Modulation of Autophagy by Sorafenib: Effects on Treatment Response

Prieto-Domínguez, Néstor; Ordóñez, Raquel; Fernández, Anna; García‐Palomo, Andrés; Muntané, Jordi; González‐Gallego, Javier; Mauriz, José L.

doi:10.3389/fphar.2016.00151

Cited by 102 publications

(75 citation statements)

References 144 publications

(272 reference statements)

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“…Moreover, autophagy is implicated in tumour cells' resistance to systemic treatments. 126 Indeed, sorafenib induces autophagy, 152 and preclinical data show that combined therapy with autophagy inhibitors (i.e. chloroquine, miR-375) improves tumour response.…”

Section: Targeting Autophagy In Hepatocellular Carcinoma: a Complex Amentioning

confidence: 99%

Autophagy in liver diseases: Time for translation?

Allaire

Rautou

Codogno

et al. 2019

Journal of Hepatology

298

222

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Autophagy is a self-eating catabolic pathway that contributes to liver homeostasis through its role in energy balance and in the quality control of the cytoplasm, by removing misfolded proteins, damaged organelles and lipid droplets. Autophagy not only regulates hepatocyte functions but also impacts on non-parenchymal cells, such as endothelial cells, macrophages and hepatic stellate cells. Deregulation of autophagy has been linked to many liver diseases and its modulation is now recognized as a potential new therapeutic strategy. Indeed, enhancing autophagy may prevent the progression of a number of liver diseases, including storage disorders (alpha-1 antitrypsin deficiency, Wilson's disease), acute liver injury, non-alcoholic steatohepatitis and chronic alcohol-related liver disease. Nevertheless, in some situations such as fibrosis, targeting specific liver cells must be considered, as autophagy displays opposing functions depending on the cell type. In addition, an optimal therapeutic time-window should be identified, since autophagy might be beneficial in the initial stages of disease, but detrimental at more advanced stages, as in the case of hepatocellular carcinoma. Finally, identifying biomarkers of autophagy and methods to monitor autophagic flux in vivo are important steps for the future development of personalized autophagy-targeting strategies. In this review, we provide an update on the regulatory role of autophagy in various aspects of liver pathophysiology, describing the different strategies to manipulate autophagy and discussing the potential to modulate autophagy as a therapeutic strategy in the context of liver diseases.

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Section: Targeting Autophagy In Hepatocellular Carcinoma: a Complex Amentioning

confidence: 99%

Autophagy in liver diseases: Time for translation?

Allaire

Rautou

Codogno

et al. 2019

Journal of Hepatology

298

222

View full text Add to dashboard Cite

show abstract

“…The majority of chemotherapy drugs (including sorafenib, gemcitabine and paclitaxel) can induce autophagy in cancer cells, and autophagy acts a protective mechanism for cell. Drug-induced autophagy can make cells resistant to the therapeutic effect of the drug (28–30). Therefore, it is necessary to detect whether chemotherapy drugs can induce autophagy in cancer cells, and to investigate the mechanism of chemotherapy drug-induced autophagy in order to design more appropriate treatments for patients.…”

Section: Discussionmentioning

confidence: 99%

Wogonin induces Beclin-1/PI3K and reactive oxygen species-mediated autophagy in human pancreatic cancer cells

Sun

Gao

et al. 2016

Oncology Letters

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Wogonin is considered to be an inhibitor of myeloid cell leukemia 1 and B-cell lymphoma 2, and a potential antitumor drug due to its ability to induce apoptosis in certain cancer cells; however, few previous studies have reported on wogonin-induced autophagy. The aim of the present study was to investigate the influence of wogonin on autophagy in human pancreatic cancer cells (HPCCs), elucidate its mechanism, and identify strategies to increase its effectiveness as an anti-cancer treatment. HPCCs were treated with wogonin and autophagy was detected in the cells. The mechanism of wogonin-related autophagy was investigated, and the antioxidant N-acetyl-L-cysteine (NAC) was used to assess the role of reactive oxygen species (ROS) in wogonin-related autophagy. The results demonstrated that wogonin may induce autophagy by activating the Beclin-1/phosphatidylinositol-3-kinase and ROS pathways in HPCCs, and may enhance ROS generation, followed by the activation of the AKT/ULK1/4E-BP1/CYLD pathway and inhibition of the mammalian target of rapamycin signaling pathway. The incubation of HPCCs with wogonin and the antioxidant NAC, revealed that the effects of wogonin-enhanced ROS generation on autophagy-related molecules were inhibited, contributing to the inhibition of autophagy and increasing the cell death ratio through apoptosis activation in HPCCs. These studies suggest that autophagy activation, via the ROS pathway, by the antitumor drug wogonin in HPCCs may partially reduce the antitumor effects of the drug, and that the antioxidant NAC may enhance the antitumor effectiveness of wogonin via the inhibition of ROS-enhanced autophagy and the subsequent promotion of apoptosis. Therefore, the present research suggests that wogonin combined with NAC may be a novel combination therapy for clinical pancreatic cancer therapy trials.

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“…Sorafenib, a multiprotein kinase inhibitor, is a drug that has demonstrated survival advantages in patients with advanced HCC [106]. Although several lines of evidence have established that sorafenib induces a protective form of autophagy for HCC cell survival, a recent study demonstrated that sorafenib and its kinase-independent derivative, SC-59, induced autophagic cell death and apoptosis by disrupting the myeloid cell leukemia-1 (MCL-1)-beclin 1 complex in HCC cells and PLC5 xenograft nude mice [64].…”

Section: Autophagic Cell Death By Small Moleculesmentioning

confidence: 99%

Modulation of the Autophagy-Lysosomal Pathway in Hepatocellular Carcinoma Using Small Molecules

Lee

Jeon

2020

Molecules

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Hepatocellular carcinoma (HCC) accounts for approximately 90% of all cases of primary liver cancer; it is the third most frequent cause of cancer-related death worldwide. In early-stage disease, surgical resection and liver transplantation are considered curative treatments. However, the majority of HCC patients present with advanced-stage disease that is treated using palliative systemic therapy. Since HCC is heterogeneous owing to its multiple etiologies, various risk factors, and inherent resistance to chemotherapy, the development of an effective systemic treatment strategy for HCC remains a considerable challenge. Autophagy is a lysosome-dependent catabolic degradation pathway that is essential for maintaining cellular energy homeostasis. Autophagy dysfunction is closely linked with the pathogenesis of various cancers; therefore, the discovery of small molecules that can modulate autophagy has attracted considerable interest in the development of a systemic treatment strategy for advanced HCC. Here, we reviewed the roles of autophagy in HCC and the recent advances regarding small molecules that target autophagy regulatory mechanisms.

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Modulation of Autophagy by Sorafenib: Effects on Treatment Response

Cited by 102 publications

References 144 publications

Autophagy in liver diseases: Time for translation?

Autophagy in liver diseases: Time for translation?

Wogonin induces Beclin-1/PI3K and reactive oxygen species-mediated autophagy in human pancreatic cancer cells

Modulation of the Autophagy-Lysosomal Pathway in Hepatocellular Carcinoma Using Small Molecules

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