Glycolysis in P‐glycoprotein‐overexpressing human tumor cell lines Effects of resistance‐modifying agents

Abstract

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 PM verapamil. The glycolytic rate in sensitive (A2780) and MDR (278wD) 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 my&ate 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 106 cells, which was estimated to be about 10% of cellular energy turnover.

Indomethacin-induced activation of the death receptor-mediated apoptosis pathway circumvents acquired doxorubicin resistance in SCLC cells

“…Therefore, a subsequent increase in cellular doxorubicin concentration by indomethacin may have partly played a role. Other mechanisms by which indomethacin might induce apoptosis are increased glutathione extrusion mediated by MRP1 (Trompier et al, 2004) or increased ATP consumption by MRP1 ATPase activity in analogy to the observed verapamil-induced ATP consumption in P-glycoprotein-overexpressing cells (Broxterman et al, 1989).…”

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

“…Another example is the natural product Austocystin D, which possesses increased toxicity against some MDR cell lines as a result of increased activation by cytochrome P450 [75]. Increased sensitivity of MDR cells to the antimetabolite 2-deoxy-dglucose, the electron transport chain inhibitors rotenone and antimycin A [71,76,77] as well as certain P-gp-substrates [72,[78][79][80] were explained by the ATP depleting effect of the transporter. According to this model, increased glycolysis compensates for the higher energy demand created by the "futile cycling" of the transporter [79,81,82], but the oxidative stress associated with oxidative phosphorylation ultimately results in the selective apoptosis of MDR cells [83].…”

ATP‐dependent efflux of calcein by the multidrug resistance protein (MRP): no inhibition by intracellular glutathione depletion

“…One type of MDR is due to the overexpression of plasma membrane drug transporters, which act as ATP-dependent drug efflux pumps, resulting in lower intracellular drug concentrations and, hence, in drug resistance [1,3]. Hitherto, two different plasma membrane drug transporters have been cloned, namely the MDR1 encoded P-glycoprotein (Pgp) [4] and the recently discovered multidrug resistance protein (MRP) [5].…”