Sorafenib resistance in hepatocarcinoma: role of hypoxia-inducible factors

Méndez-Blanco, Carolina; Fondevila, Flavia; García‐Palomo, Andrés; González‐Gallego, Javier; Mauriz, José L.

doi:10.1038/s12276-018-0159-1

Cited by 261 publications

(233 citation statements)

References 58 publications

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“…Despite its efficacy, resistance emerges soon after initial treatment, but the mechanism is still unclear. Studies had focus on PI3K/AKT 5 , JAK/STAT pathways, hypoxia-inducible pathways 6 , and epithelial-mesenchymal transition 7 . Studies revealed that microRNAs (miRNAs) may have an important role in this resistance 8 as well.…”

Section: Introductionmentioning

confidence: 99%

miR-486-3p mediates hepatocellular carcinoma sorafenib resistance by targeting FGFR4 and EGFR

Lin

Wan

et al. 2020

Cell Death Dis

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HCC is a common malignancy worldwide and surgery or reginal treatments are deemed insufficient for advancedstage disease. Sorafenib is an inhibitor of many kinases and was shown to benefit advanced HCC patients. However, resistance emerges soon after initial treatment, limiting the clinical benefit of sorafenib, and the mechanisms still remain elusive. Thus, this study aims to investigate the mechanisms of sorafenib resistance and to provide possible targets for combination therapies. Through miRNA sequencing, we found that miR-486-3p was downregulated in sorafenib resistant HCC cell lines. Cell viability experiments showed increased miR-486-3p expression could induce cell apoptosis while miR-486-3p knockdown by CRISPR-CAS9 technique could reduce cell apoptosis in sorafenib treatment. Clinical data also indicated that miR-486-3p level was downregulated in tumor tissue compared with adjacent normal tissue in HCC patients. Mechanism dissections showed that FGFR4 and EGFR were the targets of miR-486-3p, which was verified by luciferase reporter assay. Importantly, FGFR4 or EGFR selective inhibitor could enhance sorafenib efficacy in the resistant cells. Moreover, in vivo sorafenib resistant model identified that over-expressing miR-486-3p by lentivirus injection could overcome sorafenib resistance by significantly suppressing tumor growth in combination with the treatment of sorafenib. In conclusion, we found miR-486-3p was an important mediator regulating sorafenib resistance by targeting FGFR4 and EGFR, thus offering a potential target for HCC treatment.

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Section: Introductionmentioning

confidence: 99%

miR-486-3p mediates hepatocellular carcinoma sorafenib resistance by targeting FGFR4 and EGFR

Lin

Wan

et al. 2020

Cell Death Dis

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“…In these cases, systemic therapy is used, utilizing two available tyrosine kinase inhibitors (TKIs), sorafenib and lenvatinib, in the first-line setting for advanced HCC [16]. Regardless of its effectiveness, liver cancer cells are able to develop sorafenib resistance after sustained administration [17], where several TKIs (regorafenib and cabozantinib) and monoclonal antibodies (nivolumab, pembrolizumab and ramucirumab) have been recently approved [16]. Considering toxicity and adverse reactions caused by these chemotherapeutic agents, some investigations have focused on the study of antitumor effects of natural compounds against HCC, such as resveratrol, curcumin and melatonin [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Antitumor Effects of Quercetin in Hepatocarcinoma In Vitro and In Vivo Models: A Systematic Review

et al. 2019

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Quercetin is a flavonoid present in fruits, vegetables and plants with antioxidant, anti-inflammatory and anticancer properties. Its beneficial activities have been demonstrated in different human pathologies, including hepatoprotective effects against liver disorders. High mortality and late diagnosis of the primary liver tumor hepatocarcinoma (HCC) makes this cancer an interesting target for the study of quercetin effects. Our aim was to systematically review antitumor activities of quercetin in HCC preclinical studies employing single, encapsulated, combined or derived quercetin forms. Literature search was conducted in PubMed, Scopus and Web of Science (WOS), and 39 studies were finally included. We found that 17 articles evaluated quercetin effects alone, six used encapsulated strategy, 10 combined this flavonoid, two decided to co-encapsulate it and only four studied effects of quercetin derivatives, highlighting that only nine included in vivo models. Results evidence the quercetin antiproliferative and proapoptotic properties against HCC either alone and with the mentioned strategies; nevertheless, few investigations assessed specific activities on different processes related with cancer progression. Overall, further studies including animal models are needed to deeper investigate the precise mechanisms of action of quercetin as antitumor agent, as well as the potential of novel strategies aimed to improve quercetin effects in HCC.

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“…Consequently, it reduces the proliferation and migration of tumor cells; thus, it prolongs HCC patients' survival [11,37]. Despite the progress achieved, the observed survival was found to be dependent on the patients' individual sensitivity, and it lasts for one year at most [38,39]. In 2017, regorafenib (II) was approved by the FDA for the treatment of HCC patients whose therapy was not successful with sorafenib (I) [40,41].…”

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confidence: 99%

Targeting Receptor Tyrosine Kinase VEGFR-2 in Hepatocellular Cancer: Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted Benzimidazoles

et al. 2020

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In this study, a novel series of 1,2-disubstituted benzo [d]imidazoles was rationally designed as VEGFR-2 inhibitors targeting hepatocellular carcinoma. Our design strategy is two-fold; it aimed first at studying the effect of replacing the 5-methylfuryl moiety of the well-known antiangiogenic 2-furylbenzimidazoles with an isopropyl moiety on the VEGFR-2 inhibitory activity and the cytotoxic activity. Our second objective was to further optimize the structures of the benzimidazole derivatives through elongation of the side chains at their one-position for the design of more potent type II-like VEGFR-2 inhibitors. The designed 1,2-disubstituted benzimidazoles demonstrated potent cytotoxic activity against the HepG2 cell line, reaching IC 50 = 1.98 µM in comparison to sorafenib (IC 50 = 10.99 µM). In addition, the synthesized compounds revealed promising VEGFR-2 inhibitory activity in the HepG2 cell line, e.g., compounds 17a and 6 showed 82% and 80% inhibition, respectively, in comparison to sorafenib (% inhibition = 92%). Studying the effect of 17a on the HepG2 cell cycle demonstrated that 17a arrested the cell cycle at the G2/M phase and induced a dose-dependent apoptotic effect. Molecular docking studies of the synthesized 1,2-disubstituted benzimidazoles in the VEGFR-2 active site displayed their ability to accomplish the essential hydrogen bonding and hydrophobic interactions for optimum inhibitory activity.

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Sorafenib resistance in hepatocarcinoma: role of hypoxia-inducible factors

Cited by 261 publications

References 58 publications

miR-486-3p mediates hepatocellular carcinoma sorafenib resistance by targeting FGFR4 and EGFR

miR-486-3p mediates hepatocellular carcinoma sorafenib resistance by targeting FGFR4 and EGFR

Antitumor Effects of Quercetin in Hepatocarcinoma In Vitro and In Vivo Models: A Systematic Review

Targeting Receptor Tyrosine Kinase VEGFR-2 in Hepatocellular Cancer: Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted Benzimidazoles

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