Evidence map›Paper›PMID 31582741›Full record

ArticleCell death & disease2019

Verteporfin-induced lysosomal compartment dysregulation potentiates the effect of sorafenib in hepatocellular carcinoma.

Jacopo Gavini, Noëlle Dommann, Manuel O Jakob, Adrian Keogh, Laure C Bouchez, Sofia Karkampouna, Marianna Kruithof-de Julio, Michaela Medova, Yitzhak Zimmer, Anna M Schläfli and 4 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell death & disease, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
49citing papers in PubMed, 1 pooled it
6.7field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

49 citing papers in PubMed, 1 synthesis or guideline pooled it, 69 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors at 2 institutions in 1 country.

Jacopo GaviniDepartment of Visceral Surgery and Medicine, Department for BioMedical Research, Inselspital, Bern University Hospital and University of Bern, 3010, Bern, Switzerland.
Noëlle DommannDepartment of Visceral Surgery and Medicine, Department for BioMedical Research, Inselspital, Bern University Hospital and University of Bern, 3010, Bern, Switzerland.
Manuel O JakobDepartment of Visceral Surgery and Medicine, Department for BioMedical Research, Inselspital, Bern University Hospital and University of Bern, 3010, Bern, Switzerland.
Adrian KeoghDepartment of Visceral Surgery and Medicine, Department for BioMedical Research, Inselspital, Bern University Hospital and University of Bern, 3010, Bern, Switzerland.
Laure C BouchezGlenmark Pharmaceuticals, 1003, Lausanne, Switzerland.
Sofia KarkampounaDepartment of Urology, Department for BioMedical Research, Inselspital, Bern University Hospital and University of Bern, 3010, Bern, Switzerland.
Marianna Kruithof-de JulioDepartment of Urology, Department for BioMedical Research, Inselspital, Bern University Hospital and University of Bern, 3010, Bern, Switzerland.
Michaela MedovaDepartment of Radiation Oncology, Department for BioMedical Research, Inselspital, Bern University Hospital and University of Bern, 3010, Bern, Switzerland.ORCID http://orcid.org/0000-0003-0649-469X
Yitzhak ZimmerDepartment of Radiation Oncology, Department for BioMedical Research, Inselspital, Bern University Hospital and University of Bern, 3010, Bern, Switzerland.
Anna M SchläfliInstitute of Pathology, University of Bern, Murtenstrasse 31, 3008, Bern, Switzerland.
Mario P TschanInstitute of Pathology, University of Bern, Murtenstrasse 31, 3008, Bern, Switzerland.ORCID http://orcid.org/0000-0001-5897-3647
Daniel CandinasDepartment of Visceral Surgery and Medicine, Department for BioMedical Research, Inselspital, Bern University Hospital and University of Bern, 3010, Bern, Switzerland.
Deborah StrokaDepartment of Visceral Surgery and Medicine, Department for BioMedical Research, Inselspital, Bern University Hospital and University of Bern, 3010, Bern, Switzerland.
Vanessa BanzDepartment of Visceral Surgery and Medicine, Department for BioMedical Research, Inselspital, Bern University Hospital and University of Bern, 3010, Bern, Switzerland. vanessa.banz@insel.ch.
University of Bern · CHGlenmark Pharmaceuticals (Switzerland) · CH

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Indexed as

AlkaliesAnimalsAutophagyCarcinoma, HepatocellularCell Line, TumorCell SurvivalDrug SynergismHepatocytesHumansHydrogen-Ion ConcentrationIntracellular MembranesLiver NeoplasmsLysosomesMaleMiceModels, BiologicalAlkaliesNeoplasm Proteinsras ProteinsSorafenibVerteporfin

Identifiers

PMID31582741
PMCPMC6776510
OpenAlexW2978217834

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.