scholarly journals Combining Sorafenib and Immunosuppression in Liver Transplant Recipients with Hepatocellular Carcinoma

2021 ◽  
Vol 14 (1) ◽  
pp. 46
Author(s):  
Koen G. A. M. Hussaarts ◽  
Leni van Doorn ◽  
Sander Bins ◽  
Dave Sprengers ◽  
Peter de Bruijn ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Plasma Levels ◽  
Drug Exposure ◽  
Kinase Inhibitor ◽  
Combined Treatment ◽  
Sorafenib Treatment ◽  
Significant Toxicity ◽  
Small Molecule Kinase Inhibitor ◽  
Hcc Recurrence ◽  
Over Time

Hepatocellular carcinoma (HCC) recurrence after liver transplantation occurs in approximately 20% of patients. Most of these patients use immunosuppressant drugs. Meanwhile, patients with HCC recurrence are frequently treated with the small molecule kinase inhibitor (SMKI) sorafenib. However, sorafenib and many immunosuppressants are substrates of the same enzymatic pathways (e.g., CYP3A4), which may potentially result in altered SMKI or immunosuppressant plasma levels. Therefore, we investigated changes in drug exposure of both sorafenib and immunosuppressants over time in four patients with systemic immunosuppressant and sorafenib treatment after HCC recurrence. In this study, sorafenib exposure declined over time during combined treatment with immunosuppressants, while two patients also experienced declining tacrolimus plasma levels. Importantly, patients were unable to increase the sorafenib dose higher than 200 mg b.i.d. without experiencing significant toxicity. We recommend to treat patients using both sorafenib and immunosuppressants with a sorafenib starting dose of 200 mg b.i.d.

scholarly journals The Synergistic Anti-Cancer Effects of NVP-BEZ235 and Regorafenib in Hepatocellular Carcinoma

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2454
Author(s):  
Cheng-Chan Yu ◽  
Sung-Ying Huang ◽  
Shu-Fang Chang ◽  
Kuan-Fu Liao ◽  
Sheng-Chun Chiu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Western Blot ◽  
Kinase Inhibitor ◽  
Epithelial Mesenchymal Transition ◽  
Combined Treatment ◽  
Gelatin Zymography ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
Mesenchymal Transition ◽  
Anti Cancer

Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Regorafenib is a multi-kinase inhibitor and the second-line treatment for HCC. Since the PI3K/Akt/mTOR signaling pathway is dysregulated in HCC, we evaluated the therapeutic effects of regorafenib combined with a dual PI3K/mTOR inhibitor BEZ235 in the human HCC cell lines (n = 3). The combined treatment with BEZ235 and regorafenib enhanced the inhibition of cell proliferation and increased the expression of cleaved caspase-3 and cleaved PARP in HCC cells. Moreover, the combined treatment suppressed HCC cell migration and invasion in the transwell assay. Further, the Western blot analyses confirmed the involvement of epithelial-mesenchymal transition (EMT)-related genes such as slug, vimentin, and matrix metalloproteinase (MMP)-9/-2. Additionally, the proteinase activity of MMP-9/-2 was analyzed using gelatin zymography. Furthermore, the inhibition of phosphorylation of the Akt, mTOR, p70S6K, and 4EBP1 after combined treatment was validated using Western blot analysis. Therefore, these results suggest that the combined treatment with BEZ235 and regorafenib benefits patients with HCC.

scholarly journals Molecular subtype and response to dasatinib, an Src/Abl small molecule kinase inhibitor, in hepatocellular carcinoma cell linesin vitro

Hepatology ◽  
2013 ◽  
Vol 57 (5) ◽  
pp. 1838-1846 ◽  
Author(s):  
Richard S. Finn ◽  
Alexey Aleshin ◽  
Judy Dering ◽  
Peter Yang ◽  
Charles Ginther ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Small Molecule ◽  
Kinase Inhibitor ◽  
Carcinoma Cell ◽  
Molecular Subtype ◽  
Small Molecule Kinase Inhibitor ◽  
Hepatocellular Carcinoma Cell

scholarly journals Modulation of SIRT3 expression through CDK4/6 enhances the anti-cancer effect of sorafenib in hepatocellular carcinoma cells

