Verteporfin-induced lysosomal compartment dysregulation potentiates the effect of sorafenib in hepatocellular carcinoma
| Autor: | Yitzhak Zimmer, Anna M. Schläfli, Daniel Candinas, Noelle Dommann, Adrian Keogh, Manuel O. Jakob, Mario P. Tschan, Michaela Medová, Sofia Karkampouna, Marianna Kruithof-de Julio, Vanessa Banz, Deborah Stroka, Jacopo Gavini, Laure C. Bouchez |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
Sorafenib Cancer Research Carcinoma Hepatocellular Combination therapy Cell Survival Immunology 610 Medicine & health Context (language use) Alkalies Models Biological Article Permeability Mice Cellular and Molecular Neuroscience In vivo Cell Line Tumor Autophagy medicine Animals Humans lcsh:QH573-671 lcsh:Cytology Chemistry Liver Neoplasms Verteporfin Drug Synergism Intracellular Membranes Cell Biology Hydrogen-Ion Concentration In vitro Neoplasm Proteins Mechanisms of disease Cell culture Hepatocytes ras Proteins Cancer research Lysosomes Liver cancer Intracellular medicine.drug |
| Zdroj: | Gavini, Jacopo; Dommann, Noëlle; Jakob, Manuel O.; Keogh, Adrian; Bouchez, Laure C; Karkampouna, Sofia; Kruithof-de Julio, Marianna; Medova, Michaela; Zimmer, Yitzhak; Schläfli, Anna M; Tschan, Mario P.; Candinas, Daniel; Stroka, Deborah; Banz, Vanessa (2019). Verteporfin-induced lysosomal compartment dysregulation potentiates the effect of sorafenib in hepatocellular carcinoma. Cell death & disease, 10(10), p. 749. Springer Nature 10.1038/s41419-019-1989-z Cell Death and Disease, Vol 10, Iss 10, Pp 1-17 (2019) Cell Death & Disease |
| ISSN: | 2041-4889 |
| DOI: | 10.1038/s41419-019-1989-z |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|