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Proteasome Inhibition to Maximize the Apoptotic Potential of Cytokine Therapy for Murine Neuroblastoma Tumors¹

Tahira Khan^*, Jimmy K. Stauffer^*, Rebecca Williams^*, Julie A. Hixon^*, Rosalba Salcedo, Erin Lincoln, Timothy C. Back, Douglas Powell, Stephen Lockett, Alma C. Arnold, Thomas J. Sayers and Jon M. Wigginton^2,*

^* Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702; Intramural Research Support Program, SAIC-Frederick, Frederick, MD 21702; Image Analysis Laboratory, Science Applications International Corporation-Frederick, Frederick, MD 21702; and Data Management Services, National Cancer Institute at Frederick, Frederick, MD 21702

Human neuroblastomas possess several mechanisms of self-defense that may confer an ability to resist apoptosis and contribute to the observed difficulty in treating these tumors in the clinical setting. These molecular alterations may include defects in proapoptotic genes as well as the overexpression of prosurvival factors, such as Akt among others. As a key regulator of the turnover of proteins that modulate the cell cycle and mechanisms of apoptosis, the proteasome could serve as an important target for the treatment of neuroblastoma. The present studies provide the first evidence that bortezomib, a newly approved inhibitor of proteasome function, inhibits phosphorylation of Akt, induces the translocation of proapoptotic Bid, and potently enhances the apoptosis of murine neuroblastoma tumor cells in vitro. Furthermore, in that inhibitors of the Akt pathway can sensitize otherwise resistant TBJ/Neuro-2a cells to apoptosis induced by IFN- plus TNF-, we hypothesized that bortezomib also could sensitize these cells to IFN- plus TNF-. We demonstrate for the first time that bortezomib not only up-regulates the expression of receptors for IFN- and TNF- on both TBJ neuroblastoma and EOMA endothelial cell lines, but also markedly enhances the sensitivity of these cells to apoptosis induced by IFN- plus TNF- in vitro. Furthermore, bortezomib enhances the in vivo antitumor efficacy of IFN-/TNF--inducing cytokines, including both IL-2 and IL-12 in mice bearing well-established primary and/or metastatic TBJ neuroblastoma tumors. Collectively, these studies suggest that bortezomib could be used therapeutically to enhance the proapoptotic and overall antitumor activity of systemic cytokine therapy in children with advanced neuroblastoma.

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