ArticlePloS one2015
Bufalin Reverses Resistance to Sorafenib by Inhibiting Akt Activation in Hepatocellular Carcinoma: The Role of Endoplasmic Reticulum Stress.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 60 citations in OpenAlex.
- Hepatocellular carcinoma resistance to tyrosine kinase inhibitors: Current status and perspectives.World journal of gastrointestinal oncology · 2025Article
- Blocking the WNT/β-catenin pathway in cancer treatment:pharmacological targets and drug therapeutic potential.Heliyon · 2024Review
- Multi-b-value DWI to evaluate the synergistic antiproliferation and anti-heterogeneity effects of bufalin plus sorafenib in an orthotopic HCC model.European radiology experimental · 2024Article
- ATP1A1 is a promising new target for melanoma treatment and can be inhibited by its physiological ligand bufalin to restore targeted therapy efficacy.Cancer cell international · 2024Article
- Combinational Antitumor Strategies Based on the Active Ingredients of Toad Skin and Toad Venom.Drug design, development and therapy · 2024Review
- [Research progress on the mechanism and response strategies of molecular targeted drug resistance in liver cancer].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2023Article
- Bufalin suppresses esophageal squamous cell carcinoma progression by activating the PIAS3/STAT3 signaling pathway.Journal of thoracic disease · 2023Article
- Roles of conventional and complementary therapies in recurrent hepatocellular carcinoma.World journal of gastrointestinal oncology · 2023Review
- An overview of the past decade of bufalin in the treatment of refractory and drug-resistant cancers: current status, challenges, and future perspectives.Frontiers in pharmacology · 2023Review
- A review on the mechanisms underlying the antitumor effects of natural products by targeting the endoplasmic reticulum stress apoptosis pathway.Frontiers in pharmacology · 2023Review
- Flower-like Composite Material Delivery of Co-Packaged Lenvatinib and Bufalin Prevents the Migration and Invasion of Cholangiocarcinoma.Nanomaterials (Basel, Switzerland) · 2022Article
- Network Pharmacology Integrated with Transcriptomics Deciphered the Potential Mechanism ofEvidence-based complementary and alternative medicine : eCAM · 2022Article
- The Research Progress of Bufalin in the Treatment of Hepatocellular Carcinoma.OncoTargets and therapy · 2022Review
- Host-targeted Interventions as an Exciting Opportunity to Combat Malaria.Chemical reviews · 2021Review
- 3-hydroxyanthranic acid increases the sensitivity of hepatocellular carcinoma to sorafenib by decreasing tumor cell stemness.Cell death discovery · 2021Article
- PERK/ATF4-Dependent ZFAS1 Upregulation Is Associated with Sorafenib Resistance in Hepatocellular Carcinoma Cells.International journal of molecular sciences · 2021Article
- Therapeutic potential of targeting membrane-spanning proteoglycan SDC4 in hepatocellular carcinoma.Cell death & disease · 2021Article
- Tumor-Targeted Delivery of Bufalin-Loaded Modified Albumin-Polymer Hybrid for Enhanced Antitumor Therapy and Attenuated Hemolysis Toxicity and Cardiotoxicity.AAPS PharmSciTech · 2021Article
- The kynurenine derivative 3-HAA sensitizes hepatocellular carcinoma to sorafenib by upregulating phosphatases.Theranostics · 2021Article
- Recent Progress in Understanding the Action of Natural Compounds at Novel Therapeutic Drug Targets for the Treatment of Liver Cancer.Frontiers in oncology · 2021Review
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Sorafenib is the standard first-line therapeutic treatment for patients with advanced hepatocellular carcinoma (HCC), but its use is hampered by the development of drug resistance. The activation of Akt by sorafenib is thought to be responsible for this resistance. Bufalin is the major active ingredient of the traditional Chinese medicine Chan su, which inhibits Akt activation; therefore, Chan su is currently used in the clinic to treat cancer. The present study aimed to investigate the ability of bufalin to reverse both inherent and acquired resistance to sorafenib. Bufalin synergized with sorafenib to inhibit tumor cell proliferation and induce apoptosis. This effect was at least partially due to the ability of bufalin to inhibit Akt activation by sorafenib. Moreover, the ability of bufalin to inactivate Akt depended on endoplasmic reticulum (ER) stress mediated by inositol-requiring enzyme 1 (IRE1). Silencing IRE1 with siRNA blocked the bufalin-induced Akt inactivation, but silencing eukaryotic initiation factor 2 (eIF2) or C/EBP-homologous protein (CHOP) did not have the same effect. Additionally, silencing Akt did not influence IRE1, CHOP or phosphorylated eIF2α expression. Two sorafenib-resistant HCC cell lines, which were established from human HCC HepG2 and Huh7 cells, were refractory to sorafenib-induced growth inhibition but were sensitive to bufalin. Thus, Bufalin reversed acquired resistance to sorafenib by downregulating phosphorylated Akt in an ER-stress-dependent manner via the IRE1 pathway. These findings warrant further studies to examine the utility of bufalin alone or in combination with sorafenib as a first- or second-line treatment after sorafenib failure for advanced HCC.
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