scholarly journals Emodin Sensitizes Hepatocellular Carcinoma Cells to the Anti-Cancer Effect of Sorafenib through Suppression of Cholesterol Metabolism

2018 ◽  
Vol 19 (10) ◽  
pp. 3127 ◽  
Author(s):  
Young-Seon Kim ◽  
Yoon-Mi Lee ◽  
Taek-In Oh ◽  
Dong Shin ◽  
Geon-Hee Kim ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cholesterol Metabolism ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Akt Signaling ◽  
Chinese Herbs ◽  
Advanced Hepatocellular Carcinoma ◽  
Multikinase Inhibitor ◽  
Anti Cancer ◽  
Sensitizing Effect

Reduced therapeutic efficacy of sorafenib, a first-generation multikinase inhibitor, is often observed during the treatment of advanced hepatocellular carcinoma (HCC). Emodin is an active component of Chinese herbs, and is effective against leukemia, lung cancer, colon cancer, pancreatic cancer, and HCC; however, the sensitizing effect of emodin on sorafenib-based HCC therapy has not been evaluated. Here, we demonstrate that emodin significantly improved the anti-cancer effect of sorafenib in HCC cells, such as HepG2, Hep3B, Huh7, SK-HEP-1, and PLC/PRF5. Mechanistically, emodin inhibits sterol regulatory element-binding protein-2 (SREBP-2) transcriptional activity, which suppresses cholesterol biosynthesis and oncogenic protein kinase B (AKT) signaling. Additionally, attenuated cholesterol synthesis and oncogenic AKT signaling inactivated signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. Furthermore, emodin synergistically increased cell cycle arrest in the G1 phase and apoptotic cells in the presence of sorafenib. Animal models xenografted with HepG2 or SK-HEP-1 cells also showed that the combination of emodin and sorafenib was sufficient to inhibit tumor growth. Overall, these results suggested that the combination of emodin and sorafenib may offer a potential therapy for patients with advanced HCC.

scholarly journals Ursolic Acid Suppresses Cholesterol Biosynthesis and Exerts Anti-Cancer Effects in Hepatocellular Carcinoma Cells

2019 ◽  
Vol 20 (19) ◽  
pp. 4767 ◽  
Author(s):  
Geon-Hee Kim ◽  
Sang-Yeon Kan ◽  
Hyeji Kang ◽  
Sujin Lee ◽  
Hyun Myung Ko ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Chronic Diseases ◽  
Ursolic Acid ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Lowering ◽  
Anti Cancer ◽  
Sterol Regulatory Element ◽  
Cholesterol Supplementation ◽  
Hcc Cells

Abnormally upregulated cholesterol and lipid metabolism, observed commonly in multiple cancer types, contributes to cancer development and progression through the activation of oncogenic growth signaling pathways. Although accumulating evidence has shown the preventive and therapeutic benefits of cholesterol-lowering drugs for cancer management, the development of cholesterol-lowering drugs is needed for treatment of cancer as well as metabolism-related chronic diseases. Ursolic acid (UA), a natural pentacyclic terpenoid, suppresses cancer growth and metastasis, but the precise underlying molecular mechanism for its anti-cancer effects is poorly understood. Here, using sterol regulatory element (SRE)-luciferase assay-based screening on a library of 502 natural compounds, this study found that UA activates sterol regulatory element-binding protein 2 (SREBP2). The expression of cholesterol biosynthesis-related genes and enzymes increased in UA-treated hepatocellular carcinoma (HCC) cells. The UA increased cell cycle arrest and apoptotic death in HCC cells and reduced the activation of oncogenic growth signaling factors, all of which was significantly reversed by cholesterol supplementation. As cholesterol supplementation successfully reversed UA-induced attenuation of growth in HCC cells, it indicated that UA suppresses HCC cells growth through its cholesterol-lowering effect. Overall, these results suggested that UA is a promising cholesterol-lowering nutraceutical for the prevention and treatment of patients with HCC and cholesterol-related chronic diseases.

scholarly journals MiRNA-124-3p.1 sensitizes hepatocellular carcinoma cells to sorafenib by regulating FOXO3a by targeting AKT2 and SIRT1

