Mechanisms of mitochondrial toxicity of the kinase inhibitors ponatinib, regorafenib and sorafenib in human hepatic HepG2 cells

Paech, Franziska; Mingard, Cécile; Grünig, David; Abegg, Vanessa Fabienne; Bouitbir, Jamal; Krähenbühl, Stephan

doi:10.1016/j.tox.2018.01.005

Cited by 49 publications

(33 citation statements)

References 45 publications

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“…Indeed, there are numerous reports of toxicity caused by ponatinib and other broad spectrum PTK inhibitors. For example, treatment of HepG2 liver cancer cells with ponatinib at low μM concentrations resulted in severe mitochondrial toxicity and diminished ATP production [48]. All approved BCR-ABL inhibitors display some levels of myocyte, cardiovascular and hepatic toxicity, and the toxicity in general correlates to the lack of specificity [49,50,51].…”

Section: Discussionmentioning

confidence: 99%

Ponatinib Inhibits Proliferation and Induces Apoptosis of Liver Cancer Cells, but Its Efficacy Is Compromised by Its Activation on PDK1/Akt/mTOR Signaling

Liu

Wang

et al. 2019

Molecules

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Ponatinib is a multi-target protein tyrosine kinase inhibitor, and its effects on hepatocellular carcinoma cells have not been previously explored. In the present study, we investigated its effects on hepatocellular carcinoma cell growth and the underlying mechanisms. Toward SK-Hep-1 and SNU-423 cells, ponatinib induces apoptosis by upregulation of cleaved caspase-3 and -7 and promotes cell cycle arrest in the G1 phase by inhibiting CDK4/6/CyclinD1 complex and phosphorylation of retinoblastoma protein. It inhibits the growth-stimulating mitogen-activated protein (MAP) kinase pathway, the phosphorylation of Src on both negative and positive regulation sites, and Jak2 and Stat3 phosphorylation. Surprisingly, it also activates the PDK1, the protein kinase B (Akt), and the mechanistic target of rapamycin (mTOR) signaling pathway. Blocking mTOR signaling strongly sensitizes cells to inhibition by ponatinib and makes ponatinib a much more potent inhibitor of hepatocellular carcinoma cell proliferation. These findings demonstrate that ponatinib exerts both positive and negative effects on hepatocellular cell proliferation, and eliminating its growth-stimulating effects by drug combination or potentially by chemical medication can significantly improve its efficacy as an anti-cancer drug.

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Section: Discussionmentioning

confidence: 99%

Ponatinib Inhibits Proliferation and Induces Apoptosis of Liver Cancer Cells, but Its Efficacy Is Compromised by Its Activation on PDK1/Akt/mTOR Signaling

Liu

Wang

et al. 2019

Molecules

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“…Regorafenib seems to interfere with mitochondrial respiratory chain and thereby induced hepatocyte apoptosis and necroptosis in vitro . Taken together, these recently described side-effects might neutralize potential beneficial antifibrotic effects in experimental fibrosis [ 34 , 35 ]. Importantly, under acute regorafenib treatment, liver function parameters were not markedly influenced, while in the healthy livers of the portal vein ligated animals, regorafenib had no major effect on liver function parameters.…”

Section: Discussionmentioning

confidence: 99%

The multikinase inhibitor regorafenib decreases angiogenesis and improves portal hypertension

et al. 2018

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Background and AimsAngiogenesis is critically involved in the development of liver fibrosis, portal hypertension (PHT) and hepatocellular carcinoma (HCC). Regorafenib is a novel second-line therapy for HCC, but might also be beneficial in fibrosis and PHT even in absence of HCC. This study investigated the effects of regorafenib in experimental models without HCC.MethodsFibrosis (in vivo and in vitro), inflammation, liver damage (aminotransferases), angiogenesis (matrigel implantation) and in vivo systemic and portal hemodynamics were assessed in different mouse and rat models (bile duct ligation, CCl4, partial portal vein ligation) after acute and chronic treatment with regorafenib.ResultsLong-term treatment with regorafenib improved portal hypertension most likely due to blunted angiogenesis, without affecting fibrosis progression or regression. Interestingly, acute administration of regorafenib also ameliorated portal hemodynamics. Although regorafenib treatment led to hepatotoxic side effects in long-term treated fibrotic animals, in partial portal vein ligated rats, no liver toxicity due to regorafenib was observed.DiscussionRegorafenib might be especially suitable as therapy in patients with PHT and preserved liver function.

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“…The multikinase inhibitor sorafenib is one of the few systemic treatment options for advanced hepatocellular carcinoma (HCC) and exerts its anti-proliferative and angiogenesis action by blockage of the Rapidly Accelerated Fibrosarcoma (RAF) and vascular endothelial growth factor (VEGF) signaling and promises better survival for patients with advanced hepatocellular carcinoma [1]. Sorafenib was also shown to attenuate mitochondrial function in HCC cells [2]. However, not all patients respond to sorafenib.…”

Section: Introductionmentioning

confidence: 99%

Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Is Reversed by SIRT1

Garten

Grohmann

Kľučková

et al. 2019

IJMS

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Sorafenib is a multi-kinase inhibitor and one of the few systemic treatment options for patients with advanced hepatocellular carcinomas (HCCs). Resistance to sorafenib develops frequently and could be mediated by the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin (SIRT)1. We aimed to test whether sorafenib efficacy is influenced by cellular NAD levels and NAD-dependent SIRT1 function. We analyzed sorafenib effects on apoptosis induction, NAD salvage, mitochondrial function, and related signaling pathways in HCC cell lines (HepG2, Hep3B, und HUH7) overexpressing SIRT1 or supplemented with the NAD metabolite nicotinamide mononucleotide (NMN) compared to controls. Treatment of HCC cell lines with sorafenib dose-dependently induced apoptosis and a significant decrease in cellular NAD concentrations. The SIRT1 protein was downregulated in HUH7 cells but not in Hep3B cells. After sorafenib treatment, mitochondrial respiration in permeabilized cells was lower, citrate synthase activity was attenuated, and cellular adenosine triphosphate (ATP) levels were decreased. Concomitant to increased phosphorylation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), sorafenib treatment led to decreased activity of the mechanistic target of rapamycin (mTOR), indicative of energy deprivation. Transient overexpression of SIRT1, as well as NAD repletion by NMN, decreased sorafenib-induced apoptosis. We can, therefore, conclude that sorafenib influences the NAD/SIRT1/AMPK axis. Overexpression of SIRT1 could be an underlying mechanism of resistance to sorafenib treatment in HCC.

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Mechanisms of mitochondrial toxicity of the kinase inhibitors ponatinib, regorafenib and sorafenib in human hepatic HepG2 cells

Cited by 49 publications

References 45 publications

Ponatinib Inhibits Proliferation and Induces Apoptosis of Liver Cancer Cells, but Its Efficacy Is Compromised by Its Activation on PDK1/Akt/mTOR Signaling

Ponatinib Inhibits Proliferation and Induces Apoptosis of Liver Cancer Cells, but Its Efficacy Is Compromised by Its Activation on PDK1/Akt/mTOR Signaling

The multikinase inhibitor regorafenib decreases angiogenesis and improves portal hypertension

Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Is Reversed by SIRT1

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