Sorafenib: The Gold Standard Therapy in Advanced Hepatocellular Carcinoma and Beyond

Gadaleta-Caldarola, Gennaro; Divella, Rosa; Mazzocca, Antonio; Infusino, Stefania; Ferraro, Emanuela; Filippelli, Gianfranco; Daniele, Antonella; Sabbá, Carlo; Abbate, I.; Brandi, Mario

doi:10.2217/fon.15.161

Cited by 18 publications

(16 citation statements)

References 14 publications

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“…In addition, Phase III trials of novel targeted agents, including sunitinib, brivanib, linifanib and combination of sorafenib plus erlotinib, have failed to improve OS compared with sorafenib as a single agent in first line setting in HCC. These studies were useful for: a better understanding of the mechanism of action of sorafenib in vivo, which is still unknown; and deducing the importance of the various sorafenib-related targets in OS and guiding the development of new drugs [137].…”

Section: Resultsmentioning

confidence: 99%

Sorafenib: 10 years after the first pivotal trial

Gadaleta-Caldarola¹,

Infusino²,

Divella

et al. 2015

Future Oncol.

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Sorafenib is an oral multikinase inhibitor with anticancer activity against a wide spectrum of cancers. It is currently approved for the treatment of patients with hepatocellular carcinoma, advanced renal cell carcinoma or progressive, locally advanced or metastatic differentiated thyroid carcinoma. In this review, we present a number of studies that investigated the efficacy and safety of sorafenib in these settings. We also discuss the perspectives on the use of this molecule, including the role of sorafenib as comparator for the development of new drugs, the combination of sorafenib with additional therapies (such as transarterial chemoembolization for hepatocellular carcinoma) and the use of this treatment in several other advanced refractory solid tumors.

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Section: Resultsmentioning

confidence: 99%

Sorafenib: 10 years after the first pivotal trial

Gadaleta-Caldarola¹,

Infusino²,

Divella

et al. 2015

Future Oncol.

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“…Indeed, in the present study, we demonstrated a substantial decrease in the levels of E2F1, PTEN, and CDKN1A proteins during the development of NASH-derived HCC, which is in a good agreement with our previous report of prominent inhibition of apoptosis during NASH-associated liver carcinogenesis [ 20 ]. Furthermore, we showed that targeted inhibition of miR-93-5p in human Hep3B HCC cells with anti-miR-93-5p reduced the oncogenic cancer cell phenotype, as evidenced by decreased cell viability, decreased colony formation, and increased sensitivity of the cells to the multikinase inhibitor Sorafenib, the only current effective systemic chemotherapeutic agent for the treatment of advanced HCC [ 14 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA deregulation in nonalcoholic steatohepatitis-associated liver carcinogenesis

et al. 2017

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Hepatocellular carcinoma (HCC) is the fastest-rising cause of cancer-related death in the United States. Recent epidemiological studies have identified nonalcoholic steatohepatitis (NASH), a progressive form of nonalcoholic fatty liver disease (NAFLD), as a major risk factor for HCC. Elucidating the underlying mechanisms associated with the development of NASH-derived HCC is critical for identifying early biomarkers for the progression of the disease and for treatment and prevention. In the present study, using liver samples from C57BL/6J mice submitted to the Stelic Animal Model (STAM) of NASH-associated liver carcinogenesis, we investigated the role of microRNA (miRNA) alterations in the pathogenesis of NASH-derived HCC. We found substantial alterations in the expression of miRNAs, with the greatest number occurring in full-fledged HCC. Mechanistically, altered miRNA expression was associated with activation of major hepatocarcinogenesis-related pathways, including the TGF-β, Wnt/β-catenin, ERK1/2, mTOR, and EGF signaling. In addition, the over-expression of the miR-221-3p and miR-222-3p and oncogenic miR-106b∼25 cluster was accompanied by the reduced protein levels of their targets, including E2F transcription factor 1 (E2F1), phosphatase and tensin homolog (PTEN), and cyclin-dependent kinase inhibitor 1 (CDKN1A). Importantly, miR-93-5p, miR-221-3p, and miR-222-3p were also significantly over-expressed in human HCC. These findings suggest that aberrant expression of miRNAs may have mechanistic significance in NASH-associated liver carcinogenesis and may serve as an indicator for the development of NASH-derived HCC.

