Sunitinib induces hepatocyte mitochondrial damage and apoptosis in mice

Paech, Franziska; Abegg, Vanessa Fabienne; Duthaler, Urs; Terracciano, Luigi; Bouitbir, Jamal; Krähenbühl, Stephan

doi:10.1016/j.tox.2018.07.009

Cited by 21 publications

(23 citation statements)

References 42 publications

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“…Afterwards, 2.5 μL were injected into the HPLC–MS/MS system (Shimadzu HPLC Shimadzu HPLC, Kyoto, Japan coupled to an API 4000 QTrap tandem mass spectrometer, ABSciex, Concord, Canada) to determine the GSH‐NEM and GSSG levels in mouse skeletal muscle gastrocnemius. GSH‐NEM and GSSG were separated on a Symmetry Polar C18 analytical column (3.5 µM 4.6 × 75 mm (WAT066224, Waters)) at 45°C and a flow rate of 0.4 mL/min as previously described . Water as a mobile phase A and acetonitrile as a mobile phase B were both supplemented with 0.1% formic acid.…”

Section: Methodsmentioning

confidence: 99%

“…GSH-NEM and GSSG were separated on a Symmetry Polar C18 analytical column (3.5 µM 4.6 × 75 mm (WAT066224, Waters)) at 45°C and a flow rate of 0.4 mL/min as previously described. 45 Water as a mobile phase A and acetonitrile as a mobile phase B were both supplemented with 0.1% formic acid. Injected samples were then loaded into the analytical column by being inline diluted via a T union with mobile phase A during the first 0.5 min of each run.…”

Section: Quantitative Real Time Polymerase Chain Reaction (Qrt-pcr)mentioning

confidence: 99%

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PGC‐1α plays a pivotal role in simvastatin‐induced exercise impairment in mice

et al. 2019

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Aim Statins decrease cardiovascular complications, but can induce myopathy. Here, we explored the implication of PGC‐1α in statin‐associated myotoxicity. Methods We treated PGC‐1α knockout (KO), PGC‐1α overexpression (OE) and wild‐type (WT) mice orally with 5 mg simvastatin kg−1 day−1 for 3 weeks and assessed muscle function and metabolism. Results In WT and KO mice, but not in OE mice, simvastatin decreased grip strength, maximal running distance and vertical power assessed by ergometry. Post‐exercise plasma lactate concentrations were higher in WT and KO compared to OE mice. In glycolytic gastrocnemius, simvastatin decreased mitochondrial respiration, increased mitochondrial ROS production and free radical leak in WT and KO, but not in OE mice. Simvastatin increased mRNA expression of Sod1 and Sod2 in glycolytic and oxidative gastrocnemius of WT, but decreased it in KO mice. OE mice had a higher mitochondrial DNA content in both gastrocnemius than WT or KO mice and simvastatin exhibited a trend to decrease the citrate synthase activity in white and red gastrocnemius in all treatment groups. Simvastatin showed a trend to decrease the mitochondrial volume fraction in both muscle types of all treatment groups. Mitochondria were smaller in WT and KO compared to OE mice and simvastatin further reduced the mitochondrial size in WT and KO mice, but not in OE mice. Conclusions Simvastatin impairs skeletal muscle function, muscle oxidative metabolism and mitochondrial morphology preferentially in WT and KO mice, whereas OE mice appear to be protected, suggesting a role of PGC‐1α in preventing simvastatin‐associated myotoxicity.

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Section: Methodsmentioning

confidence: 99%

Section: Quantitative Real Time Polymerase Chain Reaction (Qrt-pcr)mentioning

confidence: 99%

PGC‐1α plays a pivotal role in simvastatin‐induced exercise impairment in mice

et al. 2019

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“…Another study inversely suggested that crizotinib did not significantly affect mitochondrial functions and inhibited glycolysis only weakly, but induced apoptosis in HepG2 cells (Mingard et al, 2018). Moreover, some findings inversely showed that sunitinib-induced hepatotoxicity was associated with mitochondrial dysfunction and apoptosis of HepG2 cells (Paech et al, 2017;Paech et al, 2018). The divergences can be explained by the different experimental models and experimental condition settings on crizotinib-and sunitinib-induced hepatotoxicity.…”

Section: Introductionmentioning

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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“…2 29 Böylelikle sunitinib anjiyogenezi, tümör büyümesini ve metastaz oluşumunu inhibe eder. 30 Ağrı, hipertansiyon, gastrointestinal toksisite, proteinüri, nörotoksisite, epistaksis, koagülasyon bozuklukları, hipotiroidi, tat almada değişiklik ve mukozit gibi yan etkileri görülmektedir. Yan etkilerin çoğu geri dönüşümlüdür ve sunitinibin tamamen kesilmesini gerektirmez.…”

Section: Antianjiyojenik İlaçlarunclassified

İlaca Bağli Çene Kemi̇ği̇ Osteonekrozu: Bi̇r Derleme

Ömezli¹,

Ayrancı²,

Torul³

et al. 2021

Atatürk Üniversitesi Diş Hekimliği Fakültesi Dergisi

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Medication Related Osteonecrosis of the Jawbones: A Review Medication Related Osteonecrosis of the Jaws (MRONJ) is a complication characterized by the appearance of necrotic bone in the maxilla and mandible, resulting from the use of bisphosphonates as well as drugs with antiosteoclastic and antiangiogenic activity. No consensus has been reach regarding the treatment protocol that will prevent the economic and social burden of the patients by providing optimum management of this unique complication which constitutes a serious problem for both physicians and patients. The aim of this review is to present the etiopathology and current treatment strategies of Medication Related Osteonecrosis of the Jaws in the light of the literature.

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Sunitinib induces hepatocyte mitochondrial damage and apoptosis in mice

Cited by 21 publications

References 42 publications

PGC‐1α plays a pivotal role in simvastatin‐induced exercise impairment in mice

PGC‐1α plays a pivotal role in simvastatin‐induced exercise impairment in mice

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

İlaca Bağli Çene Kemi̇ği̇ Osteonekrozu: Bi̇r Derleme

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