Acceleration of MRP-associated efflux of rhodamine 123 by genistein and related compounds

Abstract

Summary Multidrug resistance (MDR), caused by overexpression of either P-glycoprotein or the multidrug resistance protein (MRP), is characterised by a decreased cellular drug accumulation due to an enhanced drug efflux. In this study, we examined the effects of genistein and structurally related (iso)flavonoids on the transport of rhodamine 123 (Rhl23) and daunorubicin in the MRP-overexpressing MDR lung cancer cell lines COR-L23/R and MOR/R. Genistein, genistin, daidzein and quercetin showed major differences in effects on Rhl23 vs daunorubicin transport in the MRP-mediated MDR cell lines: the accumulation of daunorubicin was increased, whereas the accumulation of Rhl23 was decreased by the flavonoids. The depolarisation of the membrane potential caused by genistein might be involved in the acceleration of the efflux of Rhl23 measured in the MRP-overexpressing cell lines. These observations should be taken into account when using fluorescent dyes as probes for determination of transporter activity as a measure of MDR.

Modulation of P-glycoprotein activity in Calu-3 cells using steroids and β-ligands

“…4 intrinsic ability to be transported by Pgp (Figures 1, 2, 3). Although Rh123 has been shown to be a substrate for both Pgp and MRP1 (Twentyman et al, 1994;Versantvoort et al, 1996), we have shown predominant Pgp activity in Calu-3 cells (Hamilton et al, 2001b) using this marker compound.…”

Comparative Study on the Effects of Cyclosporin A in Renal Cells in Culture

“…This dye was early used as a mitochondrial marker, but because it is transported by ABCB1, and because cells that overexpress this protein accumulate much less Rho123, it became largely used to evaluate ABCB1 activity, including in renal cells and isolated perfused PT [10, 16, 17]. However, some authors observed that it might also be carried by the organic cation transporter system (OCT), which is not inhibited by CSA [18, 19], and by the MRP1 (or ABCC1) protein, which may be moderately inhibited by CSA [20, 21, 22]. …”

True

“…72 Other modulators such as genistein, a specific inhibitor of tyrosine kinase, or 7-chloro-4-notrobenz-2-oxa-1,3-diazole (NBD), a vacuolar H+-ATPase, have been reported to modulate MRP1 of a non-specific manner. [73][74][75] However, genistein showed major differences in effects on Rh123 vs DNR transport in the MRP1-mediated MDR cell lines: the accumulation of DNR was increased, whereas the accumulation of Rh123 was decreased by genistein. 73 Recently, van der Kolk et al 40 and ourselves 11 have demonstrated that MRP1 was functional in fresh acute myeloid leukemic blast cells using CF and calcein-AM, respectively.…”

“…[73][74][75] However, genistein showed major differences in effects on Rh123 vs DNR transport in the MRP1-mediated MDR cell lines: the accumulation of DNR was increased, whereas the accumulation of Rh123 was decreased by genistein. 73 Recently, van der Kolk et al 40 and ourselves 11 have demonstrated that MRP1 was functional in fresh acute myeloid leukemic blast cells using CF and calcein-AM, respectively. We have also seen that some substrates of MRP1 were also substrates of Pgp (calcein-AM, CF, ±Rh123 etc).…”