FIGURE 10.

Lysosomal trapping by Pgp as an alternative multidrug resistance mechanism. A, as part of endocytosis, the plasma membrane containing Pgp buds inwards to form early endosomes. During endocytosis, the topology of Pgp will be inverted, as shown for other membrane proteins (45), leading to the transport of substrates into the vesicle lumen. As the endosome matures into a lysosome, it becomes increasingly acidified. The Pgp on the lysosomal membrane remains functional because its catalytic active sites and ATP-binding domains are still exposed in the cytosol (39, 40). When a Pgp substrate, such as DOX, enters the cell, the drug is not only effluxed out of the cell by Pgp on the plasma membrane but also sequestered into the acidic lysosomes by lysosomal Pgp pumps. If the Pgp substrate is charged at acidic pH (such as DOX), then lysosomal trapping occurs. The trapping of charged drugs will prevent Pgp substrates from reaching their molecular targets (e.g. the nucleus for DOX), leading to increased resistance in Pgp-expressing cells. B, this study describes two mechanisms to overcome lysosomal Pgp-dependent multidrug resistance: direct blocking of Pgp by Pgp inhibitors, leading to prevention of increased uptake of Pgp substrates into lysosomes (1), or the combination of cytotoxic drugs (e.g. DOX) with lysosomotropic weak bases (e.g. CLQ) to prevent lysosomal trapping by raising lysosomal pH (2). These two approaches offer Pgp substrates an opportunity to overcome multidrug resistance by reaching their targets instead of becoming trapped in Pgp-containing lysosomes.