ArticleClinical cancer research : an official journal of the American Association for Cancer Research2006
BMS-345541 targets inhibitor of kappaB kinase and induces apoptosis in melanoma: involvement of nuclear factor kappaB and mitochondria pathways.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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74 citing papers in PubMed, 165 citations in OpenAlex.
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- Canonical and noncanonical NF-κB signaling in uveal melanoma: mechanisms, microenvironment, and therapeutic modulation.Medical hypothesis, discovery & innovation ophthalmology journal · 2025Review
- Progressive senescence programs induce intrinsic vulnerability to aging-related female breast cancer.Nature communications · 2024Article
- A novel 2-iminobenzimidazole compound, XYA1353, displays in vitro and in vivo anti-myeloma activity via targeting NF-κB signaling.Molecular and cellular biochemistry · 2024Article
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- Application of Single-Cell and Spatial Omics in Musculoskeletal Disorder Research.International journal of molecular sciences · 2023Review
- Hyperforin Elicits Cytostatic/Cytotoxic Activity in Human Melanoma Cell Lines, Inhibiting Pro-Survival NF-κB, STAT3, AP1 Transcription Factors and the Expression of Functional Proteins Involved in Mitochondrial and Cytosolic Metabolism.International journal of molecular sciences · 2023Article
- Small-molecule IKKβ activation modulator (IKAM) targets MAP3K1 and inhibits pancreatic tumor growth.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Dihydronicotinamide Riboside Is a Potent NADFrontiers in immunology · 2022Article
- Molecular Analysis of Elements of Melanoma Insensitivity to TCR-Engineered Adoptive Cell Therapy.International journal of molecular sciences · 2021Review
- Low-intensity ultrasound inhibits melanoma cell proliferation in vitro and tumor growth in vivo.Journal of medical ultrasonics (2001) · 2021Article
- Molecular Markers and Targets in Melanoma.Cells · 2021Review
- Aneuploid senescent cells activate NF-κB to promote their immune clearance by NK cells.EMBO reports · 2021Article
- Inhibition of kinase IKKβ suppresses cellular abnormalities induced by the human papillomavirus oncoprotein HPV 18E6.Scientific reports · 2021Article
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14 more citing papers are in PubMed but not listed here.
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5 authors at 3 institutions in 2 countries.
Funding
Abstract
purposeConstitutive activation of inhibitor of kappaB kinase (IKK) confers melanoma resistance to apoptosis and chemotherapy. Whether IKK is able to serve as a therapeutic target in melanoma is unknown. We explored the possibility of exploiting IKK as a therapeutic target in melanoma by using BMS-345541, a novel compound with a highly selective IKKbeta inhibitory activity, to trigger melanoma cell apoptosis. EXPERIMENTAL
designThree human melanoma cell lines (SK-MEL-5, Hs 294T, and A375), all of which have high constitutive IKK activities, served as in vitro and in vivo melanoma models for treatment with BMS-345541. Two known antitumor drugs (temozolomide and bortezomib) were used as parallel controls for evaluation of the therapeutic efficiency and toxicity of BMS-345541. The effects of BMS-345541 on nuclear factor kappaB (NF-kappaB) signaling and on the apoptosis machinery were investigated.
resultsInhibition of constitutive IKK activity by BMS-345541 resulted in the reduction of NF-kappaB activity, CXCL1 chemokine secretion by cultured melanoma cells and melanoma cell survival in vitro and in vivo. The effect of BMS-345541 on tumor cell growth was through mitochondria-mediated apoptosis, based on the release of apoptosis-inducing factor, dissipation of mitochondrial membrane potential, and reduced ratio of B cell lymphoma gene-2 (Bcl-2)/Bcl-associated X protein (Bax) in mitochondria. The BMS-345541 execution of apoptosis was apoptosis-inducing factor-dependent, but largely caspase-independent.
conclusionBMS-345541 down-regulation of IKK activity results in mitochondria-mediated apoptosis of tumor cells because the programmed cell death machinery in melanoma cells is highly regulated by NF-kappaB signaling. Therefore, IKK may serve as a potential target for melanoma therapy.
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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.