2020 ◽  
Author(s):  
HanHee Jo ◽  
Yusun Park ◽  
Taehun Kim ◽  
Jisu Kim ◽  
JongSook Lee ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Combined Treatment ◽  
Xenograft Model ◽  
Cancer Tissue ◽  
Sorafenib Treatment ◽  
Tumor Types ◽  
Related Proteins ◽  
Sirt3 Expression ◽  
Hcc Cells

Abstract Background : Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide. The only drug currently approved for clinical use in the treatment of advanced HCC is sorafenib. However, many patients with HCC show reduced sensitivity to sorafenib during treatment. SIRT3, a member of the mammalian sirtuin family, is a tumor suppressor in certain tumor types. However, only few studies have investigated the effects of SIRT3 on tumor prognosis and sorafenib sensitivity in patients with HCC. Here, we aimed to investigate the correlation between SIRT3 expression and glucose metabolism and proliferation in HCC and discover effective compounds that increase endogenous SIRT3 modulation effect of sorafenib. Methods: To determine the correlation between SIRT3 and glucose related proteins, immunostaining was performed with liver cancer tissue using various antibodies. To investigate whether the expression of SIRT3 in HCC is related to the resistance to sorafenib, we treated sorafenib after the modulation of SIRT3 levels in HCC cell lines (overexpression in Huh7, knockdown in HepG2). We also employed PD0332991 to modulate the SIRT3 expression in HCC cell and conducted functional assays. Results: SIRT3 expression was downregulated in high glycolytic and proliferative HCC cells of human patients, xenograft model and HCC cell lines. Moreover, SIRT3 expression was downregulated after sorafenib treatment, resulting in reduced drug sensitivity in HCC cell lines. To enhance the anti-tumor effect of sorafenib, we employed PD0332991 (CDK4/6-Rb inhibitor) based on the correlation between SIRT3 and phosphorylated retinoblastoma protein in HCC. Notably, combined treatment with sorafenib and PD0332991 showed an enhancement of the anti-tumor effect in HCC cells. Conclusions: Our data suggest that the modulation of SIRT3 by CDK4/6 inhibition might be useful for HCC therapy together with sorafenib, which, unfortunately, has limited efficacy and whose use is often associated with drug resistance.

scholarly journals Modulation of SIRT3 expression through CDK4/6 enhances the anti-cancer effect of sorafenib in hepatocellular carcinoma cells

2020 ◽  
Author(s):  
HanHee Jo ◽  
Kyung Sik Kim ◽  
Taehun Kim ◽  
Yusun Park ◽  
Jisu Kim ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Combined Treatment ◽  
Xenograft Model ◽  
Cancer Tissue ◽  
Sorafenib Treatment ◽  
Anti Cancer ◽  
Tumor Types ◽  
Related Proteins ◽  
Sirt3 Expression

Abstract Background : : Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide. The only drug currently approved for clinical use in the treatment of advanced HCC is sorafenib. However, many patients with HCC show reduced sensitivity to sorafenib during treatment. SIRT3, a member of the mammalian sirtuin family, is a tumor suppressor in certain tumor types. To date, a few studies have investigated the effects of SIRT3 on tumor prognosis and sorafenib sensitivity in patients with HCC. Thus, this study aimed to investigate the correlation between SIRT3 expression and glucose metabolism and proliferation in HCC and to discover effective compounds that increase endogenous SIRT3 modulation effect of sorafenib. Methods: To determine the correlation between SIRT3 and glucose related proteins, immunostaining was performed with liver cancer tissue using various antibodies. To investigate whether the expression of SIRT3 in HCC is related to the resistance to sorafenib, we treated sorafenib after the modulation of SIRT3 levels in HCC cell lines (overexpression in Huh7, knockdown in HepG2). We also employed PD0332991 to modulate the SIRT3 expression in HCC cell and conducted functional assays. Results: SIRT3 expression is downregulated in high glycolytic and proliferative HCC of human patients, xenograft model and HCC cell lines. We also demonstrated that SIRT3 expression was downregulated after sorafenib treatment, resulting in reduced drug sensitivity in HCC cell lines. To enhance the anti-tumor effect of sorafenib, we employed PD0332991 (CDK4/6-Rb inhibitor) based on the correlation between SIRT3 and phospho-Rb in HCC. In addition, combined treatment with sorafenib and PD0332991 showed a synergic anti-tumor effect in HCC cells. Conclusions: Taken together, our data suggest that the modulation of SIRT3 by CDK4/6 inhibition might be used for HCC therapy together with sorafenib, which, unfortunately, has limited efficacy and whose use is often associated with drug resistance.

