Proteasome Inhibitor PS-341 Induces Apoptosis in Cisplatin-resistant Squamous Cell Carcinoma Cells by Induction of Noxa

Bortezomib induces apoptosis via Bim and Bik up-regulation and synergizes with cisplatin in the killing of head and neck squamous cell carcinoma cells

“…Others have reported that bortezomib induces generation of reactive oxygen species in HNSCC cells and activation of the unfolded protein response pathway (27). Activation of this pathway was associated with phosphorylation of the stress kinase PERK, induction of ATF-4 transcription factor, and up-regulation of Noxa (32). Inhibition of Noxa up-regulation in these cells modestly inhibited bortezomib-induced cell death (32).…”

“…Activation of this pathway was associated with phosphorylation of the stress kinase PERK, induction of ATF-4 transcription factor, and up-regulation of Noxa (32). Inhibition of Noxa up-regulation in these cells modestly inhibited bortezomib-induced cell death (32). Thus, up-regulation of Bik, Bim, and Noxa all may play a role in the killing of HNSCC cells by bortezomib.…”

“…Bortezomib also promotes generation of reactive oxygen species in HNSCC, and inhibition of reactive oxygen species production attenuated bortezomib-induced cell death (27). In addition, HNSCC cells up-regulate Noxa following bortezomib treatment, and inhibition of Noxa up-regulation using small interfering RNA (siRNA) was found to moderately suppress cell death (32). Treatment of HNSCC tumors with bortezomib in vivo results in suppression of nuclear factor-nB target genes and important proangiogenic cytokines including interleukin-6, GRO-1, and vascular endothelial growth factor (26,28).…”

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

“…Investigation of the mechanisms of action of bortezomib has determined that it has pleiotropic cellular effects that contribute to its anti-myeloma activity including inhibition of nuclear factor kB, stimulation of ER stress, induction of the pro-apoptotic Bcl-2 homology 3 (BH3)-only family member NOXA, inhibition of tumor angiogenesis and the disruption of survival signaling cascades (Nawrocki et al, 2002;Hideshima et al, 2003;Qin et al, 2005). Bortezomib-mediated proteasomal inhibition results in the accumulation of large quantities of ubiquitinated protein aggregates that induce ER stress, which has been reported to be a significant contributor to bortezomib's anti-cancer activity (Nawrocki et al, 2005a(Nawrocki et al, , b, 2008Fribley et al, 2006;Carew et al, 2010). As such, we posit that agents with the ability to increase ER stress will possess strong antimyeloma activity and augment bortezomib-mediated cell death.…”

Therapeutic window for melanoma treatment provided by selective effects of the proteasome on Bcl-2 proteins

“…6 Genetic and functional studies in melanoma and other cancers have identified the proapoptotic protein NOXA as an early target of bortezomib. [5][6][7][8]10,11 The specific contribution of NOXA to cell death may be context dependent, 12 but a main role of this protein is to neutralize the antiapoptotic factor Mcl-1. 13,14 Intriguingly, while a 5-to 20-fold accumulation of NOXA in melanoma cells can be visualized as early as 6 h posttreatment with bortezomib, caspase activation may not be detected until 12-48 h later.…”