BMS-345541 targets inhibitor of kappaB kinase and induces apoptosis in melanoma: involvement of nuclear factor kappaB and mitochondria pathways.

Published

Journal Article

PURPOSE: Constitutive 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 DESIGN: Three 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. RESULTS: Inhibition 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. CONCLUSION: BMS-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.

Full Text

Duke Authors

Cited Authors

  • Yang, J; Amiri, KI; Burke, JR; Schmid, JA; Richmond, A

Published Date

  • February 1, 2006

Published In

Volume / Issue

  • 12 / 3 Pt 1

Start / End Page

  • 950 - 960

PubMed ID

  • 16467110

Pubmed Central ID

  • 16467110

International Standard Serial Number (ISSN)

  • 1078-0432

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-05-1220

Language

  • eng

Conference Location

  • United States