scholarly journals Sorafenib Treatment and Modulation of the Sphingolipid Pathway Affect Proliferation and Viability of Hepatocellular Carcinoma In Vitro

2020 ◽  
Vol 21 (7) ◽  
pp. 2409
Author(s):  
Katja Jakobi ◽  
Sandra Beyer ◽  
Alexander Koch ◽  
Dominique Thomas ◽  
Stephanie Schwalm ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Kinase Inhibitor ◽  
Fumonisin B1 ◽  
Bioactive Metabolites ◽  
Sorafenib Treatment ◽  
Antiproliferative Effects ◽  
Dismal Prognosis ◽  
In Vitro Effects

Hepatocellular carcinoma (HCC) shows a remarkable heterogeneity and is recognized as a chemoresistant tumor with dismal prognosis. In previous studies, we observed significant alterations in the serum sphingolipids of patients with HCC. This study aimed to investigate the in vitro effects of sorafenib, which is the most widely used systemic HCC medication, on the sphingolipid pathway as well as the effects of inhibiting the sphingolipid pathway in HCC. Huh7.5 and HepG2 cells were stimulated with sorafenib, and inhibitors of the sphingolipid pathway and cell proliferation, viability, and concentrations of bioactive metabolites were assessed. We observed a significant downregulation of cell proliferation and viability and a simultaneous upregulation of dihydroceramides upon sorafenib stimulation. Interestingly, fumonisin B1 (FB1) and the general sphingosine kinase inhibitor SKI II were able to inhibit cell proliferation more prominently in HepG2 and Huh7.5 cells, whereas there were no consistent effects on the formation of dihydroceramides, thus implying an involvement of distinct metabolic pathways. In conclusion, our study demonstrates a significant downregulation of HCC proliferation upon sorafenib, FB1, and SKI II treatment, whereas it seems they exert antiproliferative effects independently from sphingolipids. Certainly, further data would be required to elucidate the potential of FB1 and SKI II as putative novel therapeutic targets in HCC.

scholarly journals CISD2 Promotes Resistance to Sorafenib-Induced Ferroptosis by Regulating Autophagy in Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Bowen Li ◽  
Shibo Wei ◽  
Liang Yang ◽  
Xueqiang Peng ◽  
Yingbo Ma ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Poor Prognosis ◽  
Kinase Inhibitor ◽  
Bioinformatic Analysis ◽  
Advanced Hepatocellular Carcinoma ◽  
Iron Ions ◽  
Sorafenib Treatment ◽  
Effective Therapeutic Strategy ◽  
Detect Gene Expression ◽  
Hcc Cells

