Evidence map›Paper›PMID 33172973›Full record

ArticleThe Journal of pharmacology and experimental therapeutics2021

Lysosomal Biogenesis and Implications for Hydroxychloroquine Disposition.

Keagan P Collins, Sandra Witta, Jonathan W Coy, Yi Pang, Daniel L Gustafson

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

Article in The Journal of pharmacology and experimental therapeutics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.

0numbers the graph read from it
0cells of the map it votes in
12citing papers in PubMed
1.7field-weighted citation impact, top 16% 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

12 citing papers in PubMed, 28 citations in OpenAlex.

  1. Review
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  12. Pharmacokinetic and Pharmacodynamic Assessment of Hydroxychloroquine in Breast Cancer.The Journal of pharmacology and experimental therapeutics · 2021
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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

5 authors at 2 institutions in 1 country.

Keagan P CollinsColorado State University, School of Biomedical Engineering (K.P.C., S.W., D.L.G.) and Department of Clinical Sciences (D.L.G., J.W.C.), Colorado State University, Fort Collins, Colorado; University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, Colorado (D.L.G.); and University of Akron, Department of Chemistry, Akron, Ohio (Y.P.) daniel.gustafson@colostate.edu.
Sandra WittaColorado State University, School of Biomedical Engineering (K.P.C., S.W., D.L.G.) and Department of Clinical Sciences (D.L.G., J.W.C.), Colorado State University, Fort Collins, Colorado; University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, Colorado (D.L.G.); and University of Akron, Department of Chemistry, Akron, Ohio (Y.P.).
Jonathan W CoyColorado State University, School of Biomedical Engineering (K.P.C., S.W., D.L.G.) and Department of Clinical Sciences (D.L.G., J.W.C.), Colorado State University, Fort Collins, Colorado; University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, Colorado (D.L.G.); and University of Akron, Department of Chemistry, Akron, Ohio (Y.P.).
Yi PangColorado State University, School of Biomedical Engineering (K.P.C., S.W., D.L.G.) and Department of Clinical Sciences (D.L.G., J.W.C.), Colorado State University, Fort Collins, Colorado; University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, Colorado (D.L.G.); and University of Akron, Department of Chemistry, Akron, Ohio (Y.P.).
Daniel L GustafsonColorado State University, School of Biomedical Engineering (K.P.C., S.W., D.L.G.) and Department of Clinical Sciences (D.L.G., J.W.C.), Colorado State University, Fort Collins, Colorado; University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, Colorado (D.L.G.); and University of Akron, Department of Chemistry, Akron, Ohio (Y.P.) daniel.gustafson@colostate.edu.
Colorado State University · USUniversity of Colorado Denver · US

Funding

University of Colorado Cancer Center Support Grant - Lung Cancer Patient-Derived Xenografts with Autologous Human Immune SystemsP30CA046934 · NCI · UNIVERSITY OF COLORADO DENVER · PI James V Degregori · 1988 to 2026
$117.0M
Therapeutic targeting of autophagy-dependent cancerR01CA190170 · NCI · UNIVERSITY OF COLORADO DENVER · PI GUSTAFSON, DANIEL L, THORBURN, ANDREW M · 2015 to 2019
$2.5M
NCI NIH HHS P30 CA046934NCI NIH HHS R01 CA190170
6 · The paper itself

Abstract

Lysosomes act as a cellular drug sink for weakly basic, lipophilic (lysosomotropic) xenobiotics, with many instances of lysosomal trapping associated with multiple drug resistance. Lysosomotropic agents have also been shown to activate master lysosomal biogenesis transcription factor EB (TFEB) and ultimately lysosomal biogenesis. We investigated the role of lysosomal biogenesis in the disposition of hydroxychloroquine (HCQ), a hallmark lysosomotropic agent, and observed that modulating the lysosomal volume of human breast cancer cell lines can account for differences in disposition of HCQ. Through use of an in vitro pharmacokinetic (PK) model, we characterized total cellular uptake of HCQ within the duration of static equilibrium (1 hour), as well as extended exposure to HCQ that is subject to dynamic equilibrium (>1 hour), wherein HCQ increases the size of the lysosomal compartment through swelling and TFEB-induced lysosomal biogenesis. In addition, we observe that pretreatment of cell lines with TFEB-activating agent Torin1 contributed to an increase of whole-cell HCQ concentrations by 1.4- to 1.6-fold, which were also characterized by the in vitro PK model. This investigation into the role of lysosomal volume dynamics in lysosomotropic drug disposition, including the ability of HCQ to modify its own disposition, advances our understanding of how chemically similar agents may distribute on the cellular level and examines a key area of lysosomal-mediated multiple drug resistance and drug-drug interaction. SIGNIFICANCE STATEMENT: Hydroxychloroquine is able to modulate its own cellular pharmacokinetic uptake by increasing the cellular lysosomal volume fraction through activation of lysosomal biogenesis master transcription factor EB and through lysosomal swelling. This concept can be applied to many other lysosomotropic drugs that activate transcription factor EB, such as doxorubicin and other tyrosine kinase inhibitor drugs, as these drugs may actively increase their own sequestration within the lysosome to further exacerbate multiple drug resistance and lead to potential acquired resistance.

Indexed as

Organelle BiogenesisAntimalarialsBiological TransportCytosolHumansHydroxychloroquineLysosomesMCF-7 CellsAntimalarialsHydroxychloroquine

Identifiers

PMID33172973
PMCPMC7841421
OpenAlexW3103020087

What OpenQuestion holds

Textmetadata
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.