Study on the mechanism and intervention strategy of sunitinib induced nephrotoxicity

Xiao, Jian-Ping; Wang, Ju; Liu, Yuan; Hao, Li; Wang, Deguang

doi:10.1016/j.ejphar.2019.172709

Cited by 16 publications

(12 citation statements)

References 23 publications

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“…Crizotinib and sunitinib not only suppressed the cellullar survival and proliferation of L02 cells but also enhanced the release of ALT and AST, indicating their potential toxicity to the human liver. To date, many studies have supported that crizotinib (Mingard et al, 2018;Yan et al, 2019) and sunitinib (Teo et al, 2015;Bouitbir et al, 2019;Xiao et al, 2019) induced various toxic reactions in a concentration-and time-dependent manner, including hepatotoxicity. In our study, we examined the hepatotoxicity of crizotinib and sunitinib on the C57 mice, which are widely used as an experimental animal model of physiology and pathology.…”

Section: Discussionmentioning

confidence: 99%

Crizotinib and Sunitinib Induce Hepatotoxicity and Mitochondrial Apoptosis in L02 Cells via ROS and Nrf2 Signaling Pathway

et al. 2021

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Considerable attention has been raised on crizotinib- and sunitinib-induced hepatotoxicity, but the underlying mechanisms need further examination. In addition, limited therapeutic strategies exist to reduce the liver damage caused by crizotinib and sunitinib. This study investigated the mechanisms of crizotinib- and sunitinib-induced hepatotoxicity and the potential mitigation through ROS and Nrf2 signaling. Firstly, crizotinib and sunitinib reduced cell viability in human liver cells (L02 cells) and triggered dramatic liver injury in mice. Subsequently, we found that crizotinib and sunitinib activated the oxidative stress response (decreased level of GPx and SOD, and increased MDA content) in vivo. Crizotinib and sunitinib also stimulated hepatocyte mitochondrial apoptosis and necrosis in L02 cells in a dose-dependent manner. In vivo studies further confirmed that crizotinib and sunitinib decreased mitochondrial membrane potential and activated apoptosis-associated proteins (cleaved-PARP, cleaved caspase3, cytochrome c, Bcl2 and Bax). Furthermore, mechanistic investigations demonstrated that crizotinib and sunitinib accumulated ROS and inhibited Nrf2 signaling, and that ROS scavenger NAC and Nrf2 agonist tBHQ alleviated the extent of cell damage and the mitochondrial apoptosis during crizotinib- and sunitinib-induced hepatotoxicity in L02 cells. Collectively, these findings indicated that NAC and tBHQ play the crucial roles in crizotinib- and sunitinib-induced mitochondrial apoptosis via the regulation of oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Crizotinib and Sunitinib Induce Hepatotoxicity and Mitochondrial Apoptosis in L02 Cells via ROS and Nrf2 Signaling Pathway

et al. 2021

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“…Reduction and discontinuation inevitably lead to treatment failure and cancer progression (Xiao et al, 2019). Therefore, studying underlying mechanisms of Sunitinib-induced hepatotoxicity and finding the corresponding intervention on this basis are of great significance to provide safety to patients.…”

Section: Discussionmentioning

confidence: 99%

Sunitinib induced hepatotoxicity in L02 cells via ROS-MAPKs signaling pathway

Tang

Yang²,

Guo³

et al. 2022

Front. Pharmacol.

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Sunitinib is a multi-targeted tyrosine kinase inhibitor with remarkable anticancer activity, while hepatotoxicity is a potentially fatal adverse effect of its administration. The aim of this study was to elucidate the mechanism of hepatotoxicity induced by Sunitinib and the protective effect of glycyrrhetinic acid (GA). Sunitinib significantly reduced the survival of human normal hepatocytes (L02 cells), induced the increase of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH). Chloroquine (CQ) and Z-VAD-FMK were applied to clarify the cell death patterns induced by Sunitinib. Sunitinib significantly induced L02 cells death by triggering apoptosis and autophagy acted as a self-defense mechanism to promote survival. Sunitinib exposure caused excessive ROS generation which activated mitogen-activated protein kinases (MAPKs) signaling. Mechanistically, SP600125 (JNK inhibitor) and SB203580 (p38 inhibitor) respectively blocked apoptosis and autophagy induced by Sunitinib. And inhibition of ROS by NAC pretreatment ameliorated the effect of Sunitinib on MAPKs phosphorylation. GA alleviated Sunitinib-induced cell damage by inhibiting apoptosis and autophagy. These results suggested ROS/MAPKs signaling pathway was responsible for Sunitinib-induced hepatotoxicity and GA could be a preventive strategy to alleviate liver injury caused by Sunitinib.

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“…In our cohort, hepatocellular carcinoma was presented in eight (57.1%) patients using various antineoplastic treatments, including tyrosine kinase inhibitor, platinum, and radiotherapy. The nephrotoxicity of antineoplastic agents has been reported in recent years [15][16][17][18], but the histopathological evidence has been limited, especially in patients after liver transplantation.…”

Section: Discussionmentioning

confidence: 99%

Renal histopathological lesions after liver transplantation: What can we find besides calcineurin inhibitor-induced nephrotoxicity?

et al. 2022

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Background Chronic kidney disease (CKD) is a common complication after liver transplantation and is traditionally considered to be secondary to calcineurin inhibitors (CNIs). However, several studies have reported that the etiology of CKD after liver transplantation is broad and may only be assessed accurately by renal biopsy. The current study aimed to explore the usefulness of renal biopsies in managing CKD after liver transplantation in daily clinical practice. Method This retrospective analysis enrolled all post-liver transplantation patients who had a renal biopsy in a single center from July 2018 to February 2021. Results Fourteen renal biopsies were retrieved for review from 14 patients at a median of 35.7 (minimum-maximum: 2.80–134.73) months following liver transplantation. The male-to-female ratio was 13:1 (age range, 31–75 years). The histomorphological alterations were varied. The predominant glomerular histomorphological changes included focal segmental glomerular sclerosis (FSGS) (n = 4), diabetic glomerulopathy (n = 4), and membranoproliferative glomerulonephritis (n = 4). Thirteen (92.9%) patients had renal arteriolar sclerosis. Immune complex nephritis was present in six patients, of whom only two had abnormal serum immunological indicators. Despite interstitial fibrosis and tubular atrophy being present in all the patients, only six (42.9%) presented with severe interstitial injury. No major renal biopsy-related complications occurred. After a mean follow-up of 11.8 months (range: 1.2–29.8), three patients progressed to end-stage renal disease (ESRD). Conclusion The etiology of CKD after liver transplantation might be more complex than originally thought and should not be diagnosed simply as calcineurin inhibitors(CNI)-related nephropathy. Renal biopsy plays a potentially important role in the diagnosis and treatment of CKD after liver transplantation and might not be fully substituted by urine or blood tests. It may help avoid unnecessary changes to the immunosuppressants and inadequate treatment of primary diseases.

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Study on the mechanism and intervention strategy of sunitinib induced nephrotoxicity

Cited by 16 publications

References 23 publications

Crizotinib and Sunitinib Induce Hepatotoxicity and Mitochondrial Apoptosis in L02 Cells via ROS and Nrf2 Signaling Pathway

Crizotinib and Sunitinib Induce Hepatotoxicity and Mitochondrial Apoptosis in L02 Cells via ROS and Nrf2 Signaling Pathway

Sunitinib induced hepatotoxicity in L02 cells via ROS-MAPKs signaling pathway

Renal histopathological lesions after liver transplantation: What can we find besides calcineurin inhibitor-induced nephrotoxicity?

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