Bay 11-7085

BAY 11-7085 is a soluble inhibitor of NK-κB activation [1].

BAY 11-7085 has been reported to inhibit cell proliferation and induce cell apoptosis in a variety of cells. In addition, BAY 11-7085 has been revealed to inhibit DNA synthesis of ECSCs and induce the G0/G1 phase cell cycle arrest. Moreover, BAY 11-7085 has shown to induce cell apoptosis by inhibiting anti-apoptotic proteins. After treatment with BAY 11-7085, down-regulations of the B-cell lymphoma/leukemia-2 (Bcl-2) and Bcl-XL expressions with simultaneous activations of caspase-3, caspase-8, and caspase-9 were observed in ECSCs. [1].

References:
[1]Nasu K1, Nishida M, Ueda T, Yuge A, Takai N, Narahara H. Application of the nuclear factor-kappaB inhibitor BAY 11-7085 for the treatment of endometriosis: an in vitro study. Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E16-23

Application of the nuclear factor-kappaB inhibitor BAY 11-7085 for the treatment of endometriosis: an in vitro study.[Pubmed:16896168]

Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E16-23.

Most of the current medical treatments for endometriosis aim to downregulate estrogen activity. However, a high recurrence rate after medical treatment has been the most significant problem. Bay 11-7085, a soluble inhibitor of NK-kappaB activation, has been shown to inhibit cell proliferation and induce apoptosis of a variety of cells. To examine the potential application of Bay 11-7085 in the treatment of endometriosis, we investigated the effects of this agent on the cell proliferation and apoptosis of cultured ovarian endometriotic cyst stromal cells (ECSCs) by a modified methylthiazole tetrazolium assay, a 5-bromo-2'-deoxyuridine incorporation assay, and internucleosomal DNA fragmentation assays. The effect of Bay 11-7085 on the cell cycle of ECSCs was also determined by flow cytometry. The expression of apoptosis-related molecules was examined in ECSCs with Western blot analysis. Bay 11-7085 significantly inhibited the cell proliferation and DNA synthesis of ECSCs and induced apoptosis and the G0/G1 phase cell cycle arrest of these cells. Additionally, downregulation of the B-cell lymphoma/leukemia-2 (Bcl-2) and Bcl-X(L) expression with simultaneous activation of caspase-3, -8, and -9 was observed in ECSCs after treatment with Bay 11-7085. These results suggest that Bay 11-7085 induces apoptosis of ECSCs by suppressing antiapoptotic proteins, and that caspase-3-, -8-, and -9-mediated cascades are involved in this mechanism. Therefore, Bay 11-7085 could be used as a therapeutic agent for the treatment of endometriosis.

BAY 11-7085 induces glucocorticoid receptor activation and autophagy that collaborate with apoptosis to induce human synovial fibroblast cell death.[Pubmed:26993765]

Oncotarget. 2016 Apr 26;7(17):23370-82.

Inhibition of proapoptotic pathways in synovial fibroblasts is one of the major causes of synovial proliferation and hyperplasia in rheumatic diseases. We have shown previously that NF-kappaB inhibitor Bay 11-7085, through inactivation of PPAR-gamma, induces apoptosis in human synovial fibroblasts. In this work we showed that Bay 11-7085 induced autophagy that preceded Bay 11-7085-induced apoptosis. Of interest, Bay 11-7085 induced Serine 211 phosphorylation and degradation of glucocorticoid receptor (GR). Glucocorticoid prednisolone induced both activation and degradation of GR, as well as autophagy in synovial fibroblasts. Bay 11-7085-induced cell death was significantly decreased with glucocorticoid inhibitor mifepristone and with inhibitors of autophagy. Both Bay 11-7085-induced autophagy and GR activation were down regulated with PPAR-gamma agonist, 15d-PGJ2 and MEK/ERK inhibitor UO126. Inhibition of autophagy markedly decreased endogenous and Bay 11-7085-induced ERK phosphorylation, suggesting a positive feed back loop between ERK activation and autophagy in synovial fibroblasts. Co-transfection of MEK1 with PPAR-gamma1 in HEK293 cells caused known inhibitory phosphorylation of PPAR-gamma1 (Serine 112) and enhanced GR degradation, in the absence or presence of prednisolone. Furthermore, GR was both phosphorylated on Serine 211 and down regulated in synovial fibroblasts during serum starvation induced autophagy. These results showed that GR activation and PPAR-gamma inactivation mediated Bay 11-7085-induced autophagy.

