ArticleCell death & disease2018
Preclinical evaluation of antitumor activity of the proteasome inhibitor MLN2238 (ixazomib) in hepatocellular carcinoma cells.
Article in Cell death & disease, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 47 citations in OpenAlex.
- A Phase I/II Trial of MEC (Mitoxantrone, Etoposide, Cytarabine) in Combination with Ixazomib for Relapsed Refractory Acute Myeloid Leukemia.Clinical cancer research : an official journal of the American Association for Cancer Research · 2019Trial
- Enhancing schistosomiasis drug discovery approaches with optimized proteasome substrates.Protein science : a publication of the Protein Society · 2025Article
- Post-translational modifications and the reprogramming of tumor metabolism.Discover oncology · 2025Review
- Article
- Ubiquitination in lipid metabolism reprogramming: implications for pediatric solid tumors.Frontiers in immunology · 2025Review
- Ubiquitination and deubiquitination in cancer: from mechanisms to novel therapeutic approaches.Molecular cancer · 2024Review
- Repurposing proteasome inhibitors for improved treatment of triple-negative breast cancer.Cell death discovery · 2024Article
- RNF126, 168 and CUL1: The Potential Utilization of Multi-Functional E3 Ubiquitin Ligases in Genome Maintenance for Cancer Therapy.Biomedicines · 2023Review
- Proteasomal pathway inhibition as a potential therapy for NF2-associated meningioma and schwannoma.Neuro-oncology · 2023Article
- Progress in Anticancer Drug Development Targeting Ubiquitination-Related Factors.International journal of molecular sciences · 2022Review
- Rational drug combination design in patient-derived avatars reveals effective inhibition of hepatocellular carcinoma with proteasome and CDK inhibitors.Journal of experimental & clinical cancer research : CR · 2022Article
- Screening and identification of HTNVVirologica Sinica · 2022Article
- Proteasome inhibitor immunotherapy for the epithelial to mesenchymal transition: assessing the A549 lung cancer cell microenvironment and the role of M1, M2a and M2c 'hydrocortisone-polarised' macrophages.Molecular biology reports · 2022Article
- The anti-tumor effect of proteasome inhibitor MG132 for human adenoid cystic carcinoma: correlate with the emerging role of Nrf2/Keap1 signaling pathway.Head & face medicine · 2022Article
- Endoplasmic Reticulum Stress-Related Signature for Predicting Prognosis and Immune Features in Hepatocellular Carcinoma.Journal of immunology research · 2022Article
- MLN2238 exerts its anti-tumor effectsFrontiers in pharmacology · 2022Article
- Article
- Osteosarcoma in Children: Not Only Chemotherapy.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Research progress on proteasome subunits in regulating occurrence and development of hepatocellular carcinoma.Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2021Review
- Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hepatocellular carcinoma (HCC) is one of the common malignancies and is an increasingly important cause of cancer death worldwide. Surgery, chemotherapy, and radiation therapy extend the 5-year survival limit in HCC patients by only 6%. Therefore, there is a need to develop new therapeutic approaches for the treatment of this disease. The orally bioavailable proteasome inhibitor MLN2238 (ixazomib) has been demonstrated to have anticancer activity. In the present study, we investigated the preclinical therapeutic efficacy of MLN2238 in HCC cells through in vitro and in vivo models, and examined its molecular mechanisms of action. MLN2238 inhibited cell viability in human HCC cells HepG2, Hep3B, and SNU475 in a time- and dose-dependent manner. Flow cytometry analysis demonstrated that MLN2238 induced G2/M cell cycle arrest and cellular apoptosis in HCC cells. Cell cycle arrest was associated with increased expression levels of p21 and p27. MLN2238-induced apoptosis was confirmed by caspase-3/7 activation, PARP cleavage and caspase-dependent β-catenin degradation. In addition, MLN2238 activated ER stress genes in HCC cells and increased the expression of the stress-inducible gene nuclear protein-1. Furthermore, MLN2238 treatment induced upregulation of myeloid cell leukemia-1 (Mcl-1) protein, and Mcl-1 knockdown sensitized HCC cells to MLN2238 treatment, suggesting the contribution of Mcl-1 expression to MLN2238 resistance. This result was also confirmed using the novel Mcl-1 small molecule inhibitor A1210477. Association of A1210477 and MLN2238 determined synergistic antitumor effects in HCC cells. Finally, in vivo orally administered MLN2238 suppressed tumor growth of Hep3B cells in xenograft models in nude mice. In conclusion, our results offer hope for a new therapeutic opportunity in the treatment of HCC patients.
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