Amine-Containing Molecules and the Induction of an Expanded Lysosomal Volume Phenotype: A Structure–Activity Relationship Study

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

doi:10.1002/jps.23949

Cited by 36 publications

(26 citation statements)

References 46 publications

(108 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: 68%

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: 68%

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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“…Previously, We did observe increased pH evident by decreased LTR staining following 4 hr drug treatment in H9C2 cells [14]. However, LTR increases have been observed with multiple other cell lines following 24 hrs treatment with lysosomotropic compounds [12, 13]. With ARPE19 cells, pH increase was rather transient and only observed at 30 mins and 1 hr exposure for Chloroquine, fluoxetine, tamoxifen, chloropromazine.…”

Section: Discussionmentioning

confidence: 80%

“…The fluorescent dye, LysoTracker Red ® DND-99 (LTR), which has been reported to accumulate in lysosomes by virtue of ionic trapping requiring acidic pH [15], was used to assess the lysosomal pH change with the drug treatment. However increase of LTR staining was also observed with lysosomotropic compounds treatment [12, 13]. In the current study multiple time points (30 mins, 1 hour, 4 hours and 24 hours) with a concentration range from 200 μM to 0.82 μM were evaluated after lysosomotropic compound treatment.…”

Section: Resultsmentioning

confidence: 99%

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Lysosomal adaptation: How cells respond to lysosomotropic compounds

Sung

Lin³

et al. 2017

PLoS ONE

118

119

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Lysosomes are acidic organelles essential for degradation and cellular homoeostasis and recently lysosomes have been shown as signaling hub to respond to the intra and extracellular changes (e.g. amino acid availability). Compounds including pharmaceutical drugs that are basic and lipophilic will become sequestered inside lysosomes (lysosomotropic). How cells respond to the lysosomal stress associated with lysosomotropism is not well characterized. Our goal is to assess the lysosomal changes and identify the signaling pathways that involve in the lysosomal changes. Eight chemically diverse lysosomotropic drugs from different therapeutic areas were subjected to the evaluation using the human adult retinal pigmented epithelium cell line, ARPE-19. All lysosomotropic drugs tested triggered lysosomal activation demonstrated by increased lysosotracker red (LTR) and lysosensor green staining, increased cathepsin activity, and increased LAMP2 staining. However, tested lysosomotropic drugs also prompted lysosomal dysfunction exemplified by intracellular and extracellular substrate accumulation including phospholipid, SQSTM1/p62, GAPDH (Glyceraldehyde 3-phosphate dehydrogenase) and opsin. Lysosomal activation observed was likely attributed to lysosomal dysfunction, leading to compensatory responses including nuclear translocation of transcriptional factors TFEB, TFE3 and MITF. The adaptive changes are protective to the cells under lysosomal stress. Mechanistic studies implicate calcium and mTORC1 modulation involvement in the adaptive changes. These results indicate that lysosomotropic compounds could evoke a compensatory lysosomal biogenic response but with the ultimate consequence of lysosomal functional impairment. This work also highlights a pathway of response to lysosomal stress and evidences the role of TFEB, TFE3 and MITF in the stress response.

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“…The model consisted of three compartments: the extracellular space (pH 7.4), the cytosol [pH 7.2 (66)], and early endosomes, where BACE-1 is active (42)(43)(44) [i.e., a pH of 6 (66) and volume equal to 1% of the cytosolic volume (67)]. Accumulation of basic compounds in the endolysosomal compartment produces significant increases in the volume of these organelles (68,69). However, F endo estimates were insensitive to changes in the volume of the endosomal compartment (up to 5% of the cytosolic volume).…”

Section: Measurement Of Intracellular Compound Bioavailability (F Ic )mentioning

confidence: 99%

Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery

Mateus

Gordon

Wayne

et al. 2017

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

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Inadequate target exposure is a major cause of high attrition in drug discovery. Here, we show that a label-free method for quantifying the intracellular bioavailability (F ic ) of drug molecules predicts drug access to intracellular targets and hence, pharmacological effect. We determined F ic in multiple cellular assays and cell types representing different targets from a number of therapeutic areas, including cancer, inflammation, and dementia. Both cytosolic targets and targets localized in subcellular compartments were investigated. F ic gives insights on membrane-permeable compounds in terms of cellular potency and intracellular target engagement, compared with biochemical potency measurements alone. Knowledge of the amount of drug that is locally available to bind intracellular targets provides a powerful tool for compound selection in early drug discovery. intracellular drug bioavailability | drug exposure | target engagement | published kinase inhibitor set | MAPK14

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Amine-Containing Molecules and the Induction of an Expanded Lysosomal Volume Phenotype: A Structure–Activity Relationship Study

Cited by 36 publications

References 46 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

Lysosomal adaptation: How cells respond to lysosomotropic compounds

Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery

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