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Lysosomal Biogenesis and Implications for Hydroxychloroquine Disposition.

Keagan P Collins1, Sandra Witta2, Jonathan W Coy2

  • 1Colorado 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.

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Hydroxychloroquine (HCQ) increases its own cellular uptake by expanding lysosomes via lysosomal biogenesis. This self-sequestration mechanism impacts drug disposition and contributes to drug resistance for lysosomotropic agents.

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Area of Science:

  • Cell Biology
  • Pharmacology
  • Cancer Research

Background:

  • Lysosomes sequester lysosomotropic drugs, contributing to multidrug resistance.
  • Lysosomotropic agents can activate transcription factor EB (TFEB), promoting lysosomal biogenesis.
  • Understanding drug disposition is crucial for cancer therapy and drug interaction studies.

Purpose of the Study:

  • To investigate the role of lysosomal biogenesis in hydroxychloroquine (HCQ) disposition.
  • To determine if HCQ can modulate its own cellular uptake and lysosomal volume.
  • To explore the implications for drug resistance and drug-drug interactions.

Main Methods:

  • Utilized an in vitro pharmacokinetic (PK) model with human breast cancer cell lines.
  • Characterized HCQ cellular uptake under static and dynamic equilibrium conditions.
  • Assessed the impact of TFEB activation (using Torin1) on HCQ concentrations.

Main Results:

  • Modulating lysosomal volume influenced HCQ disposition in cancer cells.
  • HCQ exposure led to increased lysosomal compartment size via swelling and TFEB-induced biogenesis.
  • Pretreatment with Torin1 increased whole-cell HCQ concentrations by 1.4- to 1.6-fold.

Conclusions:

  • HCQ actively modulates its own pharmacokinetic uptake by increasing lysosomal volume.
  • This mechanism, involving TFEB and lysosomal swelling, is relevant to other lysosomotropic drugs.
  • Findings advance understanding of lysosomal drug sequestration, multidrug resistance, and drug interactions.