Cytotoxicity of NF-kappaB inhibitors Bay 11-7085 and caffeic acid phenethyl ester to Ramos and other human B-lymphoma cell lines.[Pubmed:17889719]

Exp Hematol. 2007 Oct;35(10):1495-509.

OBJECTIVE: The viability of normal and malignant B-cells was shown to depend on the constitutive activation of the nuclear factor (NF)- kappaB pathway. Thus, attempts to find efficient inhibitors of NF-kappaB play a central role in the search for novel anti-B lymphoma therapies. We studied the effects of two NF-kappaB inhibitors, Bay 11-7085 (BAY) and caffeic acid phenethyl ester (CAPE), on the viability of B-lymphoma cell lines. METHODS: We investigated the mechanism(s) of the cytotoxic effect of the NF-kappaB inhibitors, BAY, and CAPE on human-lymphoma and nonhematological cell lines. RESULTS: BAY and CAPE were shown to kill Ramos-Burkitt's lymphoma cells with IC(50) values of 0.7 microM and 4 microM, respectively. The rapid killing by BAY (h) vs the slower killing by CAPE (1-3 days), and their differential effects on the stages of the cell cycle, indicated that these drugs induce killing by different mechanisms. BAY and CAPE induced a loss of the cytoplasmic compartment and generated pyknotic nuclei, which lacked nuclear or nucleosomal fragmentation, features characteristic of necrosis rather than apoptosis. BAY also induced a rapid loss of the mitochondrial potential and rapid inhibition of p65 NF-kappaB binding to its kappaB motif without reducing the level of nuclear p65. CONCLUSION: Our results indicate that BAY causes a necrotic rather than apoptotic cell death, either through its effect on the NF-kappaB pathway and/or by affecting additional molecular targets. The high sensitivity of B-lymphoma cell lines to the cytotoxicity of BAY, justify further research to explore its potential therapeutic effect on human B lymphomas.

Peroxisome proliferator-activated receptor-gamma1 is dephosphorylated and degraded during BAY 11-7085-induced synovial fibroblast apoptosis.[Pubmed:16766531]

J Biol Chem. 2006 Aug 11;281(32):22597-604.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) plays a central role in whole body metabolism by regulating adipocyte differentiation and energy storage. Recently, however, PPAR-gamma has also been demonstrated to affect proliferation, differentiation, and apoptosis of different cell types. As we have previously shown that Bay 11-7085-induced synovial fibroblast apoptosis is prevented by PPAR-gamma agonist 15d-PGJ2; the expression of PPAR-gamma in these cells was studied. Both PPAR-gamma1 and PPAR-gamma2 isoforms were cloned from synovial fibroblast RNA, but only PPAR-gamma1 was detected by Western blot, showing constitutive nuclear expression. Within minutes of Bay 11-7085 treatment, a PPAR-gamma1-specific band was shifted into a form of higher mobility, suggesting dephosphorylation, as confirmed by phosphatase treatment of cell extracts. Of interest, Bay 11-7085-induced PPAR-gamma1 dephosphorylation was followed by PARP and caspase-8 cleavage as well as by PPAR-gamma1 protein degradation. PPAR-gamma1 dephosphorylation was followed by the loss of PPAR-DNA binding activity ubiquitously present in synovial fibroblast nuclear extracts. Unlike the phosphorylated form, dephosphorylated PPAR-gamma1 was found in insoluble membrane cell fraction and was not ubiquitinated before degradation. PPAR-gamma1 dephosphorylation coincided with ERK1/2 phosphorylation that accompanies Bay 11-7085-induced synovial fibroblasts apoptosis. 15d-PGJ2, PGD2, and partially UO126, down-regulated ERK1/2 phosphorylation, protected cells from Bay 11-7085-induced apoptosis, and reversed both PPAR-gamma dephosphorylation and degradation. Furthermore, PPAR-gamma antagonist BADGE induced PPAR-gamma1 degradation, ERK1/2 phosphorylation, and synovial fibroblasts apoptosis. The results presented suggest an anti-apoptotic role for PPAR-gamma1 in synovial fibroblasts. Since apoptotic marker PARP is cleaved after PPAR-gamma1 dephosphorylation but before PPAR-gamma1 degradation, dephosphorylation event might be enough to mediate Bay 11-7085-induced apoptosis in synovial fibroblasts.

