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

Yang J, Amiri KI, Burke JR, Schmid JA, Richmond A
Clin Cancer Res. 2006 12 (3 Pt 1): 950-60

PMID: 16467110 · PMCID: PMC2668250 · DOI:10.1158/1078-0432.CCR-05-1220

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.

MeSH Terms (19)

Animals Apoptosis Cell Line, Tumor Cell Proliferation Dose-Response Relationship, Drug Drug Evaluation, Preclinical Humans I-kappa B Kinase Imidazoles In Vitro Techniques Melanoma Mice Mitochondria NF-kappa B Quinoxalines Signal Transduction Structure-Activity Relationship Time Factors Tumor Cells, Cultured

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