PurposeSorafenib is a multi-kinase inhibitor that is used as a standard treatment for advanced hepatocellular carcinoma (HCC). However, the mechanism of sorafenib resistance in HCC is still unclear. It has been shown that CISD2 expression is related to the progression and poor prognosis of HCC. Here, we show a new role for CISD2 in sorafenib resistance in HCC.MethodsBioinformatic analysis was used to detect the expression of negative regulatory genes of ferroptosis in sorafenib-resistant samples. The concentration gradient method was used to establish sorafenib-resistant HCC cells. Western blot was used to detect the protein expression of CISD2, LC3, ERK, PI3K, AKT, mTOR, and Beclin1 in HCC samples. Quantitative real-time PCR (qPCR) was used to detect gene expression. CISD2 shRNA and Beclin1 shRNA were transfected to knock down the expression of the corresponding genes. Cell viability was detected by a CCK-8 assay. ROS were detected by DCFH-DA staining, and MDA and GSH were detected with a Lipid Peroxidation MDA Assay Kit and Micro Reduced Glutathione (GSH) Assay Kit, respectively. Flow cytometry was used to detect apoptosis and the levels of ROS and iron ions.ResultsCISD2 was highly expressed in HCC cells compared with normal cells and was associated with poor prognosis in patients. Knockdown of CISD2 promoted a decrease in the viability of drug-resistant HCC cells. CISD2 knockdown promoted sorafenib-induced ferroptosis in resistant HCC cells. The levels of ROS, MDA, and iron ions increased, but the change in GSH was not obvious. Knockdown of CISD2 promoted uncontrolled autophagy in resistant HCC cells. Inhibition of autophagy attenuated CISD2 knockdown-induced ferroptosis. The autophagy promoted by CISD2 knockdown was related to Beclin1. When CISD2 and Beclin1 were inhibited, the effect on ferroptosis was correspondingly weakened.ConclusionInhibition of CISD2 promoted sorafenib-induced ferroptosis in resistant cells, and this process promoted excessive iron ion accumulation through autophagy, leading to ferroptosis. The combination of CISD2 inhibition and sorafenib treatment is an effective therapeutic strategy for resistant HCC.

scholarly journals Artesunate Regulates Neurite Outgrowth Inhibitor Protein B Receptor to Overcome Resistance to Sorafenib in Hepatocellular Carcinoma Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Wubin He ◽  
Xiaoxu Huang ◽  
Bradford K. Berges ◽  
Yue Wang ◽  
Ni An ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Neurite Outgrowth ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Advanced Hepatocellular Carcinoma ◽  
Inhibitor Protein ◽  
Sorafenib Treatment ◽  
A Cell ◽  
Protein B

The multireceptor tyrosine kinase inhibitor sorafenib is a Food and Drug Administration-approved first-line drug for the treatment of advanced liver cancer that can reportedly extend overall survival in patients with advanced hepatocellular carcinoma (HCC). Primary and acquired resistance to sorafenib are gradually increasing however, leading to failure of HCC treatment with sorafenib. It is therefore crucial to study the potential mechanism of sorafenib resistance. The results of the current study indicate that neurite outgrowth inhibitor protein B receptor (NgBR) is overexpressed in cultured sorafenib-resistant cells, and that its expression is negatively correlated with the sensitivity of liver cancer cells to sorafenib. Artesunate can inhibit the expression of NgBR, and it may block sorafenib resistance. Herein we report that sorafenib treatment in combination with artesunate overcomes HCC resistance to sorafenib alone in a cell culture model.

scholarly journals Modulation of SIRT3 expression through CDK4/6 enhances the anti-cancer effect of sorafenib in hepatocellular carcinoma cells

2020 ◽  
Author(s):  
HanHee Jo ◽  
Yusun Park ◽  
Taehun Kim ◽  
Jisu Kim ◽  
JongSook Lee ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Combined Treatment ◽  
Xenograft Model ◽  
Cancer Tissue ◽  
Sorafenib Treatment ◽  
Tumor Types ◽  
Related Proteins ◽  
Sirt3 Expression ◽  
Hcc Cells

Abstract Background : Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide. The only drug currently approved for clinical use in the treatment of advanced HCC is sorafenib. However, many patients with HCC show reduced sensitivity to sorafenib during treatment. SIRT3, a member of the mammalian sirtuin family, is a tumor suppressor in certain tumor types. However, only few studies have investigated the effects of SIRT3 on tumor prognosis and sorafenib sensitivity in patients with HCC. Here, we aimed to investigate the correlation between SIRT3 expression and glucose metabolism and proliferation in HCC and discover effective compounds that increase endogenous SIRT3 modulation effect of sorafenib. Methods: To determine the correlation between SIRT3 and glucose related proteins, immunostaining was performed with liver cancer tissue using various antibodies. To investigate whether the expression of SIRT3 in HCC is related to the resistance to sorafenib, we treated sorafenib after the modulation of SIRT3 levels in HCC cell lines (overexpression in Huh7, knockdown in HepG2). We also employed PD0332991 to modulate the SIRT3 expression in HCC cell and conducted functional assays. Results: SIRT3 expression was downregulated in high glycolytic and proliferative HCC cells of human patients, xenograft model and HCC cell lines. Moreover, SIRT3 expression was downregulated after sorafenib treatment, resulting in reduced drug sensitivity in HCC cell lines. To enhance the anti-tumor effect of sorafenib, we employed PD0332991 (CDK4/6-Rb inhibitor) based on the correlation between SIRT3 and phosphorylated retinoblastoma protein in HCC. Notably, combined treatment with sorafenib and PD0332991 showed an enhancement of the anti-tumor effect in HCC cells. Conclusions: Our data suggest that the modulation of SIRT3 by CDK4/6 inhibition might be useful for HCC therapy together with sorafenib, which, unfortunately, has limited efficacy and whose use is often associated with drug resistance.

