NEMO-binding domain peptide inhibits proliferation of human melanoma cells

Ianaro, Angela; Tersigni, Mariaroberta; Belardo, Giuseppe; Martino, Silvana; Napolitano, Maria; Palmieri, Giuseppe; Sini, Maria Cristina; Maio, Anna De; Ombra, Maria Neve; Gentilcore, Giusy; Capone, Mariaelena; Ascierto, MariaLibera; Satriano, Rocco A.; Farina, Biancamaria; Faraone-Mennella, Maria Rosaria; Ascierto, Paolo A.; Ialenti, Armando

doi:10.1016/j.canlet.2008.09.038

Cited by 31 publications

(30 citation statements)

References 19 publications

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“…Recent reports have shown that IKK is constitutively active in many cancers, including melanomas (49–51). For melanomas, silencing IKK activation results in their apoptotic cell death.…”

Section: Discussionmentioning

confidence: 99%

The MC159 Protein from the Molluscum Contagiosum Poxvirus Inhibits NF-κB Activation by Interacting with the IκB Kinase Complex

Randall

Jokela

Shisler

2012

The Journal of Immunology

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Molluscum contagiosum virus (MCV) causes persistent neoplasms in healthy and immunocompromised people. Its ability to persist likely is due to its arsenal of viral immune evasion proteins. For example, the MCV MC159 protein inhibits TNFR1-induced NF-κB activation and apoptosis. The MC159 protein is a viral FLIP and, as such, possesses two tandem death effector domains (DEDs). We show here that, in HEK293T cells, the expression of wild-type MC159 or a mutant MC159 protein containing the first DED (MC159 A) inhibited TNF-induced NF-κB, or NF-κB activated by PMA or MyD88 over-expression, whereas a mutant protein lacking the first DED (MC159 B) did not. We hypothesized that the MC159 protein targeted the IKK complex to inhibit these diverse signaling events. Indeed, the MC159 protein, but not MC159 B, co-immunoprecipitated with IKKγ. MC159 co-immunoprecipitated with IKKγ when using MEFs lacking either IKKα or IKKβ, suggesting that the MC159 protein interacted directly with IKKγ. MC159-IKKγ co-immunoprecipitations were detected during infection of cells with either MCV isolated from human lesions or with a recombinant MC159-expressing vaccinia virus. MC159 also interacts with TRAF2, a signaling molecule involved in NF-κB activation. However, mutational analysis of MC159 failed to reveal a correlation between MC159-TRAF2 interactions and MC159’s inhibitory function. We propose that MC159-IKK interactions, but not MC159-TRAF2 interactions, are responsible for inhibiting NF-κB activation.

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“…Recent reports have shown that IKK is constitutively active in many cancers, including melanomas (49–51). For melanomas, silencing IKK activation results in their apoptotic cell death.…”

Section: Discussionmentioning

confidence: 99%

The MC159 Protein from the Molluscum Contagiosum Poxvirus Inhibits NF-κB Activation by Interacting with the IκB Kinase Complex

Randall

Jokela

Shisler

2012

The Journal of Immunology

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“…Interestingly, NBD peptide does not block basal NF-κB activity and following systemic administration, it safely and effectively ameliorates disease in multiple rodent models of acute and chronic inflammation [16]–[20]. NBD peptide also inhibits constitutive NF-κB activity in malignant cell lines derived from many different cancer types, including ABC-DLBCL resulting in increased sensitization to chemotherapeutic agents and increased apoptosis [21]–[26]. Given these findings, NBD peptide may represent a safe and effective therapy either alone or in combination with cytotoxic agents for patients with treatment-naïve or refractory ABC-DLBCL.…”

Section: Introductionmentioning

confidence: 99%

A Phase I Clinical Trial of Systemically Delivered NEMO Binding Domain Peptide in Dogs with Spontaneous Activated B-Cell like Diffuse Large B-Cell Lymphoma

