Anti-tumor activity of sorafenib in a model of a pediatric hepatocellular carcinoma

Nagel, Carmen; Armeanu–Ebinger, Sorin; Dewerth, Alexander; Warmann, Steven W.; Fuchs, Joerg

doi:10.1016/j.yexcr.2014.10.018

Cited by 17 publications

(11 citation statements)

References 24 publications

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“…Sorafenib can inhibit RAF-1, VGFR-2 and VGFR-3 and other RTK activity [ 80 ]. It is the first anti-tumor drugs targeting and inhibiting RAF kinase and VEGFR kinase at the same time [ 81 , 82 ]. It can directly inhibit the proliferation of tumor cells by blocking the cell signaling pathway mediated by RAF/MEK/ERK [ 83 ], but also through the action of VEGFR to inhibit the formation of angiogenesis and cut off the nutritional supply of tumor cells to limit the tumor growth [ 84 , 85 ].…”

Section: Tkis Biologymentioning

confidence: 99%

Advances in studies of tyrosine kinase inhibitors and their acquired resistance

et al. 2018

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Protein tyrosine kinase (PTK) is one of the major signaling enzymes in the process of cell signal transduction, which catalyzes the transfer of ATP-γ-phosphate to the tyrosine residues of the substrate protein, making it phosphorylation, regulating cell growth, differentiation, death and a series of physiological and biochemical processes. Abnormal expression of PTK usually leads to cell proliferation disorders, and is closely related to tumor invasion, metastasis and tumor angiogenesis. At present, a variety of PTKs have been used as targets in the screening of anti-tumor drugs. Tyrosine kinase inhibitors (TKIs) compete with ATP for the ATP binding site of PTK and reduce tyrosine kinase phosphorylation, thereby inhibiting cancer cell proliferation. TKI has made great progress in the treatment of cancer, but the attendant acquired acquired resistance is still inevitable, restricting the treatment of cancer. In this paper, we summarize the role of PTK in cancer, TKI treatment of tumor pathways and TKI acquired resistance mechanisms, which provide some reference for further research on TKI treatment of tumors.

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Section: Tkis Biologymentioning

confidence: 99%

Advances in studies of tyrosine kinase inhibitors and their acquired resistance

et al. 2018

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“…HepG2 cells resistant to sorafenib showed increased metastatic and invasive ability compared to the parental cells, in part due to EMT, since the silencing of Snail blocked EMT and partially reversed MDR, invasion and metastasis [115]. A potent effect of sorafenib was observed in vitro in a cell line derived from a pediatric HCC and in HB cell lines, but only a moderate tumor growth inhibition occurred in vivo, which was associated with resistance during treatment [116]. This was accompanied by a decrease in E-cadherin and an enhanced activity of the transcription factor β-catenin, a major player in EMT.…”

Section: Mechanisms Of Hb Resistance To Tyrosine-kinase Inhibitorsmentioning

confidence: 99%

Mechanisms of Anticancer Drug Resistance in Hepatoblastoma

Marin

Cives-Losada

Asensio

et al. 2019

Cancers

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The most frequent liver tumor in children is hepatoblastoma (HB), which derives from embryonic parenchymal liver cells or hepatoblasts. Hepatocellular carcinoma (HCC), which rarely affects young people, causes one fourth of deaths due to cancer in adults. In contrast, HB usually has better prognosis, but this is still poor in 20% of cases. Although more responsive to chemotherapy than HCC, the failure of pharmacological treatment used before and/or after surgical resection is an important limitation in the management of patients with HB. To advance in the implementation of personalized medicine it is important to select the best combination among available anti-HB drugs, such as platinum derivatives, anthracyclines, etoposide, tyrosine-kinase inhibitors, Vinca alkaloids, 5-fluorouracil, monoclonal antibodies, irinotecan and nitrogen mustards. This requires predicting the sensitivity to these drugs of each tumor at each time because, it should be kept in mind, that cancer chemoresistance is a dynamic process of Darwinian nature. For this goal it is necessary to improve our understanding of the mechanisms of chemoresistance involved in the refractoriness of HB against the pharmacological challenge and how they evolve during treatment. In this review we have summarized the current knowledge on the multifactorial and complex factors responsible for the lack of response of HB to chemotherapy.

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“…Because sorafenib is an inhibitor of multiple receptor tyrosine kinases (VEGFR-2, PDGFR-β, Flt-3, and Kit) and Raf kinases, it can inhibit the ERK signaling pathway in HCC (28,35). Previous studies have revealed that higher p-ERK levels are associated with increased time to progression (TTP) in HCC and are potentially a predictive biomarker for poor outcomes in patients with advanced HCC who are treated with sorafenib (36,37).…”

Section: Discussionmentioning

confidence: 99%

miR-126-3p contributes to sorafenib resistance in hepatocellular carcinoma via downregulating SPRED1

Tan¹,

Zhong²,

Chen³

et al. 2021

Ann Transl Med

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Background: Sorafenib can prolong the survival of patients with advanced hepatocellular carcinoma (HCC).However, drug resistance remains the main obstacle to improving its efficiency. This study aimed to explore the likely molecular mechanism of sorafenib resistance. Methods: Differentially expressed microRNAs (miRNAs) related to sorafenib response were analyzed with the Limma package in R software. The expression levels of miR-126-3p and sprouty-related EVH1 domain-containing protein 1 (SPRED1) in HCC cells were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell viability and proliferation were detected with Cell Counting Kit-8 (CCK-8), EdU proliferation, and clone formation assays. Transwell assays were performed to measure cell migration and invasion. TargetScan, MicroRNA Target Prediction Database (miRDB), and StarBase v2.0 were used to predict the targets of miR-126-3p. SPRED1 was confirmed as a target gene of miR-126-3p by dual-luciferase reporter assay and Western blotting. Finally, the in vivo anti-tumor effect of LV-miR-126-3p inhibitor combined with sorafenib was evaluated via subcutaneous tumor models.Results: HCC cells with high expression of miR-126-3p exhibited increased resistance to sorafenib.The results of bioinformatics analysis and the dual-luciferase reporter assay showed that miR-126-3p directly targeted SPRED1. The sensitivity of HCC cells to sorafenib was markedly enhanced by SPRED1 upregulation. Gain-and loss-of function experiments verified that miR-126-3p induced sorafenib resistance in HCC through downregulating SPRED1. Furthermore, the inhibition of miR-126-3p markedly increased the effectiveness of sorafenib against HCC in vivo. Mechanistically, our results suggested that miR-126-3p promoted sorafenib resistance via targeting SPRED1 and activating the ERK signaling pathway.Conclusions: Our study demonstrates that regulating the miR-126-3p/SPRED1 axis might be a promising strategy for enhancing the antitumor effect of sorafenib in the treatment of HCC.

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Anti-tumor activity of sorafenib in a model of a pediatric hepatocellular carcinoma

Cited by 17 publications

References 24 publications

Advances in studies of tyrosine kinase inhibitors and their acquired resistance

Advances in studies of tyrosine kinase inhibitors and their acquired resistance

Mechanisms of Anticancer Drug Resistance in Hepatoblastoma

miR-126-3p contributes to sorafenib resistance in hepatocellular carcinoma via downregulating SPRED1

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