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Systemic Targeting Inhibitor of B Kinase Inhibits Melanoma Tumor Growth

¹ Department of Cancer Biology, Vanderbilt University School of Medicine and Veterans Affairs Medical Center, Nashville, Tennessee and ² Department of Pathology, Department of Biochemistry and Molecular Biology, The Gittlen Cancer Research Institute, Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania

Requests for reprints: Ann Richmond, Department of Cancer Biology, Vanderbilt University School of Medicine, 771 PRB, 21st Avenue South at Pierce, Nashville, TN 37232. Phone: 615-343-7777; Fax: 615-936-2911; E-mail: ann.richmond{at}vanderbilt.edu.

Constitutive activation of nuclear factor-B (NF-B) has been directly implicated in tumorigenesis of various cancer types, including melanoma. Inhibitor of B kinase (IKK) functions as a major mediator of NF-B activation. Thus, development of an IKK-specific inhibitor has been a high priority, although it remains unclear whether systemic inhibition of IKK will provide therapeutic benefit. In this study, we show that inhibition of NF-B activity in melanocytes that are persistently expressing an active H-Ras^V12 gene and are deficient in the tumor suppressors inhibitor A of cyclin-dependent kinase 4/alternative reading frame results in reduction of melanoma tumor growth in vivo. This effect is, at least in part, via regulation of NF-B nuclear activation and RelA phosphorylation. Based on this result, we developed a double hammerhead ribozyme long-term expression system to silence either IKK or IKKß. The ribozymes were placed in an EBV construct and delivered i.v. to nude mice bearing melanoma lesions, which developed after i.v. injection of H-Ras–transformed melanoma cells. Our in vivo data show that knockdown of endogenous IKKß significantly reduces the growth of the melanoma lesions and knockdown of either IKK or IKKß prolongs the life span of immunocompetent mice. [Cancer Res 2007;67(7):3127–34]

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