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Zhe-bin Dong ◽  
Heng-miao Wu ◽  
Yi-cheng He ◽  
Zhong-ting Huang ◽  
Yi-hui Weng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Acquired Resistance ◽  
Xenograft Model ◽  
Early Recurrence ◽  
Advanced Hepatocellular Carcinoma ◽  
Curative Surgery ◽  
Multikinase Inhibitor ◽  
Key Factor ◽  
Nuclear Location ◽  
Induced Apoptosis

AbstractAs a multikinase inhibitor, sorafenib is commonly used to treat patients with advanced hepatocellular carcinoma (HCC), however, acquired resistance to sorafenib is a major obstacle to the effectiveness of this treatment. Thus, in this study, we investigated the mechanisms underlying sorafenib resistance as well as approaches devised to increase the sensitivity of HCC to sorafenib. We demonstrated that miR-124-3p.1 downregulation is associated with early recurrence in HCC patients who underwent curative surgery and sorafenib resistance in HCC cell lines. Regarding the mechanism of this phenomenon, we identified FOXO3a, an important cellular stress transcriptional factor, as the key factor in the function of miR-124-3p.1 in HCC. We showed that miR-124-3p.1 binds directly to AKT2 and SIRT1 to reduce the levels of these proteins. Furthermore, we showed that AKT2 and SIRT1 phosphorylate and deacetylate FOXO3a. We also found that miR-124-3p.1 maintains the dephosphorylation and acetylation of FOXO3a, leading to the nuclear location of FOXO3a and enhanced sorafenib-induced apoptosis. Moreover, the combination of miR-124-3p.1 mimics and sorafenib significantly enhanced the curative efficacy of sorafenib in a nude mouse HCC xenograft model. Collectively, our data reveal that miR-124-3p.1 represents a predictive indicator of early recurrence and sorafenib sensitivity in HCC. Furthermore, we demonstrate that miR-124-3p.1 enhances the curative efficacy of sorafenib through dual effects on FOXO3a. Thus, the miR-124-3p.1-FOXO3a axis is implicated as a potential target for the diagnosis and treatment of HCC.

Imaging approaches to assess mechanism-of-action and response in patients with advanced hepatocellular carcinoma treated with the novel oncolytic poxvirus JX-594.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 210-210
Author(s):  
Richard H. Patt ◽  
David H. Kirn ◽  
Caroline Breitbach ◽  
James M. Burke ◽  
Riccardo Lencioni
Keyword(s):  
Hepatocellular Carcinoma ◽  
Oncolytic Virus ◽  
Advanced Hepatocellular Carcinoma ◽  
The Novel ◽  
Mri Imaging ◽  
Vascular Disruption ◽  
Imaging Results ◽  
Anti Cancer ◽  
Mri Scans ◽  
Tumor Measurements

210 Background: The novel oncolytic virus JX-595 has demonstrated anti-cancer mechanisms of action, as defined in preclinical models, which includes cytolysis, intra-tumoral vascular disruption, and immune-mediated tumor targeting. Methods: To determine whether mechanism(s) of action (MOA) of the novel anti-cancer oncolytic virus JX-594 could be demonstrated by MRI imaging in patients with advanced hepatocellular carcinoma (HCC), dynamic contrast-enhanced MRI of the liver was performed at baseline, day 5, and week 8 following intra-tumoral injection. Images were evaluated by a central reviewer blinded to treatment and dose using both modified RECIST and Choi response criteria. 17/30 subjects underwent day 5 (D5) post-treatment imaging; 28/30 had week 8 (W8) imaging. Results: Choi responses correlated more reliably than RECIST with JX-594 MOA. Evidence of intra-tumoral vascular shutdown, manifest by areas of reduced or non-enhancement (Choi response), was observed in 6 of 17 subjects on D5 5 MRI scans. Day 5 Choi responses were a predictor of week 8 Choi responses in all but 1 subject. Of the 11/17 D5 Choi non-responders, 3 were Choi responders at 8 weeks. Increase in size at D5 of small lesions present at baseline (“unmasking”) is compatible with oncolytic flare due to intra-tumoral edema contributed to by cell lysis and immune infiltration. RECIST criteria tumor measurements did not identify MOA of JX-594, and resulted in the appearance of pseudoprogression at D5 in some subjects. Conclusions: Hyperacute MRI post-therapy can be used to detect activity of the JX-594, a novel oncolytic anti-cancer therapy. Day 5 Choi responses were a predictor of subsequent response at week 8. Clinical trial information: NCT00554372.

