ArticleCancers2020
Regorafenib Alteration of the BCL-xL/MCL-1 Ratio Provides a Therapeutic Opportunity for BH3-Mimetics in Hepatocellular Carcinoma Models.
Article in Cancers, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 31 citations in OpenAlex.
- Immune remodeling via mitochondria-dependent STING activation enhances cabozantinib response in hepatocellular carcinoma.Journal of experimental & clinical cancer research : CR · 2026Article
- Role of cellular senescence in hepatic diseases (Review).International journal of molecular medicine · 2025Review
- The latest progress of personalized drug screening and therapy research for common clinical tumors through the PDX model platform.Journal of pharmaceutical analysis · 2025Review
- Patient-derived xenograft model: Applications and challenges in liver cancer.Chinese medical journal · 2025Review
- Comprehensive characterization of MCL-1 in patients with colorectal cancer: Expression, molecular profiles, and outcomes.International journal of cancer · 2025Article
- Mitochondrial priming and response to BH3 mimetics in "one-two punch" senogenic-senolytic strategies.Cell death discovery · 2025Article
- Mitochondrial alterations and signatures in hepatocellular carcinoma.Cancer metastasis reviews · 2025Review
- Article
- The Role of Bcl-2 Family Proteins and Sorafenib Resistance in Hepatocellular Carcinoma.International journal of cell biology · 2024Review
- A feedback loop of PPP and PI3K/AKT signal pathway drives regorafenib-resistance in HCC.Cancer & metabolism · 2023Article
- Simultaneous Inhibition of Mcl-1 and Bcl-2 Induces Synergistic Cell Death in Hepatocellular Carcinoma.Biomedicines · 2023Article
- Review
- Review
- Antioxidants Threaten Multikinase Inhibitor Efficacy against Liver Cancer by Blocking Mitochondrial Reactive Oxygen Species.Antioxidants (Basel, Switzerland) · 2021Article
- CKS1B promotes the progression of hepatocellular carcinoma by activating JAK/STAT3 signal pathway.Animal cells and systems · 2021Article
- Mitochondrial Quality Control in Hepatocellular Carcinoma.Frontiers in oncology · 2021Review
- Mitochondrial Glutathione: Recent Insights and Role in Disease.Antioxidants (Basel, Switzerland) · 2020Review
Corrections and comments
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Authors and funding
12 authors at 6 institutions in 1 country.
Funding
Abstract
backgroundThe multikinase inhibitor regorafenib, approved as second-line treatment for hepatocellular carcinoma (HCC) after sorafenib failure, may induce mitochondrial damage. BH3-mimetics, inhibitors of specific BCL-2 proteins, are valuable drugs in cancer therapy to amplify mitochondrial-dependent cell death.
methodsIn in vitro and in vivo HCC models, we tested regorafenib's effect on the BCL-2 network and the efficacy of BH3-mimetics on HCC treatment.
resultsIn hepatoma cell lines and Hep3B liver spheroids, regorafenib cytotoxicity was potentiated by BCL-xL siRNA transfection or pharmacological inhibition (A-1331852), while BCL-2 antagonism had no effect. Mitochondrial outer membrane permeabilization, cytochrome c release, and caspase-3 activation mediated A-1331852/regorafenib-induced cell death. In a patient-derived xenograft (PDX) HCC model, BCL-xL inhibition stimulated regorafenib activity, drastically decreasing tumor growth. Moreover, regorafenib-resistant HepG2 cells displayed increased BCL-xL and reduced MCL-1 expression, while A-1331852 reinstated regorafenib efficacy in vitro and in a xenograft mouse model. Interestingly, BCL-xL levels, associated with poor prognosis in liver and colorectal cancer, and the BCL-xL/MCL-1 ratio were detected as being increased in HCC patients.
conclusionRegorafenib primes tumor cells to BH3-mimetic-induced cell death, allowing BCL-xL inhibition with A-1331852 or other strategies based on BCL-xL degradation to enhance regorafenib efficacy, offering a novel approach for HCC treatment, particularly for tumors with an elevated BCL-xL/MCL-1 ratio.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.