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The toll-like receptor-nuclear factor kappaB pathway in rheumatoid arthritis in University of Sussex Research Online, Andreakos, Evangelos, Sacre, Sandra, Foxwell, Brian M and Feldmann, Marc (2005) The toll-like receptor-nuclear factor kappaB pathway in rheumatoid arthritis. Frontiers in Biosciences, November 2012
Abstract:
"The study of the role cytokines play in the pathogenesis of rheumatoid arthritis (RA) has provided a whole new range of targets for drug development. Many of them (e.g. TNF, IL-1, IL-6, IL-15 and IL-18) are already being targeted in the clinic with success using neutralizing monoclonal antibodies or soluble cytokine receptors. Targeting TNF, in particular, has shown great efficacy in controlling both the inflammation and structural damage of the joints, setting a new gold standard for the treatment of RA. However, what triggers the production of inflammatory cytokines such as TNF in RA remains to be determined. In this article, we review evidence suggesting that the transcription factor Nuclear Factor kappaB (NF-kappaB) is essential for the expression of both inflammatory cytokines and tissue destructive enzymes in RA. Also, we discuss whether Toll-like receptors (TLRs), major receptors involved in pathogen recognition and potent activators of the NF-kappaB pathway, are involved in triggering the inflammatory and joint destructive process in RA and whether they constitute sensible targets for monoclonal antibodies/soluble receptors and small molecule inhibitors. We conclude that although the TLR- NF-kappaB pathway offers ample opportunities for therapeutic intervention, future drugs to be approved will need to match or exceed the efficacy and safety of anti-TNF agents, with safety the most difficult aspect to predict."
Article at:
http://sro.sussex.ac.uk/41153/
Head injuries linked to dementia in NursingTimes.net,
22 July, 2011 | By The Press Association
Article:
"Brain similarities between dementia and head injury have been discovered in a joint study by Scottish and US scientists.
The researchers found large numbers of proteins in the brains of people who had recovered from a single head injury. This is typically seen in people with Alzheimer’s disease.
The study involved comparing the brain tissue, post mortem, of 39 people who had recovered from a brain injury with 47 people who had never had a brain injury. All of the people were from the west of Scotland.
The large number of proteins - referred to as “abnormalities” - were discovered in a third of those who had a head injury.
The findings followed analysis carried out by a team at the Southern General Hospital in Glasgow and the University of Pennsylvania in Philadelphia.
Dr William Stewart, who led the team in Glasgow, said: “We were really quite astonished to find up to a third had extensive pathology.
“The abnormalities that we saw in the brain are normally seen in people with dementia or very old people but we are seeing this in people in their 20s, 30s, 40s. The proteins are typical of those you might find in Alzheimer’s disease.”
The research is published on the website of the journal Brain Pathology.
Article at:
http://www.nursingtimes.net/nursing-practice/clinical-zones/neurology/head-injuries-linked-to-dementia/5032918.article
Hypertension drugs may prove effective in treating Alzheimer's. There are dozens of articles recently bringing to light current research into using existing blood-pressure drugs for treating Alzheimer's. The first article is about the phase III Roskamp clinical trials in Ireland. (my comments)
Search for AD Drugs Turns to a Hypertension Medicine
http://www.alzforum.org/news/research-news/search-ad-drugs-turns-hypertension-medicine
Can a Protein Controlling Blood Pressure Enhance Immune Responses and Prevent Alzheimer's?
