Drug Sequestration in Lysosomes as One of the Mechanisms of Chemoresistance of Cancer Cells and the Possibilities of Its Inhibition

Abstract

Resistance to chemotherapeutics and targeted drugs is one of the main problems in successful cancer therapy. Various mechanisms have been identified to contribute to drug resistance. One of those mechanisms is lysosome-mediated drug resistance. Lysosomes have been shown to trap certain hydrophobic weak base chemotherapeutics, as well as some tyrosine kinase inhibitors, thereby being sequestered away from their intracellular target site. Lysosomal sequestration is in most cases followed by the release of their content from the cell by exocytosis. Lysosomal accumulation of anticancer drugs is caused mainly by ion-trapping, but active transport of certain drugs into lysosomes was also described. Lysosomal low pH, which is necessary for ion-trapping is achieved by the activity of the V-ATPase. This sequestration can be successfully inhibited by lysosomotropic agents and V-ATPase inhibitors in experimental conditions. Clinical trials have been performed only with lysosomotropic drug chloroquine and their results were less successful. The aim of this review is to give an overview of lysosomal sequestration and expression of acidifying enzymes as yet not well known mechanism of cancer cell chemoresistance and about possibilities how to overcome this form of resistance.

Overcoming Chemoresistance: Altering pH of Cellular Compartments by Chloroquine and Hydroxychloroquine

“…Endolysosomes also play an important role in chemoresistance ( Zhitomirsky and Assaraf, 2016 ; Geisslinger et al, 2020 ; Hrabeta et al, 2020 ). The acidic environment of endolysosomes facilitates luminal accumulation of lipophilic, weakly basic chemotherapeutic drugs.…”

“…Such trapped weak-base chemotherapeutic drugs can directly alter endolysosome structure and function, such as alteration in endolysosome pH and influence endolysosome-dependent signaling that results in enhanced endolysosome biogenesis ( Fassl et al, 2020 ). Alternatively, trapped weak-base chemotherapeutic drugs can be eliminated from the cell via an increase in the lysosomal exocytosis cellular process, which is known to be directly due to these drugs themselves ( Hrabeta et al, 2020 ).…”

Autophagy Triggers Tamoxifen Resistance in Human Breast Cancer Cells by Preventing Drug-Induced Lysosomal Damage

“…First characterized as the main degrading organelles, lysosomes are now granted with complex regulatory functions in both normal and pathological conditions, including cancer development and progression [ 13 ]. Lysosomes are known to account for the lower susceptibility of cancer cells to chemotherapeutics which are weak bases by favoring their intralysosomal sequestration and ensuing removal from the cell by exocytosis [ 14 , 15 ]. However, intralysosomal accumulation of drugs to high concentrations, when not followed by their extracellular release, has also been reported to trigger lysosomal membrane permeabilization (LMP) and activation of lysosomal death pathways [ 16 ].…”

Repurposing Cationic Amphiphilic Drugs and Derivatives to Engage Lysosomal Cell Death in Cancer Treatment

“…Certainly, the intrinsic ability of CADs to concentrate in lysosomes, the site of their molecular target, facilitates efficacy, and the abundance and lability of transformed cell lysosomes relative to those of normal cells minimizes off-target concerns. At the same time, CADs tend to accumulate within tumors relative to normal tissue because of their lower cytosolic pH and the lower difference between cytosolic and lysosomal pH (56,57). On the other hand, CADs also distribute efficiently to tissue types rich in lysosomes, including lung, liver, and kidney (56), suggesting these sites may be most susceptible to CADinduced side effects.…”