Evaluating the Roles of Autophagy and Lysosomal Trafficking Defects in Intracellular Distribution-Based Drug-Drug Interactions Involving Lysosomes

Logan, Randall; Kong, Alex C.; Krise, Jeffrey P.

doi:10.1002/jps.23706

Cited by 19 publications

(35 citation statements)

References 38 publications

(68 reference statements)

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“…The effect of these drugs on lysosomal volume are consistent with the effects of other amphipathic, cationic molecules containing aromatic rings, which cause an increase in lysosomal volume, purportedly through intercalation of lysosomotropic drugs within lipid bilayers, but with no change in lysosomal pH (43). Such compounds also have been shown to increase the trafficking of proteins from the plasma membrane or endoplasmic reticulum to lysosomes (44,45), and by doing so would be expected to reduce the quantity of APP exposed to amyloidogenic processing by BACE and γ-secretase.…”

Section: Discussionsupporting

confidence: 61%

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

Netzer

Bettayeb

Sinha

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Neurotoxic amyloid-β peptides (Aβ) are major drivers of Alzheimer's disease (AD) and are formed by sequential cleavage of the amyloid precursor protein (APP) by β-secretase (BACE) and γ-secretase. Our previous study showed that the anticancer drug Gleevec lowers Aβ levels through indirect inhibition of γ-secretase activity. Here we report that Gleevec also achieves its Aβ-lowering effects through an additional cellular mechanism. It renders APP less susceptible to proteolysis by BACE without inhibiting BACE enzymatic activity or the processing of other BACE substrates. This effect closely mimics the phenotype of APP A673T, a recently discovered mutation that protects carriers against AD and age-related cognitive decline. In addition, Gleevec induces formation of a specific set of APP C-terminal fragments, also observed in cells expressing the APP protective mutation and in cells exposed to a conventional BACE inhibitor. These Gleevec phenotypes require an intracellular acidic pH and are independent of tyrosine kinase inhibition, given that a related compound lacking tyrosine kinase inhibitory activity, DV2-103, exerts similar effects on APP metabolism. In addition, DV2-103 accumulates at high concentrations in the rodent brain, where it rapidly lowers Aβ levels. This study suggests that long-term treatment with drugs that indirectly modulate BACE processing of APP but spare other BACE substrates and achieve therapeutic concentrations in the brain might be effective in preventing or delaying the onset of AD and could be safer than nonselective BACE inhibitor drugs.Alzheimer's disease | Gleevec | nonamyloidogenic | β-cleavage

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Section: Discussionsupporting

confidence: 61%

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

Netzer

Bettayeb

Sinha

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…This can be studied using this model as depolymerization of the MT will cause centralization of all melanosomes being conveyed on such microtubule tracts. Aside having aggregation of malfolded MT proteins, accumulation of vesicles will induce cell death by autophagy [33]. In a similar way, synaptic denervation is a function of depolymerization of the axo-dendritic cytoskeletal structure [34].…”

Section: Discussionmentioning

confidence: 99%

VDR Potentiation and NMDA R Inhibition Facilitates Axo-Dendritic Process Formation in Melanocyte Model for Pigmented Cells in Parkinsonism

Michael

Ajonijebu²,

Chris³

et al. 2013

Cell Development Biol

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Background: A major cellular change in dopaminergic neurons leading to Parkinsonism is the alteration of microtubule proteins that causes accumulation of tau protein, α-syn and β-amyloid plaque in the cells. In this study we investigate the role of Vitamin D 3 in relieving the symptoms of Parkinsonism as it is capable of stimulating polymerization of microtubules. The Microtubules (MT) system in the fish scale melanocytes has been modeled for the dopaminergic neurons of the Substantia Nigra (SN). These cells are capable of forming cellular processes similar to what is seen in the dopaminergic neurons; in this study, we investigate the protective effect of Vitamin D 3 Receptor Agonist (VDRA) and N-Methyl-D-Aspartate Receptor (NMDA R) inhibition in process formation, synaptic denervation and melanin loss in fish scale melanocytes modeled as pigmented adrenergic cells.

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“…This makes them substrates in the process of sequestration (substances capture and their long-term storage) into intracellular compartments with acidic features. Such compartments may be lysosomes, which capture drugs via ion trapping mechanism [79]. …”

Section: Proven and Probable Processes Causing Resistance To Tkis In mentioning

confidence: 99%

“…Such results may help to rationalize how sequestration may work when other tyrosine kinase inhibitors are taken into consideration [74,79]. …”

Section: Proven and Probable Processes Causing Resistance To Tkis In mentioning

confidence: 99%

Mechanisms of Acquired Resistance to Tyrosine Kinase Inhibitors in Clear - Cell Renal Cell Carcinoma (ccRCC)

Bielecka¹,

Czarnecka²,

Solarek³

et al. 2014

CST

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Clear - cell renal cell carcinoma (ccRCC) is a histological subtype of renal cell carcinoma - the most prevalent adult kidney cancer. Causes of ccRCC are not completely understood and therefore number of available therapies is limited. As a consequence of tumor chemo- and radioresistance as well as restrictions in offered targeted therapies, overall response rate is still unsatisfactory. Moreover, a significant group of patients (circa 1/4) does not respond to the targeted first-line treatment, while in other cases, after an initial period of stable improvement, disease progression occurs. Owing to this, more data on resistance mechanisms are needed, especially those concerning widely used, relatively lately approved and more successful than previous therapies - tyrosine kinase inhibitors (TKIs). Up to date, five TKIs have been licensed for ccRCC treatment: sunitinib (SUTENT®, Pfizer Inc.), sorafenib (Nexavar®, Bayer HealthCare/Onyx Pharmaceuticals), pazopanib (Votrient®, GlaxoSmithKline), axitinib (Inlyta®, Pfitzer Inc.) and tivozanib (AV-951®, AVEO Pharmaceuticals).Researchers have specified different subsets of tyrosine kinase inhibitors potential resistance mechanisms in clear-cell renal cell carcinoma. In most papers published until now, drug resistance is divided into intrinsic and acquired, and typically multi-drug resistance (MDR) protein is described. Herein, the authors focus on molecular analysis concerning acquired, non-genetic resistance to TKIs, with insight into specific biological processes.

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Evaluating the Roles of Autophagy and Lysosomal Trafficking Defects in Intracellular Distribution-Based Drug-Drug Interactions Involving Lysosomes

Cited by 19 publications

References 38 publications

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

VDR Potentiation and NMDA R Inhibition Facilitates Axo-Dendritic Process Formation in Melanocyte Model for Pigmented Cells in Parkinsonism

Mechanisms of Acquired Resistance to Tyrosine Kinase Inhibitors in Clear - Cell Renal Cell Carcinoma (ccRCC)

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