Troglitazone-induced fulminant hepatitis

Li, Hong; Heller, Debra S.; Leevy, Carroll B.; Zierer, K.; Klein, Kenneth M.

doi:10.1016/s1056-8727(00)00076-3

Cited by 22 publications

(4 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Based on these findings, regulating the position of lysosomes emerges as a possible target for future development of drugs that reduce cancer invasion. EIPA and Tro cannot be advanced into the clinic owing to their toxic profiles [ 20 ]. Thus, we have designed an imaging-based high throughput assay to screen for repositioned drugs, already used in clinic for non-cancer indications, which prevent lysosome trafficking.…”

Section: Discussionmentioning

confidence: 99%

“…Robust Z’ factor was calculated using the median and median absolute deviation of the control positive and negative of each plate and only plates with positive value were validated [ 24 – 27 ]. Z’ factor = 1 –{3(SDn + SDp)/(Mn—Mp)} [ 20 ], where Mp, Mn, SDp, SDn are mean and standard deviation of positive control (EIPA) or negative control (acid alone). Size effect of each compound was calculated using normalized percentage of inhibition (NPI).…”

Section: Methodsmentioning

confidence: 99%

“…As previously characterized inhibitors of anterograde lysosome trafficking, such as Tro and EIPA cannot be advanced into the clinical arena [ 20 ], we sought to identify additional novel repurposed and natural product compounds many of which are already in clinical use for non-cancer indications. Our goal was to identify novel inhibitors of anterograde lysosome trafficking with a good safety profile.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A Novel High Content Imaging-Based Screen Identifies the Anti-Helminthic Niclosamide as an Inhibitor of Lysosome Anterograde Trafficking and Prostate Cancer Cell Invasion

et al. 2016

View full text Add to dashboard Cite

Lysosome trafficking plays a significant role in tumor invasion, a key event for the development of metastasis. Previous studies from our laboratory have demonstrated that the anterograde (outward) movement of lysosomes to the cell surface in response to certain tumor microenvironment stimulus, such as hepatocyte growth factor (HGF) or acidic extracellular pH (pHe), increases cathepsin B secretion and tumor cell invasion. Anterograde lysosome trafficking depends on sodium-proton exchanger activity and can be reversed by blocking these ion pumps with Troglitazone or EIPA. Since these drugs cannot be advanced into the clinic due to toxicity, we have designed a high-content assay to discover drugs that block peripheral lysosome trafficking with the goal of identifying novel drugs that inhibit tumor cell invasion. An automated high-content imaging system (Cellomics) was used to measure the position of lysosomes relative to the nucleus. Among a total of 2210 repurposed and natural product drugs screened, 18 “hits” were identified. One of the compounds identified as an anterograde lysosome trafficking inhibitor was niclosamide, a marketed human anti-helminthic drug. Further studies revealed that niclosamide blocked acidic pHe, HGF, and epidermal growth factor (EGF)-induced anterograde lysosome redistribution, protease secretion, motility, and invasion of DU145 castrate resistant prostate cancer cells at clinically relevant concentrations. In an effort to identify the mechanism by which niclosamide prevented anterograde lysosome movement, we found that this drug exhibited no significant effect on the level of ATP, microtubules or actin filaments, and had minimal effect on the PI3K and MAPK pathways. Niclosamide collapsed intralysosomal pH without disruption of the lysosome membrane, while bafilomycin, an agent that impairs lysosome acidification, was also found to induce JLA in our model. Taken together, these data suggest that niclosamide promotes juxtanuclear lysosome aggregation (JLA) via modulation of pathways involved in lysosome acidification. In conclusion, we have designed a validated reproducible high-content assay to screen for drugs that inhibit lysosome trafficking and reduce tumor invasion and we summarize the action of one of these drugs.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Novel High Content Imaging-Based Screen Identifies the Anti-Helminthic Niclosamide as an Inhibitor of Lysosome Anterograde Trafficking and Prostate Cancer Cell Invasion

et al. 2016

View full text Add to dashboard Cite

show abstract

“… 171 Although thiazolidinediones have been demonstrated to lower blood glucose levels in patients with type 2 diabetes, 172 some reports have reported liver damage and death from acute liver failure in patients with thiazolidinedione administration. 173 , 174 Troglitazone, neotroglitazone, pioglitazone, and rosiglitazone are thiazolidinedione derivatives. Troglitazone was the first thiazolidinedione approved for use in the USA in 1997.…”

Section: Role Of Clinical Ppar Agents In Liver Diseasementioning

confidence: 99%

An Overview of the Role of Peroxisome Proliferator-activated Receptors in Liver Diseases

Changizi,

Kajbaf,

Moslehi

2023

J Clin Transl Hepatol

View full text Add to dashboard Cite

Peroxisome proliferator-activated receptors (PPARs) are a superfamily of nuclear transcription receptors, consisting of PPARα, PPARγ, and PPARβ/δ, which are highly expressed in the liver. They control and modulate the expression of a large number of genes involved in metabolism and energy homeostasis, oxidative stress, inflammation, and even apoptosis in the liver. Therefore, they have critical roles in the pathophysiology of hepatic diseases. This review provides a general insight into the role of PPARs in liver diseases and some of their agonists in the clinic.

show abstract

Troglitazone and liver injury: In search of answers

Chojkier

2005

Hepatology

112

View full text Add to dashboard Cite

Troglitazone-induced fulminant hepatitis

Cited by 22 publications

References 4 publications

A Novel High Content Imaging-Based Screen Identifies the Anti-Helminthic Niclosamide as an Inhibitor of Lysosome Anterograde Trafficking and Prostate Cancer Cell Invasion

A Novel High Content Imaging-Based Screen Identifies the Anti-Helminthic Niclosamide as an Inhibitor of Lysosome Anterograde Trafficking and Prostate Cancer Cell Invasion

An Overview of the Role of Peroxisome Proliferator-activated Receptors in Liver Diseases

Troglitazone and liver injury: In search of answers

Contact Info

Product

Resources

About