scholarly journals Phase II Trial of the Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma with Tumor Mutation Profiling

Liver Cancer ◽  
2021 ◽  
pp. 1-11
Author(s):  
Robin K. Kelley ◽  
Nancy M. Joseph ◽  
Halla S. Nimeiri ◽  
Jimmy Hwang ◽  
Laura M. Kulik ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Mammalian Target Of Rapamycin ◽  
Advanced Hepatocellular Carcinoma ◽  
Next Generation ◽  
Serious Adverse Events ◽  
Multikinase Inhibitor

<b><i>Background:</i></b> The mammalian target of rapamycin (<i>mTOR</i>) pathway is upregulated in nearly half of hepatocellular carcinoma (HCC) tumors and is associated with poor prognosis. In preclinical models of HCC, the combination of <i>mTOR</i> pathway inhibition with the multikinase inhibitor sorafenib improves treatment efficacy. A prior phase I study of the allosteric mTOR inhibitor temsirolimus combined with sorafenib demonstrated acceptable safety at the recommended phase II dose. <b><i>Methods:</i></b> We conducted a single-arm, multicenter phase II trial of the combination of temsirolimus 10 mg intravenously weekly plus sorafenib 200 mg b.i.d<i>.</i> The primary endpoint was time to progression (TTP) with efficacy target of median TTP of at least 6 months; secondary endpoints included overall survival (OS), objective response rate, safety, and alpha-fetoprotein (AFP) tumor marker response. Next-generation tumor sequencing was performed as an exploratory endpoint. <b><i>Results:</i></b> Twenty-nine patients were enrolled, including 48% with hepatitis C virus infection and 28% with hepatitis B virus; 86% had Barcelona clinic liver cancer stage C disease. Among 28 patients evaluable for efficacy, the median TTP was 3.7 (95% confidence interval [CI]: 2.2, 5.3) months, with 14% of patients achieving TTP of at least 6 months. The median OS was 8.8 (95% CI: 6.8, 14.8) months. There were no complete or partial responses; 75% of patients had stable disease as best response. AFP decline by at least 50% was associated with prolonged TTP and OS. Serious adverse events occurred in 21%; the most common treatment-related adverse events of CTCAE grade 3 or higher were hypophosphatemia (36%), thrombocytopenia (14%), and rash (11%). There were no grade 5 events attributed to sorafenib or temsirolimus. Tumor next-generation sequencing (NGS) was performed in a subgroup of 24 patients with adequate tumor samples. Tumor <i>mTOR</i> pathway mutations were identified in 42%. There was no association between tumor mutation profile and OS or TTP. <b><i>Conclusions:</i></b> The combination of temsirolimus and sorafenib demonstrated acceptable safety but did not achieve the target threshold for efficacy in this phase II study. Tumor NGS including the presence of <i>mTOR</i> pathway mutations was not associated with treatment response in an exploratory subgroup analysis.

scholarly journals Maprotiline Suppresses Cholesterol Biosynthesis and Hepatocellular Carcinoma Progression Through Direct Targeting of CRABP1

