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

Abstract

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-γ plus TNF-α, we hypothesized that bortezomib also could sensitize these cells to IFN-γ plus TNF-α. We demonstrate for the first time that bortezomib not only up-regulates the expression of receptors for IFN-γ and TNF-α on both TBJ neuroblastoma and EOMA endothelial cell lines, but also markedly enhances the sensitivity of these cells to apoptosis induced by IFN-γ plus TNF-α in vitro. Furthermore, bortezomib enhances the in vivo antitumor efficacy of IFN-γ/TNF-α-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.

Evaluation of Long-Term Toxicity of Ad/hIFN-γ, an Adenoviral Vector Encoding the Human Interferon-γGene, in Nonhuman Primates

“…This latter effect increases the susceptibility of tumor antigens processed by antigenpresenting cells (APCs) then submitted to CD8 ϩ cytotoxic T cells for lysis of tumor cells (Carrel et al, 1985;Guadagni et al, 1994). IFN-␥ can exert direct antiproliferative and antimetabolic effects on a variety of tumor cells and it synergizes with tumor necrosis factor (TNF)-␣ and -␤ in inhibiting the proliferation of various cell types (Farrar and Schreiber, 1993;Ikeda et al, 2002;Khan et al, 2006). Other evidence indicates that some of the antitumor effects of IFN-␥ may be mediated through a mechanism involving inhibition of angiogenesis within the tumor (Ribatti et al, 2006).…”

“…Extensive research has demonstrated that IFN-␥ also plays a vital role in antitumor responses (Ikeda et al, 2002;Khan et al, 2006). In this study, the potential tox- icity of Ad/hIFN-␥ was evaluated in cynomolgus macaques before translating the delivery approach to the clinic.…”

Bortezomib augments lymphocyte stimulatory cytokine signaling in the tumor microenvironment to sustain CD8+T cell antitumor function

“…Unlike other non-boronic acid proteasome inhibitors, the boronic acid moiety of bortezomib prevents it from being transported out of the cell by the multidrug resistance system [15]. It has been observed that bortezomib administration enhances the expression of TNF-R1 and IFN-γ-Rα in TBJ neuroblastoma cells [16] suggesting that bortezomib may potentially modulate the tumor microenvironment. In our previous studies, we showed that bortezomib can also sensitize various mouse and human solid tumor cells to apoptosis by tumor necrosis factor family members [17, 18].…”

Powerful inner/outer controlled multi-target magnetic nanoparticle drug carrier prepared by liquid photo-immobilization

“…On the other hand, Interferon-γ (IFN-γ) is an important cytokine which can enhance the antitumor effects of antimetabolite on cancer cells and induce or modulate apoptosis either as a single agent or in combination with tumor necrosis factor-α (TNF-α), which is another kind of cytokine produced by activated monocytes and phagocytes that could effectively kill many sorts of cancer cells both in vivo and in vitro 32333435. In our earlier works, co-immobilized TNF-α plus IFN-γ was prepared by this approach to synthesize a series of polymeric anti-cancer drugs.…”