http://www.cedars-sinai.edu/About-Us/News/News-Releases-2014/Can-a-Protein-Controlling-Blood-Pressure-Enhance-Immune-Responses-and-Prevent-Alzheimers.aspx
Canadian researchers probing if blood-pressure drugs can slow effects of Alzheimer's
http://www.ctvnews.ca/health/canadian-researchers-probing-if-blood-pressure-drugs-can-slow-effects-of-alzheimer-s-1.1723878#ixzz33fz8sW3c
High Blood Pressure Protein May Prevent Alzheimer’s
http://www.alzheimers.net/2014-02-05/high-blood-pressure-protein/
Blood Pressure Protein Could Rid Alzheimer's Brain Of Amyloid Plaques
http://www.medicaldaily.com/blood-pressure-protein-could-rid-alzheimers-brain-amyloid-plaques-268413
Blood pressure drugs can lower Alzheimer's risk by up to 50 per cent
:http://www.dailymail.co.uk/health/article-2050632/Blood-pressure-drugs-lower-Alzheimers-risk-50-cent.html#ixzz33fzuoy2l ;
Blood pressure drugs may help Alzheimer’s, study suggests
http://www.nbcnews.com/health/aging/blood-pressure-drugs-may-help-alzheimers-study-suggests-f6C10755394
There are dozens of articles about the same subject over the last year, Google search for 'hypertension Alzheimers'
Nuclear factor-kappaB as a potential therapeutic target for the novel cytotoxic agent LC-1 in acute myeloid leukaemia in Queens University Belfast Publications, British Journal of Hematology, Christopher Jenkins, Saman Hewamana, Amanda Gilkes, Sundar Neelakantan, Peter Crooks, Ken Mills
Chris Pepper, Alan Burnett, School of Medicine, Dentistry and Biomedical Sciences Centre for Cancer Research and Cell Biology
December 2008
Excerpt:
"Nuclear factor-kappaB (NF-kappaB) has been implicated in a number of malignancies and has been suggested to be a potential molecular target in the treatment of leukaemia. This study demonstrated the constitutive activation of NF-kappaB in human myeloid blasts and a clear correlation between NF-kappaB expression and in vitro cytoprotection. High NF-kappaB expression was found in many of the poor prognostic acute myeloid leukaemia (AML) subtypes, such as French-American-British classification M0 and M7, and the poor cytogenetic risk group. The in vitro effects of LC-1, a novel dimethylamino-parthenolide analogue, were assessed in 62 primary untreated AML samples. LC-1 was found to be cytotoxic to AML cells in a dose-dependent manner, mediated through the induction of apoptosis. The median drug concentration necessary to kill 50% of the cells was 4.5 micromol/l for AML cells, compared with 12.8 micromol/l for normal marrow cells. LC-1 was shown to reduce the five individual human NF-kappaB Rel proteins in a dose-dependent manner. The subsequent inhibition of many NF-kappaB-regulated cytokines was also demonstrated. Importantly, sensitivity to LC-1 was correlated with the basal NF-kappaB activity. Consequently, [b]LC-1 treatment provides a proof of principle for the use of NF-kappaB inhibitors in the treatment of AML."
Article at:
http://pure.qub.ac.uk/portal/en/publications/nuclear-factorkappab-as-a-potential-therapeutic-target-for-the-novel-cytotoxic-agent-lc1-in-acute-myeloid-leukaemia(c2b82d08-e05c-4a67-a6ad-e59602bb32c1).html
Nuclear factor-kappaB (NF-kappaB) is a novel positive transcriptional regulator of the oncogenic Wip1 phosphatase in ReadCube, J.M. Lowe, no date
Excerpt:
The nuclear factor-kappaB (NF-kappaB) family of transcription factors plays a key role in inflammation and augments the initiation, promotion, and progression of cancer. NF-kappaB activation generally leads to transcriptional enhancement of genes important in cell survival and cell growth, which is exploited in cancer cells. In this study, we identify an additional oncogene, PPM1D, which encodes for Wip1, as a transcriptional target of NF-kappaB in breast cancer cells. Inhibition of NF-kappaB or activation of NF-kappaB resulted in decreased or increased Wip1 expression, respectively, at both the mRNA and protein levels. PPM1D promoter activity was positively regulated by NF-kappaB, and this regulation was dependent on the presence of the conserved kappaB site in the PPM1D promoter region. Chromatin immunoprecipitation analysis showed basal binding of the p65 NF-kappaB subunit to the PPM1D promoter region encompassing the kappaB site, which is enhanced after NF-kappaB activation by tumor necrosis factor-alpha. Finally, we show that Wip1 expression is induced in lipopolysaccharide-stimulated mouse splenic B-cells and is required for maximum proliferation. Taken together, these data suggest an additional mechanism by which NF-kappaB may promote tumorigenesis, support the selective use of NF-kappaB inhibitors as chemotherapeutic agents for the treatment of human cancers, and further define a function for Wip1 in inflammation.