2021 ◽  
Vol 12 ◽  
Author(s):  
Cancan Zheng ◽  
Yidong Zhu ◽  
Qinwen Liu ◽  
Tingting Luo ◽  
Wenwen Xu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Binding Protein ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Antitumor Effects ◽  
Element Binding Protein ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related death and has a poor prognosis worldwide, thus, more effective drugs are urgently needed. In this article, a small molecule drug library composed of 1,056 approved medicines from the FDA was used to screen for anticancer drugs. The tetracyclic compound maprotiline, a highly selective noradrenergic reuptake blocker, has strong antidepressant efficacy. However, the anticancer effect of maprotiline remains unclear. Here, we investigated the anticancer potential of maprotiline in the HCC cell lines Huh7 and HepG2. We found that maprotiline not only significantly restrained cell proliferation, colony formation and metastasis in vitro but also exerted antitumor effects in vivo. In addition to the antitumor effect alone, maprotiline could also enhance the sensitivity of HCC cells to sorafenib. The depth studies revealed that maprotiline substantially decreased the phosphorylation of sterol regulatory element-binding protein 2 (SREBP2) through the ERK signaling pathway, which resulted in decreased cholesterol biosynthesis and eventually impeded HCC cell growth. Furthermore, we identified cellular retinoic acid binding protein 1 (CRABP1) as a direct target of maprotiline. In conclusion, our study provided the first evidence showing that maprotiline could attenuate cholesterol biosynthesis to inhibit the proliferation and metastasis of HCC cells through the ERK-SREBP2 signaling pathway by directly binding to CRABP1, which supports the strategy of repurposing maprotiline in the treatment of HCC.

A randomized controlled phase II study of the prophylactic effect of urea-based cream on the hand-foot skin reaction associated with sorafenib in advanced hepatocellular carcinoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4008-4008 ◽  
Author(s):  
Zhenggang Ren ◽  
Kangshun Zhu ◽  
Haiyan Kang ◽  
Minqiang Lu ◽  
Zengqiang Qu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Skin Reaction ◽  
Controlled Trial ◽  
Statistical Significance ◽  
Advanced Hepatocellular Carcinoma ◽  
Prophylactic Effect ◽  
Multikinase Inhibitor ◽  
Advanced Hcc ◽  
Randomized Controlled ◽  
Hand Foot Skin Reaction

4008 Background: Sorafenib (SOR) has become the standard treatment for advanced hepatocellular carcinoma (HCC). Hand-foot skin reaction (HFSR) is one of the most common adverse events associated with SOR and its occurrence can impact patient quality of life and lead to dose modification or interruption, both of which may negatively impact clinical outcomes. This randomized controlled trial is the first large prospective study to investigate the prophylactic effect of urea-based creams on HFSR associated with SOR. Methods: Patients with advanced HCC treated with SOR were randomly assigned 1:1 to receive prophylactic urea-based cream (Arm A) or best supportive care (BSC) following development of HFSR (Arm B). SOR was administered 800 mg daily. Urea-based cream was given twice daily for up to 12 weeks starting on Day 1. BSC was at the physician’s discretion and excluded urea-based creams. The primary endpoint was the incidence of all-grade HFSR in the first12 weeks. Results: Eight hundred sixty eight patients were enrolled; 439 patients in Arm A and 432 patients in Arm B. There was no difference of baseline characteristics between two arms. Over the 12 week period of study, the incidence of all-grade HFSR was significantly lower in Arm A compared to Arm B; n=246 (56.0%) patients in Arm A versus n=318 (73.6%) patients in Arm B, p<0.0001. The incidence of grade ≥2 HFSR tended to be lower in Arm A compared to Arm B, but did not reach statistical significance; n=96 (21.9%) patients Arm A versus n=126 (29.2%) patients in Arm B, p=0.1638. The median time to the first HFSR event was 2.5 fold longer in Arm A compared to Arm B; 84 days (95% CI 45-93 days) in Arm A and 34 days (95% CI 29-43 days) in Arm B (p<0.001). Conclusions: This is the first large prospective, randomized control trial examining the prophylactic use of urea-based creams for treatment of HFSR associated with a multikinase inhibitor. Compared to BSC, prophylactic topical use of a urea-based cream appears to be effective in preventing and/or delaying the incidence of HFSR associated with SOR treatment in patients with advanced HCC.

scholarly journals Hypoxia induces sorafenib resistance mediated by autophagy via activating FOXO3a in hepatocellular carcinoma

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Chao Liang ◽  
Zhebin Dong ◽  
Xianlei Cai ◽  
Jie Shen ◽  
Yuan Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Term Therapy ◽  
Advanced Hepatocellular Carcinoma ◽  
Multikinase Inhibitor ◽  
Sorafenib Treatment ◽  
Clinical Prognosis ◽  
Nuclear Location ◽  
Long Term Therapy ◽  
Hcc Cells

