid; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008985:Monensin / Q000494:pharmacology; D009550:Nigericin / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001798:Blood Proteins; D007773:Lactates; D008562:Membrane Glycoproteins; D019344:Lactic Acid; D003571:Cytochalasin B; D000584:Amiloride; D002738:Chloroquine; D000255:Adenosine Triphosphate; D008985:Monensin; D014700:Verapamil; D005982:Glutathione Transferase; D013755:Tetradecanoylphorbol Acetate; D009550:Nigericin