Sophoridine suppresses lenvatinib‐resistant hepatocellular carcinoma growth by inhibiting RAS/MEK/ERK axis via decreasing VEGFR2 expression

Zhao, Zhongwei; Zhang, Dengke; Wu, Fazong; Tu, Jianfei; Shen, Jingjing; Xu, Min; Ji, Jiansong

doi:10.1111/jcmm.16108

Cited by 50 publications

(42 citation statements)

References 33 publications

(76 reference statements)

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“…RAS/MEK/ERK (also known as the MAPK pathway) axis is recognized as the downstream pathway of vascular endothelial growth factor receptor 2 (VEGFR2). RAS is the first intracellular effector of the MEK/ERK pathway, and ERK is the main substrate of MEK (Zhao et al, 2021). Polyguluronate sulfate (PGS) enhances the secretion of IFN-b by upregulating the NF-kB and RAF/MEK/ERK pathways, which effectively inhibits the expression and secretion of HBsAg and HBeAg in HepG2.2.15 cells, as well as the replication of HBV (Wu et al, 2016).…”

Section: Therapeutics That Modulate Ras/ Mek/erk Signaling Pathways T...mentioning

confidence: 99%

Novel Molecular Therapeutics Targeting Signaling Pathway to Control Hepatitis B Viral Infection

Yan

Qiu

Davgadorj

et al. 2022

Front. Cell. Infect. Microbiol.

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Numerous canonical cellular signaling pathways modulate hepatitis B virus (HBV) replication. HBV genome products are known to play a significant role in regulating these cellular pathways for the liver’s viral-related pathology and physiology and have been identified as the main factor in hepatocarcinogenesis. Signaling changes during viral replication ultimately affect cellular persistence, multiplication, migration, genome instability, and genome damage, leading to proliferation, evasion of apoptosis, block of differentiation, and immortality. Recent studies have documented that numerous signaling pathway agonists or inhibitors play an important role in reducing HBV replication in vitro and in vivo, and some have been used in phase I or phase II clinical trials. These optional agents as molecular therapeutics target cellular pathways that could limit the replication and transcription of HBV or inhibit the secretion of the small surface antigen of HBV in a signaling-independent manner. As principle-based available information, a combined strategy including antiviral therapy and immunomodulation will be needed to control HBV infection effectively. In this review, we summarize recent findings on interventions of molecular regulators in viral replication and the interactions of HBV proteins with the components of the various targeting cellular pathways, which may assist in designing novel agents to modulate signaling pathways to prevent HBV replication or carcinogenesis.

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Section: Therapeutics That Modulate Ras/ Mek/erk Signaling Pathways T...mentioning

confidence: 99%

Novel Molecular Therapeutics Targeting Signaling Pathway to Control Hepatitis B Viral Infection

Yan

Qiu

Davgadorj

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Lenvatinib-resistant HCC cells, established by culturing with long-term exposure to lenvatinib, were commonly used cell models in these studies. In vitro results showed that the vascular endothelial growth factor (VEGF), VEGFR2, plateletderived growth factor-AA (PDGF-AA), and angiogenin were increased significantly in lenvatinib-resistant cells (Ao et al, 2021;Zhao et al, 2021). Both activation of the MAPK/MEK/ ERK signaling pathway and the upregulation of epithelial mesenchymal transition (EMT) markers were observed in lenvatinib-resistant cells (Ao et al, 2021;Zhao et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…In vitro results showed that the vascular endothelial growth factor (VEGF), VEGFR2, plateletderived growth factor-AA (PDGF-AA), and angiogenin were increased significantly in lenvatinib-resistant cells (Ao et al, 2021;Zhao et al, 2021). Both activation of the MAPK/MEK/ ERK signaling pathway and the upregulation of epithelial mesenchymal transition (EMT) markers were observed in lenvatinib-resistant cells (Ao et al, 2021;Zhao et al, 2021). However, the researchers did not explore the detailed mechanism in these studies.…”

Section: Discussionmentioning

confidence: 99%

YRDC Mediates the Resistance of Lenvatinib in Hepatocarcinoma Cells via Modulating the Translation of KRAS