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“…Sorafenib is the first-line treatment for advanced hepatocellular carcinoma. However, resistance of tumor cells to sorafenib is one of the main reasons for drug utilization [ 9 ]. It seems that finding an effective way to inhibit the resistance may improve the efficiency of sorafenib.…”

Section: Discussionmentioning

confidence: 99%

“…Some evidence suggest that sorafenib can block Raf⁄MEK⁄ERK signaling pathway to inhibit tumor cell proliferation and it can also target the tyrosine kinase receptor vascular endothelial growth factor receptor-2 (VEGFR-2) or platelet-derived growth factor receptor (PDGFR) to produce inhibition of angiogenesis [ 6 – 8 ]. However, sorafenib has been proved to have limited survival benefits with very low response rates because of drug resistance [ 9 ]. Hypoxic environment in solid tumor is one of the vital factors for the treatment of resistance [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Metformin sensitizes sorafenib to inhibit postoperative recurrence and metastasis of hepatocellular carcinoma in orthotopic mouse models

et al. 2016

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BackgroundSorafenib is recognized as a standard treatment for advanced hepatocellular carcinoma (HCC). However, many patients have to adopt dose reduction or terminate the use of sorafenib because of side effects. In addition, a large number of patients are resistant to sorafenib. Thus, it is essential to investigate the underlying mechanisms of the resistance to sorafenib and seek potential strategy to enhance its efficacy.MethodsThe protein expression of hypoxia-inducible factors (HIF)-2α, 30-kDa HIV Tat-interacting protein (TIP30), E-cadherin, N-cadherin, and pAMPK was detected by Western blot. Cell viability assays were performed to study the influence of metformin and sorafenib on cell proliferation. Annexin V-FITC apoptosis assays were used to detect the influence of metformin and sorafenib on cell apoptosis. The relationship between HIF-2α and TIP30 was studied using gene silencing approach and chromatin immunoprecipitation assay. To investigate the effect of metformin and sorafenib on postoperative recurrence and lung metastasis of HCC in tumor-bearing mice, the mice were orally treated either with metformin or sorafenib once a day for continuous 37 days after the operation to remove the lobe where the tumor was implanted. CD31, Ki67, and TUNEL were examined by immunohistochemistry.ResultsOur study demonstrated that metformin synergized with sorafenib reduced HIF-2α expression as examined by Western blot. Gene silencing approach indicated TIP30 was upregulated after knocking-down of HIF-2α and chromatin immunoprecipitation assay revealed that HIF-2α could bind to TIP30 promoter under hypoxic condition. Cell Counting Kit-8 (CCK8) cell viability assay and Annexin V-FITC apoptosis assay showed that metformin in combination with sorafenib suppressed cell proliferation and promoted cell apoptosis. Besides, combined therapy suppressed epithelial-mesenchymal transition (EMT) process both in vitro and in vivo. Moreover, metformin in combination with sorafenib significantly minimized postoperative recurrence and lung metastasis of HCC in orthotopic mouse model. Combined therapy inhibited CD31 and Ki67 expression but promoted TUNEL expression.ConclusionsMetformin may potentially enhance the effect of sorafenib to inhibit HCC recurrence and metastasis after liver resection by regulating the expression of HIF-2α and TIP30.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0253-6) contains supplementary material, which is available to authorized users.

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Sorafenib: The Gold Standard Therapy in Advanced Hepatocellular Carcinoma and Beyond

Cited by 18 publications

References 14 publications

Sorafenib: 10 years after the first pivotal trial

Sorafenib: 10 years after the first pivotal trial

MicroRNA deregulation in nonalcoholic steatohepatitis-associated liver carcinogenesis

Metformin sensitizes sorafenib to inhibit postoperative recurrence and metastasis of hepatocellular carcinoma in orthotopic mouse models

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