(A) Pgp localized on the plasma membrane protects the cell by effluxing substrates out of the cells. During endocytosis, which is further facilitated by the tumor microenvironmental stressors, the plasma membrane invaginates, which results in topical inversion of Pgp orientation in the membrane of early endosome. The endosomes then mature into lysosomes with Pgp on their membrane still being functional with its active sites facing the cytosol. When a Pgp substrate, such as Paclitaxel enters the cells, it is not only pumped out via plasma membrane Pgp, but also pumped into lysosomes via lysosomal Pgp. Weakly basic Pgp substrates (ex: paclitaxel) tends to get entrapped within the lysosome through their ionization at the lysosomal pH. This mechanism leads to inactivity of Pgp substrates which target other organelles in the cell such as nucleus for paclitaxel. (B) In contrast, lysosomal targeting agents such as DpC hijacks this resistance pathway to induce lysosomal damage, which results in potent anti-cancer activity.