et al. 2021

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Lenvatinib is the latest and promising agent that has demonstrated a significant improvement of progression-free survival in advanced hepatocellular carcinoma (HCC). However, resistance emerges soon after initial treatment, limiting the clinical benefits of lenvatinib. Therefore, understanding the mechanism of resistance is necessary for improving lenvatinib efficacy. YRDC promotes the proliferation of hepatocarcinoma cells via regulating the activity of the RAS/RAF/MEK/ERK pathway, which was the primary pathway of the anticancer effect of lenvatinib. The purpose of this study is to investigate whether YRDC modulates the sensitivity of lenvatinib in hepatocarcinoma cells. Using the CCK-8 cell viability assay, wound-healing assay and clone formation assay in cell models, and xenograft assay in null mouse, we demonstrated that Huh7 cells with YRDC knockdown showed decreased susceptibility to lenvatinib than their control cells. Furthermore, we found that lenvatinib inhibited the expression of YRDC in a time-dependent manner. This effect may aggravate resistance to lenvatinib in hepatocarcinoma cells and may be an underlying cause of resistance, which emerges soon after lenvatinib initial treatment. To investigate how YRDC modulates the sensitivity of lenvatinib, we assessed the effect of tRNA with different t6A levels on the translation of the KRAS gene by in vitro rabbit reticulocyte translation system and measured the expression levels of the KRAS gene by western blot together with qPCR. We found that YRDC regulates the protein translation of KRAS in cell models, and the tRNA with low t6A modification level reduces the translation of the KRAS in the in vitro translation system. These results suggested that YRDC mediates the resistance of lenvatinib in hepatocarcinoma cells via modulating the translation of the KRAS. In this study, YRDC was confirmed to be a potential novel predictive biomarker of lenvatinib sensitivity in HCC.

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“…Per these reports, combining sophoridine with lenvatinib could be a novel therapeutic strategy for HCC treatment. 17 …”

Section: Pharmacological Activities Of Sophoridinementioning

confidence: 99%

“… Anti-cancer In vitro HepG2 cells 20, 40, and 80 μM Regulating PTEN/PI3K/Akt signaling pathway and caspase-3/-9 and MMP-2/-9 signaling pathway. [ 10 ] In vivo Nude mice 20, 40, and 80 μM Decreasing the PTEN protein expression, tumor volume and weight [ 10 ] In vitro HepG2 and Huh7 human HCC cell lines 20, 40, and 80 μM Reducing VEGFR2 expression and RAS/MEK/ERK axis [ 17 ] In vivo BALB/c nude mice 50 mg/kg, ip Inhibiting the tumour cell proliferation and angiogenesis. [ 17 ] In vitro BRL-3A cells 1, 2, and 3 mM Up-regulating intracellular ROS accumulation [ 16 ] In vitro MKN45 cells 8, 14 mM Down-regulation of HMGB3 protein expression [ 20 ] In vitro Gastric cancer cell lines (SGC7901 and AGS) 1, 3, and 5 μM Up-regulating ESRRG /β-catenin pathway [ 21 ] In vitro MFC cancer cells 2, 4, and 8 mM Up-regulating TLR4/IRF3 signal pathway and CD8+ T cytotoxic function against gastric cancer [ ...…”

Section: Introductionmentioning

confidence: 99%

Research Progress in the Pharmacological Activities, Toxicities, and Pharmacokinetics of Sophoridine and Its Derivatives

Tang

Liu

Peng

et al. 2022

DDDT

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Sophoridine is a natural quinolizidine alkaloid and a bioactive ingredient that can be isolated and identified from certain herbs, including Sophora flavescens Alt, Sophora alopecuroides L , and Sophora viciifolia Hance . In recent years, this quinolizidine alkaloid has gained widespread attention because of its unique structure and minimal side effects. Modern pharmacological investigations have uncovered sophoridine’s multiple wide range biological activities, such as anti-cancer, anti-inflammatory, anti-viral, anti-arrhythmia, and analgesic functions, among others. These pharmacological activities and beneficial effects point to sophoridine as a strong potential therapeutic candidate for the treatment of various diseases, including several cancer types, hepatitis B virus, enterovirus 71, coxsackievirus B3, cerebral edema, cancer pain, heart failure, acute myocardial ischemia, arrhythmia, inflammation, acute lung injury, and osteoporosis. The data showed that sophoridine had adverse reactions, including hepatotoxicity and neurotoxicity. Additionally, analyses of sophoridine’s safety, bioavailability, and pharmacokinetic parameters in animal models of research have been limited, especially in the clinic, as have been investigations on its structure-activity relationship. In this article, we comprehensively summarize the biological activities, toxicity, and pharmacokinetic characteristics of sophoridine and its derivatives, as currently reported in publications, as we attempt to provide an overall perspective on sophoridine analogs and the prospects of its application clinically.

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Sophoridine suppresses lenvatinib‐resistant hepatocellular carcinoma growth by inhibiting RAS/MEK/ERK axis via decreasing VEGFR2 expression

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 50 publications

References 33 publications

Novel Molecular Therapeutics Targeting Signaling Pathway to Control Hepatitis B Viral Infection

Novel Molecular Therapeutics Targeting Signaling Pathway to Control Hepatitis B Viral Infection

YRDC Mediates the Resistance of Lenvatinib in Hepatocarcinoma Cells via Modulating the Translation of KRAS

Research Progress in the Pharmacological Activities, Toxicities, and Pharmacokinetics of Sophoridine and Its Derivatives

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