Regorafenib Alteration of the BCL-xL/MCL-1 Ratio Provides a Therapeutic Opportunity for BH3-Mimetics in Hepatocellular Carcinoma Models

Cucarull, Blanca; Tutusaus, Anna; Subías, Marina Uruen; Stefanović, Milica; Hernáez-Alsina, Tania; Boix, Loreto; Reig, María; Frutos, Pablo García de; Marı́, Montserrat; Colell, Anna; Bruix, Jordi; Morales, Albert

doi:10.3390/cancers12020332

Cited by 21 publications

(15 citation statements)

References 54 publications

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“… Chemotherapy—standard chemotherapeutic agents such as doxorubicin and cisplatin are well-known inducers of mitochondrial ROS during their anti-tumoral action [ 159 , 160 ]. However, the mitochondrial effects of other more recently approved anti-cancer drugs, such as sorafenib or regorafenib, are being just revealed [ 161 , 162 ]. More importantly, mitochondrial antioxidants may reduce the effectivity of these drugs, while glutathione depressors potentiate their effect in hepatocellular carcinoma cells (Cucarull et al, unpublished results).…”

Section: Mgsh In Pathological Settingsmentioning

confidence: 99%

Mitochondrial Glutathione: Recent Insights and Role in Disease

et al. 2020

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Mitochondria are the main source of reactive oxygen species (ROS), most of them deriving from the mitochondrial respiratory chain. Among the numerous enzymatic and non-enzymatic antioxidant systems present in mitochondria, mitochondrial glutathione (mGSH) emerges as the main line of defense for maintaining the appropriate mitochondrial redox environment. mGSH’s ability to act directly or as a co-factor in reactions catalyzed by other mitochondrial enzymes makes its presence essential to avoid or to repair oxidative modifications that can lead to mitochondrial dysfunction and subsequently to cell death. Since mitochondrial redox disorders play a central part in many diseases, harboring optimal levels of mGSH is vitally important. In this review, we will highlight the participation of mGSH as a contributor to disease progression in pathologies as diverse as Alzheimer’s disease, alcoholic and non-alcoholic steatohepatitis, or diabetic nephropathy. Furthermore, the involvement of mitochondrial ROS in the signaling of new prescribed drugs and in other pathologies (or in other unmet medical needs, such as gender differences or coronavirus disease of 2019 (COVID-19) treatment) is still being revealed; guaranteeing that research on mGSH will be an interesting topic for years to come.

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Section: Mgsh In Pathological Settingsmentioning

confidence: 99%

Mitochondrial Glutathione: Recent Insights and Role in Disease

et al. 2020

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“…Regorafenib was approved for treatment of unresectable HCC following progression on sorafenib in 2017 8 . In the past 3 years, lots of studies have focused on the antiproliferation and antiapoptosis of regorafenib in HCC cells, and its mechanisms involve in the inhibition of ERK/nuclear factor kappa B activation, Bcl‐xL/Mcl‐1 ratio, and Cyclin E1/Mcl‐1 signaling pathway, and so forth 30–32 . Importantly, regorafenib was approved for refractory mCRC in 2013, and a number of recent clinical trials for regorafenib were carried out in metastatic malignancies 11–13 .…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, we observed a distinct reduction of tumor VM in the regorafenib-treated xenografts noted by CD34 − PAS + ( Figure 7D Mcl-1 signaling pathway, and so forth. [30][31][32] Importantly, regorafenib was approved for refractory mCRC in 2013, and a number of recent clinical trials for regorafenib were carried out in metastatic malignancies. [11][12][13] Nonetheless, the role of regorafenib in HCC metastasis and related mechanisms are still unclear.…”

Section: Regorafenib Suppresses Tumor Growth and Vm Formation In Pdmentioning

confidence: 99%

Regorafenib inhibits migration, invasion, and vasculogenic mimicry of hepatocellular carcinoma via targeting ID1‐mediated EMT

