Introduction: The most characterised mechanism of cancer cell resistance is drug efflux through plasma membrane transporters [Eckford and Sharom Chem Rev. (2009)109,2989-3011]. One such pump, P-glycoprotein (Pgp), also serves an intracellular resistance role [Yamagishi et al., J Biol Chem (2013)288:31761-71]. In this case, Pgp bound to lysosomal membranes transports drugs into the acidic lumen, which acts as a “safe house” to prevent chemotherapeutics, such as Doxorubicin (DOX; Fig. 4.1A), reaching their intracellular target.
Weexamined how stress present within the tumour microenvironment, namely variation in the availability of glucose, regulated the formation of lysosomes via induction of the endocytosis pathway, and consequently how this increased lysosomal DOX trapping, resulting in enhanced cancer cell resistance.
Interestingly, in contrast to the “safe house” trapping of DOX, a class of novel thiosemicarbazones have been shown to “hijack” the lysosomal Pgp pump to increase drug accumulation in this organelle, resulting in enhanced cytotoxicity [Jansson et al., J Biol Chem (2015)290:9588-603]. These agents potently react with copper to generate reactive oxygen species (ROS) that, in turn, cause lysosomal membrane permeabilisation (LMP) and apoptosis.
Results: These studies showed that glucose variation-induced stress stimulate endocytosis, thereby redistributing plasma membrane Pgp to the lysosomal membrane. This lysosomal Pgp was confirmed to be actively transporting DOX into the lysosome where it becomes trapped. Consequently, Pgp-expressing cells became more resistant to DOX treatment. In contrast, the thiosemicarbazones became more toxic to multidrug resistant (MDR) cells in the presence of more lysosomes as they were able to cause more LMP, which is necessary for their induction of apoptotic cell death.
Conclusion: These studies highlight the rapid intracellular MDR response of tumour cells to glucose variation-induced stress. This intracellular Pgp-resistance mechanism was utilised by agents that can “hijack” Pgp in the lysosomal compartment to increase lysosomal damage and overcome MDR.