Systemic targeting inhibitor of kappa B kinase inhibits melanoma tumor growth

Constitutive activation of nuclear factor-kappa B (NF-kappa B) has been directly implicated in tumorigenesis of various cancer types, including melanoma. Inhibitor of kappa B kinase (IKK) functions as a major mediator of NF-kappa 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-kappa 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-kappa B nuclear activation and ReIA phosphorylation. Based on this result, we developed a double hammerhead ribozyme long-term expression system to silence either IKK alpha or IKK beta. 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 IKK beta significantly reduces the growth of the melanoma lesions and knockdown of either IKK alpha or IKK beta prolongs the life span of immunocompetent mice.