BMS-345541 targets inhibitor of κB kinase and induces apoptosis in melanoma:: Involvement of nuclear factor κB and mitochondria pathways

Purpose: Constitutive activation of inhibitor of kappa B 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 IKK 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 kappa B (NF-kappa B) signaling and on the apoptosis machinery were investigated. Results: Inhibition of constitutive IKK activity by BMS-345541 resulted in the reduction of NF-kappa B 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-kappa B signaling. Therefore, IKK may serve as a potential target for melanoma therapy.