Abstract
Lysosomal sequestration of anti-cancer compounds reduces drug availability at intracellular target sites, thereby limiting drug-sensitivity and inducing chemoresistance. For hepatocellular carcinoma (HCC), sorafenib (SF) is the first line systemic treatment, as well as a simultaneous activator of autophagy-induced drug resistance. The purpose of this study is to elucidate how combination therapy with the FDA-approved photosensitizer verteporfin (VP) can potentiate the antitumor effect of SF, overcoming its acquired resistance mechanisms. HCC cell lines and patient-derived in vitro and in vivo preclinical models were used to identify the molecular mechanism of action of VP alone and in combination with SF. We demonstrate that SF is lysosomotropic and increases the total number of lysosomes in HCC cells and patient-derived xenograft model. Contrary to the effect on lysosomal stability by SF, VP is not only sequestered in lysosomes, but induces lysosomal pH alkalinization, lysosomal membrane permeabilization (LMP) and tumor-selective proteotoxicity. In combination, VP-induced LMP potentiates the antitumor effect of SF, further decreasing tumor proliferation and progression in HCC cell lines and patient-derived samples in vitro and in vivo. Our data suggest that combination of lysosome-targeting compounds, such as VP, in combination with already approved chemotherapeutic agents could open a new avenue to overcome chemo-insensitivity caused by passive lysosomal sequestration of anti-cancer drugs in the context of HCC.
Highlights
Autophagy and lysosomes play an important role in all eukaryotic cells, by restoring homeostasis after intra- or extracellular stress conditions[1,2]
Using an in vivo patient-derived xenograft (PDX) model, we demonstrated that SF in combination with VP markedly reduced tumor growth and progression compared to vehicle and SF alone (Fig. 1g)
Hepatocyte survival was not affected by VP, whereas malignant cells underwent lysosomal membrane permeabilization (LMP), with an increased proteotoxicity mainly caused by lysosomal pH alkalinization and consequent non-functional intracellular catabolic mechanisms
Summary
Autophagy and lysosomes play an important role in all eukaryotic cells, by restoring homeostasis after intra- or extracellular stress conditions[1,2] They are both part of the intracellular catabolic machinery, often driving chemotherapy resistance, as well as tumor proliferation[1,3,4]. The acidic environment of the lysosomes, together with the fact that chemotherapeutics are often formulated as weak-bases, enables their accumulation within their lumen by simple diffusion. After their internalization, lysosomotropic compounds become protonated, resulting in their lysosomal compartmentalization[9,10,11,12]. Various strategies are being sought to overcome lysosome-mediated chemoresistance, such as lysosomal photodestruction, targeting lysosomal acid sphingomyelinase (ASM) and inducing lysosomal
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