Nuclear factor kappaB inhibitors induce adhesion-dependent colon cancer apoptosis: implications for metastasis.[Pubmed:12460901]

Cancer Res. 2002 Dec 1;62(23):6870-8.

The transcription factor nuclear factor kappaB (NFkappaB) is constitutively active in many types of cancercells and regulates the expression of several antiapoptotic genes. Previous studies demonstrated a role for the inhibition of NFkappaB in cancer therapyusing a transgenic approach in mice. We found that NFkappaB was transiently activated much greater than background constitutive levels during colon cancer cell readhesion, which rendered the readhering colon cancer cells exquisitely susceptible to apoptosis in the presence of soluble NFkappaB inhibitors. These compounds greatly reduced colon cancer cell implantation in an in vivo seeding model of metastasis. The ability of soluble NFkappaB inhibitors to significantly induce apoptosis of readherent colon cancer cells makes them prospective candidates for preventing colon cancer metastasis.

An IkappaBalpha inhibitor causes leukemia cell death through a p38 MAP kinase-dependent, NF-kappaB-independent mechanism.[Pubmed:11507084]

Cancer Res. 2001 Aug 15;61(16):6290-6.

Treatment of U937 cells with an IkappaBalpha phosphorylation inhibitor, Bay 11-7085, induced a rapid phosphorylation of p38 mitogen-activated protein (MAP) kinase, significant apoptosis, extensive necrosis, and a weak phosphorylation of MAP kinase kinase. Bay 11-7085 had no effect on the basal levels of phosphorylated IkappaBalpha but completely inhibited phorbol 12-myristate 13-acetate-induced phosphorylation of IkappaBalpha. Although Bay 11-7085 prevented phorbol 12-myristate 13-acetate-induced NF-kappaB nuclear translocation, SN50, a specific inhibitor of nuclear translocation and function of NF-kappaB, did not induce any significant nuclear/DNA fragmentation, caspase 3 activation, or cell death. The p38 MAP kinase-specific inhibitor, SB203580, completely inhibited the phosphorylation of p38 MAP kinase and significantly decreased Bay 11-7085-induced apoptosis. In contrast, the MAP kinase kinase-specific inhibitor PD98059 had no effect on Bay 11-7085-induced apoptosis. Caspase-specific inhibitor, z-Val-Ala-Asp-fluoromethyl ketone prevented Bay 11-7085-induced activation of caspase 3 but was not able to block Bay 11-7085-induced phosphorylation of p38 MAP kinase. These data suggest that Bay 11-7085 induces apoptosis through a p38 MAP kinase-dependent, NF-kappaB-independent mechanism.

Novel inhibitors of cytokine-induced IkappaBalpha phosphorylation and endothelial cell adhesion molecule expression show anti-inflammatory effects in vivo.[Pubmed:9261113]

J Biol Chem. 1997 Aug 22;272(34):21096-103.

We have identified two compounds that inhibit the expression of endothelial-leukocyte adhesion molecules intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin. These compounds act by inhibiting tumor necrosis factor-alpha-induced phosphorylation of IkappaB-alpha, resulting in decreased nuclear factor-kappaB and decreased expression of adhesion molecules. The effects on both IkappaB-alpha phosphorylation and surface expression of E-selectin were irreversible and occurred at an IC50 of approximately 10 microM. These agents selectively and irreversibly inhibited the tumor necrosis factor-alpha-inducible phosphorylation of IkappaB-alpha without affecting the constitutive IkappaB-alpha phosphorylation. Although these compounds exhibited other activities, including stimulation of the stress-activated protein kinases, p38 and JNK-1, and activation of tyrosine phosphorylation of a 130-140-kDa protein, these effects are probably distinct from the effects on adhesion molecule expression since they were reversible. One compound was evaluated in vivo and shown to be a potent anti-inflammatory drug in two animal models of inflammation. The compound reduced edema formation in a dose-dependent manner in the rat carrageenan paw edema assay and reduced paw swelling in a rat adjuvant arthritis model. These studies suggest that inhibitors of cytokine-inducible IkappaBalpha phosphorylation exert anti-inflammatory activity in vivo.