2015
DOI: 10.7717/peerj.1314
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Autophagic flux inhibition and lysosomogenesis ensuing cellular capture and retention of the cationic drug quinacrine in murine models

Abstract: The proton pump vacuolar (V)-ATPase is the driving force that mediates the concentration of cationic drugs (weak bases) in the late endosome-lysosome continuum; secondary cell reactions include the protracted transformation of enlarged vacuoles into autophagosomes. We used the inherently fluorescent tertiary amine quinacrine in murine models to further assess the accumulation and signaling associated with cation trapping. Primary fibroblasts concentrate quinacrine ∼5,000-fold from their culture medium (KM 9.8 … Show more

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Cited by 18 publications
(23 citation statements)
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References 53 publications
(85 reference statements)
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“…Next, we performed total internal reflection fluorescence microscopy (TIRF) to directly visualize and quantitate lysosomal exocytosis through the kinetics of ATP-laden vesicles and their fusion with the plasma membrane (40). WT and iTat astrocytes were treated with Dox for 3 days; labeled with quinacrine, a fluorescent marker of intracellular ATP vesicles co-localized with the lysosome-specific marker LAMP-1 (41,42); and analyzed by TIRF. The overall lysosomal exocytosis in Dox-treated WT astrocytes and Dox-treated iTat astrocytes was recorded (supplemental Movies S1 and S2).…”
Section: Neurotoxic Factors Other Than Tat For Astrocyte-mediatedmentioning
confidence: 99%
“…Next, we performed total internal reflection fluorescence microscopy (TIRF) to directly visualize and quantitate lysosomal exocytosis through the kinetics of ATP-laden vesicles and their fusion with the plasma membrane (40). WT and iTat astrocytes were treated with Dox for 3 days; labeled with quinacrine, a fluorescent marker of intracellular ATP vesicles co-localized with the lysosome-specific marker LAMP-1 (41,42); and analyzed by TIRF. The overall lysosomal exocytosis in Dox-treated WT astrocytes and Dox-treated iTat astrocytes was recorded (supplemental Movies S1 and S2).…”
Section: Neurotoxic Factors Other Than Tat For Astrocyte-mediatedmentioning
confidence: 99%
“…Previously, we observed that CFZ biocrystals can also be phagocytosed by macrophages, where they are stable inside low-pH (4, 5) and counterion (Cl Ϫ )-containing (9) membrane-bound compartments. As a weakly basic lysosomotropic drug, CFZ is prone to pH-dependent ion trapping in lysosomes and could therefore activate transcription factor EB (TFEB [55]), a master transcription factor of lysosomal biogenesis and homeostasis (56)(57)(58). In turn, this could attenuate inflammasome activation pathways and IL-1␤ processing (59).…”
Section: Figmentioning
confidence: 99%
“…() to evaluate autophagic flux inhibition and lysomogenesis by a cationic drug in several murine models. These investigators found quinicrine to be present in perinuclear granules that are positive for Rab7 and LAMP1 proteins (Parks et al ., ). The Rab7 and LAMP1 proteins are both essential for autolysosome maturation (Chua et al ., ; Wang et al ., ).…”
Section: Drug Toxicity Induced Autophagic Dysfunctionmentioning
confidence: 99%
“…Quinicrine, a tertiary amine antihelmintic or antiprotozoal used in the treatment of malaria, giardiasis and tapeworm, was used in a study by Parks et al (2015) to evaluate autophagic flux inhibition and lysomogenesis by a cationic drug in several murine models. These investigators found quinicrine to be present in perinuclear granules that are positive for Rab7 and LAMP1 proteins (Parks et al, 2015). The Rab7 and LAMP1 proteins are both essential for autolysosome maturation (Chua et al, 2011;Wang et al, 2013).…”
Section: Drug Toxicity Induced Autophagic Dysfunctionmentioning
confidence: 99%
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