scholarly journals Infiltrative hepatocellular carcinoma with multiple lung metastasis completely cured using nivolumab: a case report

2021 ◽  
Vol 21 (2) ◽  
pp. 169-176
Author(s):  
Ji Eun Han ◽  
Hyo Jung Cho ◽  
Soon Sun Kim ◽  
Jae Youn Cheong
Keyword(s):  
Hepatocellular Carcinoma ◽  
Lung Metastasis ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Rescue Therapy ◽  
Advanced Hepatocellular Carcinoma ◽  
Sorafenib Treatment ◽  
Advanced Hcc ◽  
Infusion Chemotherapy ◽  
Systemic Treatments

The current Food and Drug Administration-approved systemic treatments for advanced hepatocellular carcinoma (HCC) include multikinase inhibitors (tyrosine kinase inhibitor [TKI]) and immune checkpoint inhibitors (ICIs). Among ICIs, nivolumab is used as secondline therapy for advanced HCC after sorafenib failure or patient intolerance. In this case, a patient with infiltrative HCC and portal vein tumor thrombosis was treated with hepatic arterial infusion chemotherapy (HAIC) and radiation therapy. New lung metastasis developed after HAICs; thus, lenvatinib treatment was initiated. However, the disease progressed. Thereafter, sorafenib treatment was initiated but he developed intolerance, with grade 3 sorafenib-related diarrhea. Subsequently, nivolumab was administered as rescue therapy. He demonstrated a partial response to nivolumab after the third treatment and viable HCCs in the lungs and liver completely disappeared after the 24th treatment. These findings suggest that nivolumab could be used as an effective rescue therapy for advanced HCC progression after TKI treatment.

scholarly journals Effect of radiotherapy on survival in advanced hepatocellular carcinoma patients treated with sorafenib: a nationwide cancer-registry-based study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shou-Sheng Chu ◽  
Yu-Hsuan Kuo ◽  
Wen-Shan Liu ◽  
Shih-Chang Wang ◽  
Chung-Han Ho ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Registry ◽  
Proportional Hazards Model ◽  
Combined Treatment ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Rank Test ◽  
Study Cohort ◽  
Advanced Hepatocellular Carcinoma ◽  
Sorafenib Treatment

AbstractSorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC) patients. This study aims to determine whether combining radiotherapy with sorafenib administration increases its efficacy. The study cohort included 4763 patients with diagnosed advanced HCC who received sorafenib between January 2012 and December 2015, as reported in medical records in the Taiwan Cancer Registry database. The effect of sorafenib with or without radiotherapy on survival was calculated using the Kaplan–Meier method and compared using the log-rank test. A Cox proportional hazards model was used for multivariate analysis. Patients receiving sorafenib plus radiotherapy had greater 1-year survival than did those receiving sorafenib alone (P < 0.001). Uni- and multivariate analyses also showed that radiotherapy increased survival after adjusting for confounders (adjusted HR 0.57; 95% CI 0.51–0.63). Further stratified analysis according to the timing of radiotherapy relative to sorafenib treatment revealed that patients who underwent radiotherapy after sorafenib had greater 1-year survival than did those undergoing radiotherapy within sorafenib use or sorafenib alone (adjusted HR 0.39; 95% CI 0.27–0.54). Combined treatment with sorafenib and radiotherapy results in greater HCC patient survival and should be considered an option for treating this challenging disease.

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