Zhang

et al. 2021

Molecular Carcinogenesis

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Regorafenib is approved for patients with unresectable hepatocellular carcinoma (HCC) following sorafenib. However, the effect of regorafenib on HCC metastasis and its mechanism are poorly understood. Here, our data showed that regorafenib significantly restrained the migration, invasion and vasculogenic mimicry (VM) of HCC cells, and downregulated the expression of epithelial-to-mesenchymal transition (EMT)/VM-related molecules. Using RNAseq and cellular thermal shift assays, we found that inhibitor of differentiation 1 (ID1) was a key target of regorafenib. In HCC tissues, the protein expression of ID1 was positively correlated with EMT and VM formation (CD34 − /PAS +). Functionally, ID1 knockdown inhibited HCC cell migration, invasion, metastasis, and VM formation in vitro and in vivo, with upregulation of E-cadherin and downregulation of Snail and VE-cadherin. Moreover, Snail overexpression promoted the migration, invasion, and VM formation of ID1 knockdown cells. Snail knockdown reduced the migration, invasion, and VM formation of ID1 overexpression cells. Finally, regorafenib suppressed VM formation and decreased the expression of ID1, VE-cadherin and Snail in HCC PDX model. In conclusion, we manifested that regorafenib distinctly inhibited EMT in HCC cells via targeting ID1, leading to the suppression of cell migration, invasion and VM formation. These findings suggest that regorafenib may be developed as a suitable therapeutic agent for HCC metastasis.

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“…This study further elucidated that CKS1B plays a regulatory role in HCC through the JAK/STAT3 pathway and regulates the expression of STAT3 target genes, including Mcl-1, c-Myc, TIMP-1, Bcl-2 and VEGF. Among them, Mcl-1 and Bcl-2 exerted anti-apoptotic effects in HCC cells (Cucarull et al 2020 ), c-Myc and VEGF showed strong pro-tumor growth effects(Zhang et al 2020 ), and TIMP-1 was involved in the regulation of HCC metastasis (Wu et al 2020 ). Taken together, CKS1B was involved in HCC progression by influencing the expression of downstream target genes of JAK/STAT3 pathway.…”

Section: Discussionmentioning

confidence: 99%

CKS1B promotes the progression of hepatocellular carcinoma by activating JAK/STAT3 signal pathway

Liu

Zhao

2021

Animal Cells and Systems

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Hepatocellular carcinoma (HCC) is a malignancy of considerable concern due to its continuous increase in morbidity and mortality. This study attempts to identify the molecules that play a key role in the progression of HCC, explore its potential mechanism, and provide more target choices for targeted therapy. Using overexpression plasmid and shRNA, CKS1B was respectively overexpressed and knocked down to explore its biological function roles in HCC progression and development. MTT and colony formation assays showed that knockdown of CKS1B inhibited the survival and proliferation of HCC cell lines (Hep3B and Huh7). The flow cytometry and western blot analysis showed that knockdown of CKS1B significantly induced the apoptosis of Hep3B and Huh7 cells. The wound healing and transwell invasion assays showed that knockdown of CKS1B had a significant inhibitory effect on the migration and invasion of Hep3B and Huh7 cells. These functional tests confirmed that CKS1B acts as an oncogene that regulates the malignant progression of HCC. Moreover, this study also demonstrated that knockdown of CKS1B inhibited the activation of JAK/STAT3 pathway, evidenced by the significantly downregulated p-STAT3 protein expression. Furthermore, knockdown of CKS1B also downregulated STAT3 target genes TIMP-1, Bcl-2 and VEGF, which were involved in controlling cell apoptosis and migration. On the contrary, overexpression of CKS1B caused the completely opposite results. Taken together, CKS1B acts as an oncogene to promote the proliferation and metastasis of HCC cells by activating JAK/STAT3 signaling pathway.

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Regorafenib Alteration of the BCL-xL/MCL-1 Ratio Provides a Therapeutic Opportunity for BH3-Mimetics in Hepatocellular Carcinoma Models

Cited by 21 publications

References 54 publications

Mitochondrial Glutathione: Recent Insights and Role in Disease

Mitochondrial Glutathione: Recent Insights and Role in Disease

Regorafenib inhibits migration, invasion, and vasculogenic mimicry of hepatocellular carcinoma via targeting ID1‐mediated EMT

CKS1B promotes the progression of hepatocellular carcinoma by activating JAK/STAT3 signal pathway

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