Lysyl oxidase-like protein 2 (LOXL2) modulates barrier function in cholangiocytes in cholestasis

Pollheimer, Marion J.; Racedo, Silvia; Mikels‐Vigdal, Amanda; Marshall, Derek; Bowlus, Christopher L.; Lackner, Carolin; Madl, Tobias; Karlsen, Tom H.; Hov, Johannes R.; Lyman, Susan K.; Adamkewicz, Joanne I.; Smith, Victoria; Moreau, Emmanuel; Zollner, Gernot; Eide, Tor J.; Stojaković, Tatjana; Scharnagl, Hubert; Gruber, Hans Jürgen; Stauber, Rudolf; Trauner, Michael; Fickert, Peter

doi:10.1016/j.jhep.2018.04.009

Cited by 31 publications

(28 citation statements)

References 39 publications

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“…Based on the present results ( Fig. S2, supporting information) and recent literature, inhibiting profibrotic lysyl oxidase-like (LOXL) proteins may decelerate cholestasis-induced fibrogenesis 12 . Agents targeting TNF-α or inflammasome signalling have already been approved for other indications.…”

supporting

confidence: 77%

Effect of preoperative biliary drainage on cholestasis-associated inflammatory and fibrotic gene signatures in perihilar cholangiocarcinoma

Reiniers

Haan

Weijer

et al. 2019

Journal of British Surgery

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Preoperative biliary drainage (PBD) is used routinely in the evaluation of patients with potentially resectable perihilar cholangiocarcinoma to relieve cholestasis and improve the liver's resilience to surgery. Little preclinical or translatational data are, however, currently available to guide the use of PBD in this patient group. The effect of PBD on hepatic gene expression profiles was therefore studied by microarray analysis. Drainage affects inflammatory and fibrotic gene signatures

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supporting

confidence: 77%

Effect of preoperative biliary drainage on cholestasis-associated inflammatory and fibrotic gene signatures in perihilar cholangiocarcinoma

Reiniers

Haan

Weijer

et al. 2019

Journal of British Surgery

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Section: Modulation Of Loxl2 Activitymentioning

confidence: 99%

“…D‐pen has also been tested in disease states with higher levels of LOXL2, for instance cholangiopathies . Cultured murine biliary epithelial cells were treated with 150 µ m D‐pen to inhibit the activity of LOX enzymes, alongside 150 µ m bathocuproinedisulfonic acid . The main outcome does support the use of anti‐LOXL2 therapy in primary sclerosing cholangitis (PSC); however, potential consequences such as bile duct injury should be considered .…”

Section: Modulation Of Loxl2 Activitymentioning

confidence: 99%

“…Cultured murine biliary epithelial cells were treated with 150 µ m D‐pen to inhibit the activity of LOX enzymes, alongside 150 µ m bathocuproinedisulfonic acid . The main outcome does support the use of anti‐LOXL2 therapy in primary sclerosing cholangitis (PSC); however, potential consequences such as bile duct injury should be considered . It is important to highlight that D‐pen was clinically tested in patients with primary sclerosing cholangitis in the 1980s and the conclusion was that D‐pen was not an effective treatment in this disease …”

Section: Modulation Of Loxl2 Activitymentioning

confidence: 99%

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Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target

Chopra

Sangarappillai

Romero‐Canelón

et al. 2020

Advanced Therapeutics

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Lysyl oxidase‐like 2 (LOXL2) is an emerging drug target against metastatic disease owing to its role in the upregulation of key processes including epithelial‐mesenchymal transition (EMT) and invasion. Recent activity in the field of small molecule LOXL2 inhibitor development by pharmaceutical and academic laboratories has renewed interest in targeting LOXL2. Herein, 1) the viability of LOXL2 as a drug target for the treatment of metastatic disease through an investigation of its biological actions is determined; 2) the pitfalls of an antibody approach are considered; and 3) the small molecule approaches emerging in the scientific and patent literature are reviewed. This review identifies that LOXL2 is localized and active intracellularly and extracellularly in invasive cancer cells. LOXL2 has been implicated in a number of established signaling pathways involved in tumor progression, further highlighting its appeal as a target in metastatic disease. Previously, limited chemical inhibitors have been developed; however, their selectivity profile for the LOX family has proven controversial. Antibodies, such as simtuzumab, have been developed selectively against LOXL2. Simtuzumab, in particular, progresses into phase II trials but it was ultimately terminated. The small molecule inhibitors of LOXL2 are summarized, some of which are now in the early stages of clinical trials.

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“…Lysyl oxidase‐like protein 2 (LOXL2) is a member of the large and diverse LOX and LOXL family that promotes stabilization of the extracellular matrix, chemotaxis, cell growth, and cell mobility and may also be engaged in the regulation of bile duct permeability . Induction of LOXL2 activity was demonstrated in fibrotic liver diseases .…”

mentioning

confidence: 99%