Figure 1.

Schematic summary model for hydrophobic weak base drug-induced lysosome-mediated drug resistance. Hydrophobic weak base drugs enter the lysosomes by simple diffusion and undergo protonation in the acidic lysosomal lumen, thereby becoming irreversibly sequestered in lysosomes and acidic intracellular vesicles such as late endosomes. In turn, lysosomal drug sequestration triggers TFEB-mediated lysosomal biogenesis, resulting in a significant increase in the number of lysosomes per cell. Increased lysosome number per cell enhances the efficiency of lysosomal drug sequestration, with lysosomes acting as a sink pulling hydrophobic weak base drugs away from their cellular target sites, thereby resulting in MDR (21).