Article at:
http://www.readcube.com/articles/10.1074/jbc.m109.034579
Targeting nuclear factor-kappa B to overcome resistance to chemotherapy in Frontiers in Oncology, P. Godwin, A. M. Baird, S. Heavey, M. P. Barr, K. J. O’Byrne and K. Gately*, Department of Clinical Medicine, Thoracic Oncology Research Group, Trinity College Dublin, St. James’s Hospital Ireland, Dublin, Ireland, May 2013
Excerpt:
Intrinsic or acquired resistance to chemotherapeutic agents is a common phenomenon and a major challenge in the treatment of cancer patients. Chemoresistance is defined by a complex network of factors including multi-drug resistance proteins, reduced cellular uptake of the drug, enhanced DNA repair, intracellular drug inactivation, and evasion of apoptosis. Pre-clinical models have demonstrated that many chemotherapy drugs, such as platinum-based agents, antracyclines, and taxanes, promote the activation of the NF-?B pathway. NF-?B is a key transcription factor, playing a role in the development and progression of cancer and chemoresistance through the activation of a multitude of mediators including anti-apoptotic genes. Consequently, NF-?B has emerged as a promising anti-cancer target. Here, we describe the role of NF-?B in cancer and in the development of resistance, particularly cisplatin. Additionally, the potential benefits and disadvantages of targeting NF-?B signaling by pharmacological intervention will be addressed.
Article at:
http://journal.frontiersin.org/Journal/10.3389/fonc.2013.00120/abstract
Secret Clinical Trial Data to Go Public in Scientific American,
Drug companies have begun to share their clinical trial data. The long-overdue shift heralds a new era in medicine
Jun 1, 2014 |By The Editors
Excerpts:
"How well does a prescription drug work? It can be hard for even doctors to know. Pharmaceutical companies frequently withhold the results of negative or inconclusive trials. Without a full accounting, a physician who wants to counsel a patient about whether a drug works better than a sugar pill is frequently at a loss. Drug companies share only airbrushed versions of data on safety and usefulness.
As a consequence, regulators can approve drugs that have hidden health hazards. Clinical trials of GlaxoSmithKline's diabetes drug Avandia (rosiglitazone) and Merck's anti-inflammatory Vioxx (celecoxib) revealed an elevated cardiac risk from the drugs, but relevant findings were held back from regulators or never published. Far more drugs have gone to market with critical safety data kept secret. These scandals have tarnished the reputation of the pharmaceutical industry."
"Yet the challenge of how to share the data is not simple. A few manufacturers, including GlaxoSmithKline, Roche and Pfizer, have set up Web portals to open their files to outsiders with few, if any, restraints on access. Other companies worry that opening their doors too wide will compromise trade secrets, as well as the confidentiality of patient records.
Europe has recently taken the lead in adopting measures to ensure openness of data collected throughout drug trials. In early April the European Parliament voted to require that clinical trial results be published within a year of completion, whether or not the data are positive—a regulation that mirrors a similar effort being developed by the European Medicines Agency, an organization roughly equivalent to the U.S. Food and Drug Administration. (Physician and transparency advocate Ben Goldacre has pointed out that the vote is only a first step because it does not make public the data for already approved drugs.)
