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BMS-345541 Targets Inhibitor of B Kinase and Induces Apoptosis in Melanoma: Involvement of Nuclear Factor B and Mitochondria Pathways

Authors' Affiliations: ¹ Veterans Affairs Medical Center and Department of Cancer Biology, Vanderbilt University School of Medicine, ² Meharry Medical College, Nashville, Tennessee, ³ Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey, and ⁴ Department of Vascular Biology and Thrombosis Research, University of Vienna Medical School, Vienna, Austria

Requests for reprints: Ann Richmond, Department of Cancer Biology, 771 PRB, Vanderbilt University School of Medicine, Nashville, TN 37232. Phone: 615-343-7777; Fax: 615-936-2911; E-mail: Ann.Richmond{at}vanderbilt.edu.

Purpose: Constitutive activation of inhibitor of 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 IKKß 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 B (NF-B) signaling and on the apoptosis machinery were investigated.

Results: Inhibition of constitutive IKK activity by BMS-345541 resulted in the reduction of NF-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-B signaling. Therefore, IKK may serve as a potential target for melanoma therapy.

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