Triarylpyridine Compounds and Chloroquine Act in Concert to Trigger Lysosomal Membrane Permeabilization and Cell Death in Cancer Cells.

Jennifer Beauvarlet,Mojgan Djavaheri-Mergny,Jean-Louis Mergny,Isabelle Martins,Guido Kroemer,Pierre Soubeyran,Jean Guillon,Elodie Richard,Karla Alvarez-Valadez,Rabindra Nath Das,Alexandra Muller,Elodie Darbo

doi:10.3390/cancers12061621

Abstract

Lysosomes play a key role in regulating cell death in response to cancer therapies, yet little is known on the possible role of lysosomes in the therapeutic efficacy of G-quadruplex DNA ligands (G4L) in cancer cells. Here, we investigate the relationship between the modulation of lysosomal membrane damage and the degree to which cancer cells respond to the cytotoxic effects of G-quadruplex ligands belonging to the triarylpyridine family. Our results reveal that the lead compound of this family, 20A promotes the enlargement of the lysosome compartment as well as the induction of lysosome-relevant mRNAs. Interestingly, the combination of 20A and chloroquine (an inhibitor of lysosomal functions) led to a significant induction of lysosomal membrane permeabilization coupled to massive cell death. Similar effects were observed when chloroquine was added to three new triarylpyridine derivatives. Our findings thus uncover the lysosomal effects of triarylpyridines compounds and delineate a rationale for combining these compounds with chloroquine to increase their anticancer effects.

Highlights

Lysosomes are the end points of several vesicular pathways that mediate degradation of intra- and extra-cellular material in cells [1]
We have previously shown that 20A, a G-quadruplex ligand belonging to the triarylpyridine family, exerts potent cytotoxic and cytostatic effects on several cancer cells
Our study uncovers the lysosomal effects of G4 ligands belonging to the triarylpyridine family and proposes a rationale for combining these compounds with chloroquine to increase their effectiveness against cancer

Summary

Introduction

Lysosomes are the end points of several vesicular pathways that mediate degradation of intra- and extra-cellular material in cells [1]. Lysosomes ensure the regulation of numerous biological processes including nutrient sensing, signaling to the nucleus, and the ignition of cell death pathways [2]. Mounting evidence indicates that lysosomes are involved in the resistance to anticancer compounds with weak base properties. These drugs may be sequestered within the lysosome, resulting in a loss of accessibility of the drug to its cellular targets and thereby a reduction of its effectiveness [7,8,9,10]. Inhibition of lysosomal sequestration (by increasing lysosomal pH, or inhibiting active transport) may increase the sensitivity of cancer cells to several antineoplastic therapies [13]. The modifications of the lysosomal compartment that occur during cellular transformation can paradoxically render cancer cells more susceptible to lysosomal membrane permeabilization (LMP) [14,15], and lead to lysosomal-dependent cell death (LDCD) induced by anticancer agents [13,16]

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