Lysosomes and Phospholipidosis in Drug Development and Regulation

Willard, James M.; Felice, Albert De

doi:10.1002/9781118978320.ch20

Cited by 3 publications

(2 citation statements)

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“…12 The endoplasmic reticulum (ER) synthesizes lipids and proteins that are subsequently sorted and modified through post-translational modifications in the Golgi apparatus, 13,14 and lysosomes are responsible for cellular digestion essential to autophagy. 15 While previously-tested H + /Cltransporting anionophores have been found to exert their cytotoxic effects through the lysosomes, 10 the effect of anionophore-induced transport on other subcellular compartments is currently unknown. Cltransport proteins have been identified in other subcellular compartments such as the ER, Golgi apparatus and mitochondria, which highlights the importance of this anion to the cellular function of many membrane-bound organelles.…”

Section: Introductionmentioning

confidence: 99%

Subcellular targeted anion transporters

Ryder,

Graziotto,

Levina

et al. 2024

Preprint

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Synthetic anion transporters that mediate electroneutral (H+/Cl–) transport have demonstrated anti-cancer activity due to their ability to disrupt subcellular homeostatic environments. Elucidation of the cell death mechanism revealed the transporters’ ability to neutralize lysosomal pH gradients and inhibit autophagy. However, their effect on other subcellular compartments is unknown. Herein, we disclose the first subcellular targeted anionophores that accumulate in various membrane bound organelles to bias their natural propensity to depolarize lysosomes. Confocal microscopy revealed the ability of the naphthalimide-based transporters to localize within their intended membrane-bound organelles. Analogues that contained endoplasmic reticulum (ER) and lysosomal targeting motifs showed an enhanced H+/Cl– transport ability and cytotoxicity compared to non-targeted analogues. Moreover, ER and mitochondrial localization was found to enhance apoptosis in cancerous cells. Our work provides an alternative approach to the design of therapeutically focused synthetic anion transporters and an insight into possible subcellular compartment-specific effects on homeostasis.

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Section: Introductionmentioning

confidence: 99%

Subcellular targeted anion transporters

Ryder,

Graziotto,

Levina

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…12 The endoplasmic reCculum (ER) is involved in synthesising lipids and proteins that are subsequently sorted and modified through post-translaConal modificaCons in the Golgi apparatus, [13][14] and lysosomes are responsible for cellular digesCon essenCal to autophagy. 15 While the determinants of cancer cell death exhibited by the previously-tested anionophores were found to exert their effects on the lysosomes, 10 the effect of anionophore-induced transport on other subcellular compartments is currently unknown. Concomitant chloride transport proteins have been idenCfied in other subcellular compartments such as the ER, Golgi apparatus and mitochondria, which highlights the importance of this anion to the cellular funcCon of many membrane-bound organelles.…”

Section: Introduconmentioning

confidence: 99%

Subcellular targeted anionophores

Ryder

Graziotto

New

et al. 2023

Preprint

View full text Add to dashboard Cite

Synthetic anion transporters that mediate electroneutral (H+/Cl-) transport have demonstrated anti-cancer activity due to their ability to disrupt subcellular homeostasis. Elucidation of the cell death mechanism revealed the transporters’ ability to neutralise lysosomal pH gradients and inhibit autophagy. However, their effect on other subcellular compartments is unknown. Herein, we disclose the first subcellular targeted anionophores that accumulate in various membrane bound organelles to bias their natural propensity to depolarise lysosomes. The series of naphthalimide-based transporters were studied by confocal microscopy, and were found to accumulate in different subcellular organelles. The analogues that contained endoplasmic reticulum (ER)- and lysosomal targeting motifs showed enhanced the H+/Cl- transport ability compared to their non-targeted analogues. Moreover, ER and lysosomal localisation was found to enhance the cytotoxic effect of the transporters on cancerous cells. Our work provides an alternative approach in the design of therapeutically focused synthetic anion transporters and an insight into possible subcellular compartment-specific effects on homeostasis.

show abstract