AbstractSorafenib, a multikinase inhibitor, is considered as the only approved drug to cure the advanced hepatocellular carcinoma (HCC); however, the acquired chemoresistance caused by intratumoral hypoxia through sorafenib long term therapy induces sorafenib inefficacy. We demonstrated here that hypoxia significantly attenuated sensitivity of HCC cells to sorafenib treatment and reduced its proliferation. Autophagy was observed in sorafenib-treated HCC cells in hypoxia, and inhibition of autophagy by 3-MA eliminated hypoxia-induced sorafenib resistance. Further study revealed hypoxia-activated FOXO3a, an important cellular stress transcriptional factor, via inducing its dephosphorylation and nuclear location; and FOXO3a-dependent transcriptive activation of beclin-1 was responsible for hypoxia-induced autophagy in HCC cells. Knockout of FOXO3a inhibited the autophagy induced by sorafenib itself in normoxia and significantly enhanced the cytotoxicity of sorafenib in HCC cells; and it also inhibited the hypoxia-induced autophagy and achieved the same effect in sorafenib sensitivity-enhancement in HCC cells as it in normoxia. Finally, knockout of intratumoral FOXO3a significantly enhanced curative efficacy of sorafenib via inhibition of autophagy in xenograft tumors in nude mice. Collectively, our study suggests that FOXO3a plays a key role in regulating hypoxia-induced autophagy in sorafenib-treated HCC, and FOXO3-targeted therapy may serve as a promising approach to improve clinical prognosis of patients suffering from HCC.

scholarly journals Early MRI response monitoring of patients with advanced hepatocellular carcinoma under treatment with the multikinase inhibitor sorafenib

BMC Cancer ◽  
2009 ◽  
Vol 9 (1) ◽  
Author(s):  
Marius Horger ◽  
Ulrich M Lauer ◽  
Christina Schraml ◽  
Christoph P Berg ◽  
Ursula Koppenhöfer ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Response Monitoring ◽  
Advanced Hepatocellular Carcinoma ◽  
Multikinase Inhibitor

TACE plus sorafenib for the treatment of advanced hepatocellular carcinoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15178-e15178
Author(s):  
Vijay Sukhdeo Palwe ◽  
Rajnish Vasant Nagarkar
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Hypoxia Inducible Factor ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Good Method ◽  
Advanced Hepatocellular Carcinoma ◽  
Multikinase Inhibitor ◽  
Unresectable Hepatocellular Carcinoma ◽  
Ecog Ps

e15178 Background: Hepatocellular carcinoma (HCC) is considered to be a hypervascular tumor. Therefore, Trans Arterial Chemo Embolization (TACE) and inhibition of angiogenesis appear rational treatment strategies for those patients who have localised disease not amenable to surgical resection. TACE causes increased hypoxia leading to an up regulation in hypoxia inducible factor-1α (HIF-1α), which in turn up regulates vascular endothelial growth factor (VEGF), platelet-derived growth factor receptor, and increases tumor angiogenesis. The present study investigated for the combination of TACE and Sorafenib, a multikinase inhibitor with anti-angiogenic activities approved for the treatment of HCC. Methods: Patients included histologically confirmed, unresectable hepatocellular carcinoma beyond Milan criteria, no extrahepatic spread, Child Pugh score ≤8, ECOG PS 0-2, platelets >100K/µl, and bilirubin <2.5 mg/dl. We present our experience with 42 patients of HCC treated with Trans Arterial Chemo Embolisation (TACE) with Cisplatin, Lipodol and PVA of which 14 pts received TACE along with Sorafenib. Results: Between May 2007 to Jan 2013, 42 patients were enrolled. Patients received a mean of 1.45 TACE interventions (range 1-4). The longest survival was 53 months after 1stTACE and median overall survival was 443 days. Grade 3 and 4 toxicities were noted in 18% and 7% of patients. Conclusions: TACE is a very good method for palliation of unresectable hepatocellular carcinoma (HCC) with improved survival and quality of life.The combination of TACE with sorafenib is tolerable for most patients and associated with a promising rate of radiographic response and OS.

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