In vitro and In vivo Activity of the Nuclear Factor-κB Inhibitor Sulfasalazine in Human Glioblastomas

Abstract

Glioblastomas, the most common primary brain cancers, respond poorly to current treatment modalities and carry a dismal prognosis. In this study, we demonstrated that the transcription factor nuclear factor (NF)-B is constitutively activated in glioblastoma surgical samples, primary cultures, and cell lines and promotes their growth and survival. Sulfasalazine, an anti-inflammatory drug that specifically inhibits the activation of NF-B, blocked the cell cycle and induced apoptosis in several glioblastoma cell lines and primary cultures, as did gene therapy with a vector encoding a super-repressor of NF-B. In vivo, sulfasalazine also significantly inhibited the growth of experimental human glioblastomas in nude mice brains. Given the documented safety of sulfasalazine in humans, these results may lead the way to a new class of glioma treatment.

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

“…Interestingly, celecoxib can induce apoptosis in a variety of leukemia cell lines in a manner that is correlated with the suppression of NF-kB activation (Subhashini et al, 2005). Sulfasalazine, another NSAID that blocks NF-kB activation, has been shown to inhibit growth and induce apoptosis in both glioblastoma cell lines and primary cultures to a similar level as obtained by the expression of a degradation-resistant super-repressor form of IkBa (Robe et al, 2004). Thus, it is possible that NSAIDs might prevent cancer progression through the inhibition of NF-kB.…”

Roles for NF-κB in nerve cell survival, plasticity, and disease

“…55,56 In most cases, however, it remains unknown how NF-kB activation influences the oncogenic potential of the tumor. NF-kB-regulated gene products associated with tumor progression and metastasis include intercellular adhesion molecule-1 (ICAM-1), matrix protein tenascin C, vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), cyclooxygenase-2 (COX-2), and matrix metalloprotease 9 (MMP9).…”

Signal Transducer and Activator of Transcription-3: A Molecular Hub for Signaling Pathways in Gliomas

“…Taken together, these observations indicate that down-regulation of PIAS3 may cause or exacerbate gliomagenesis, and that reintroduction of PIAS3 could potentially inhibit glioblastoma progression. Although PIAS3 was first described as a negative regulator of STAT-3 transcriptional activity, it is now known to also modulate nuclear factor-nB, phosphoinositide-3 kinase, and transforming growth factor-h signaling pathways, all of which are associated with poor prognosis in glioblastoma patients (51,(85)(86)(87)(88)(89)(90). In vitro, PIAS3 down-regulated the nuclear factor-nB pathway by interacting with p65 and repressing its transcriptional activity (91).…”