Ndikuyeze

Gaurnier-Hausser

Patel³

et al. 2014

PLoS ONE

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Activated B-Cell (ABC) Diffuse Large B-Cell Lymphoma (DLBCL) is a common, aggressive and poorly chemoresponsive subtype of DLBCL, characterized by constitutive canonical NF-κB signaling. Inhibition of NF-κB signaling leads to apoptosis of ABC-DLBCL cell lines, suggesting targeted disruption of this pathway may have therapeutic relevance. The selective IKK inhibitor, NEMO Binding Domain (NBD) peptide effectively blocks constitutive NF-κB activity and induces apoptosis in ABC-DLBCL cells in vitro. Here we used a comparative approach to determine the safety and efficacy of systemic NBD peptide to inhibit constitutive NF-κB signaling in privately owned dogs with spontaneous newly diagnosed or relapsed ABC-like DLBCL. Malignant lymph nodes biopsies were taken before and twenty-four hours after peptide administration to determine biological effects. Intravenous administration of <2 mg/kg NBD peptide was safe and inhibited constitutive canonical NF-κB activity in 6/10 dogs. Reductions in mitotic index and Cyclin D expression also occurred in a subset of dogs 24 hours post peptide and in 3 dogs marked, therapeutically beneficial histopathological changes were identified. Mild, grade 1 toxicities were noted in 3 dogs at the time of peptide administration and one dog developed transient subclinical hepatopathy. Long term toxicities were not identified. Pharmacokinetic data suggested rapid uptake of peptide into tissues. No significant hematological or biochemical toxicities were identified. Overall the results from this phase I study indicate that systemic administration of NBD peptide is safe and effectively blocks constitutive NF-κB signaling and reduces malignant B cell proliferation in a subset of dogs with ABC-like DLBCL. These results have potential translational relevance for human ABC-DLBCL.

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“…Ianaro et al previously reported that treatment of A375 cells with Antp-NBD decreased the NF- κ B activity and induced growth arrest and apoptosis. 47 …”

Section: Resultsmentioning

confidence: 99%

Cell-Permeable Bicyclic Peptidyl Inhibitors against NEMO-IκB Kinase Interaction Directly from a Combinatorial Library

et al. 2018

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Macrocyclic peptides are capable of binding to flat protein surfaces such as the interfaces of protein–protein interactions with antibody-like affinity and specificity, but generally lack cell permeability in order to access intracellular targets. In this work, we designed and synthesized a large combinatorial library of cell-permeable bicyclic peptides, in which the first ring consisted of randomized peptide sequences for potential binding to a target of interest, while the second ring featured a family of different cell-penetrating motifs, for both cell penetration and target binding. The library was screened against the IκB kinase α/β (IKKα/β)-binding domain of NF-κB essential modulator (NEMO), resulting in the discovery of several cell-permeable bicyclic peptides, which inhibited the NEMO-IKKβ interaction with low μM IC50 values. Further optimization of one of the hits led to a relatively potent and cell-permeable NEMO inhibitor (IC50 = 1.0 μM), which selectively inhibited canonical NF-κB signaling in mammalian cells and the proliferation of cisplatin-resistant ovarian cancer cells. The inhibitor provides a useful tool for investigating the biological functions of NEMO/NF-κB and a potential lead for further development of a novel class of anti-inflammatory and anticancer drugs.

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NEMO-binding domain peptide inhibits proliferation of human melanoma cells

Cited by 31 publications

References 19 publications

The MC159 Protein from the Molluscum Contagiosum Poxvirus Inhibits NF-κB Activation by Interacting with the IκB Kinase Complex

The MC159 Protein from the Molluscum Contagiosum Poxvirus Inhibits NF-κB Activation by Interacting with the IκB Kinase Complex

A Phase I Clinical Trial of Systemically Delivered NEMO Binding Domain Peptide in Dogs with Spontaneous Activated B-Cell like Diffuse Large B-Cell Lymphoma

Cell-Permeable Bicyclic Peptidyl Inhibitors against NEMO-IκB Kinase Interaction Directly from a Combinatorial Library

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