Modulation of tamoxifen-induced hepatotoxicity by tamoxifen–phospholipid complex

The spectrum of alcoholic liver disease (ALD) is a major cause of mortality with limited therapies available. Because alcohol targets numerous signaling pathways in hepatocytes and in immune cells, the identification of a master regulatory target that modulates multiple signaling processes is attractive. In this report, we assessed the role of spleen tyrosine kinase (SYK), a non-receptor tyrosine kinase, which has a central modulatory role in multiple pro-inflammatory signaling pathways involved in the pathomechanism of ALD. Using mouse disease models that represent various phases in the progression of human ALD, we found that alcohol, in all of these models, induced SYK activation in the liver, both in hepatocytes and liver mononuclear cells. Further, significant SYK activation also occurred in liver samples and peripheral blood mononuclear cells of patients with ALD/alcoholic hepatitis compared to controls. Functional inhibition of SYK activation in vivo abrogated alcohol-induced hepatic neutrophil infiltration, resident immune cell activation, as well as inflammasome and ERK1/2-mediated NF-κB activation in mice. Strikingly, inhibition of SYK activation diminished alcohol-induced hepatic steatosis and IRF3-mediated apoptosis. Conclusion Our data demonstrate a novel, functional, and multicellular role for SYK phosphorylation in modulating immune cell-driven liver inflammation, hepatocyte cell death, and steatosis at different stages of ALD. These novel findings highlight SYK as a potential multifunctional target in the treatment of alcoholic steatohepatitis.

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“…In vivo administration of the SYK inhibitor prevented SYK activation (pSYK Y525/526 levels) induced by chronic alcohol feeding (Fig. A) …”

Section: Resultsmentioning

confidence: 94%

“…Because of embryonic lethality, studies with SYK knockouts are limited . The available SYK conditional knockout mice with inducible SYK inactivation by tamoxifen also has limitations for ALD given the known adverse effects of tamoxifen on the liver …”

Section: Discussionmentioning

confidence: 99%

Inhibition of spleen tyrosine kinase activation ameliorates inflammation, cell death, and steatosis in alcoholic liver disease

et al. 2016

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“…Animals of all groups were sacrificed by cervical decapitation under light ether anaesthesia on the 22nd day. Blood and liver samples were collected and processed accordingly for the estimation of antioxidant enzymes . Postmitochondrial supernatant was prepared as per the previously reported method and used for the assay of marker enzymes, namely reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) as per the reported methods .…”

Section: Methodsmentioning

confidence: 99%

“…Long‐term TMX therapy has some major side effects, including higher prevalence of endometrial cancer, thromboembolic disorders, liver cancer and development of drug resistance . Very recently, we demonstrated that TMX metabolism in the liver leads to oxidative liver damage …”

Section: Introductionmentioning

confidence: 99%

“…[18] Very recently, we demonstrated that TMX metabolism in the liver leads to oxidative liver damage. [19] Over the last 10 years, solid lipid nanoparticles are being formulated as a drug delivery carrier for poorly water-soluble compounds. [20][21][22] These nanoparticles are of the submicron size ranging from 50 to 1000 nm and are composed of physiological lipids that remain solid at room temperature.…”

Section: Introductionmentioning

confidence: 99%

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Alpha-lipoic acid–stearylamine conjugate-based solid lipid nanoparticles for tamoxifen delivery: formulation, optimization, in-vivo pharmacokinetic and hepatotoxicity study

Dhaundiyal

Jena

Samal

et al. 2016

Journal of Pharmacy and Pharmacology

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Tamoxifen and oxidative stress: an overlooked connection

et al. 2021

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Tamoxifen is the gold standard drug for the treatment of breast cancer in pre and post-menopausal women. Its journey from a failing contraceptive to a blockbuster is an example of pharmaceutical innovation challenges. Tamoxifen has a wide range of pharmacological activities; a drug that was initially thought to work via a simple Estrogen receptor (ER) mechanism was proven to mediate its activity through several non-ER mechanisms. Here in we review the previous literature describing ER and non-ER targets of tamoxifen, we highlighted the overlooked connection between tamoxifen, tamoxifen apoptotic effects and oxidative stress.

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Modulation of tamoxifen-induced hepatotoxicity by tamoxifen–phospholipid complex

Abstract: Data of the present study suggests that phospholipid may prove as a useful component of combination therapy in cancer patients under the TMX treatment regimen.

Cited by 15 publications

References 36 publications

Inhibition of spleen tyrosine kinase activation ameliorates inflammation, cell death, and steatosis in alcoholic liver disease

Inhibition of spleen tyrosine kinase activation ameliorates inflammation, cell death, and steatosis in alcoholic liver disease

Alpha-lipoic acid–stearylamine conjugate-based solid lipid nanoparticles for tamoxifen delivery: formulation, optimization, in-vivo pharmacokinetic and hepatotoxicity study

Tamoxifen and oxidative stress: an overlooked connection

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