FIGURE 8.
Drug resistance conferred by Pgp is dependent on the charge of Pgp substrates at acidic pH. A, lysosomal trapping ability of a range of Pgp substrates as shown by speciation plots (derived from pKa values of each substrate (9, 11, 12, 29)). At lysosomal pH (pH ∼5), DOX (100%), DNR (100%), and VBL (71%) are charged, whereas COL and PAC are not. Incubation (IC50/72 h) of KB31 (−Pgp) cells (B) or 2008 (−Pgp) cells (C) with the lysosomotropic weak bases ammonium chloride (NH4Cl, 3 mm), CLQ (1 μm), or MA (100 μm) did not significantly change cytotoxicity to the Pgp substrates DOX, DNR, VBL, COL, or PAC. However, incubation of Pgp-expressing KBV1 (+Pgp) cells (B) or 2008/P200 (+Pgp) cells (C) with the lysosomotropic weak bases markedly increased sensitivity to the Pgp substrates DOX, DNR, and VBL but not to COL or PAC. The graphs (B and C) show mean ± S.D. ***, p < 0.001 versus control (i.e. drug alone).