The FDA, meanwhile, has followed these proceedings intently as it contemplates requiring new levels of openness from pharmaceutical companies. As the agency deliberates, it should consider that the companies' poor track record is mirrored by its own. Since 2007 the FDA has required drugmakers to post some trial results in the government registry (ClinicalTrials.gov) within a year of a drug's approval, but the agency has failed to enforce this edict. A 2012 study showed that fewer than one in four approved drugs had results that were filed in time.
Fortunately, there are other ways to ensure that drug data get shared. The FDA should carefully consider a collaboration with the kind of independent institution that is already up and running at Yale University. In 2011 Yale's Open Data Access (YODA) Project reached an agreement with medical device maker Medtronic to act as an intermediary for releasing all data on clinical trials of a controversial bone-growth protein whose safety had been questioned. In an effort to defend its reputation, the company gave up any right to decide who would get the information. YODA then commissioned two systematic reviews of the protein, which conveyed mixed results that were then published. Following Medtronic's example, Johnson & Johnson pledged in January to make all its clinical trial data available for perusal by outsiders through YODA. Such early signs of successes might serve as the basis for devising a national system that replicates a YODA-like model for all U.S. drug trials, perhaps backed up by FDA-enforced penalties for companies that refuse to comply.
The most important reason for moving ahead has nothing to do with costs. An open data system—perhaps one like Yale's, backed with some regulatory clout—is the only way that physicians can weigh available evidence to make informed, timely decisions about what to tell their patients."
Article at:
http://www.scientificamerican.com/article/secret-clinical-trial-data-to-go-public/?&WT.mc_id=SA_HLTH_20140603
Inhibition of nuclear factor kappa-B signaling reduces growth in medulloblastoma in vivo in BioMed Central, Susan E Spiller12*, Naomi J Logsdon1, Lindsey A Deckard1 and Harald Sontheimer23
1 Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Ave S., Birmingham, AL 35294, USA, 2 Civitan International Research Center 1719 6thAve. S., Birmingham, AL 35294, USA, 3 Department of Neurobiology, University of Alabama at Birmingham, 911 Shelby Biomedical Research Building, 1825 University Blvd, Birmingham, AL 35294, USA, November 2011
Abstract:
Background
Medulloblastoma is a highly malignant pediatric brain tumor that requires surgery, whole brain and spine irradiation, and intense chemotherapy for treatment. A more sophisticated understanding of the pathophysiology of medulloblastoma is needed to successfully reduce the intensity of treatment and improve outcomes. Nuclear factor kappa-B (NF?B) is a signaling pathway that controls transcriptional activation of genes important for tight regulation of many cellular processes and is aberrantly expressed in many types of cancer.
Methods
To test the importance of NF?B to medulloblastoma cell growth, the effects of multiple drugs that inhibit NF?B, pyrrolidine dithiocarbamate, diethyldithiocarbamate, sulfasalazine, curcumin and bortezomib, were studied in medulloblastoma cell lines compared to a malignant glioma cell line and normal neurons. Expression of endogenous NF?B was investigated in cultured cells, xenograft flank tumors, and primary human tumor samples. A dominant negative construct for the endogenous inhibitor of NF?B, I?B, was prepared from medulloblastoma cell lines and flank tumors were established to allow specific pathway inhibition.
Results
We report high constitutive activity of the canonical NF?B pathway, as seen by Western analysis of the NF?B subunit p65, in medulloblastoma tumors compared to normal brain. The p65 subunit of NF?B is extremely highly expressed in xenograft tumors from human medulloblastoma cell lines; though, conversely, the same cells in culture have minimal expression without specific stimulation. We demonstrate that pharmacological inhibition of NF?B in cell lines halts proliferation and leads to apoptosis. We show by immunohistochemical stain that phosphorylated p65 is found in the majority of primary tumor cells examined. Finally, expression of a dominant negative form of the endogenous inhibitor of NF?B, dnI?B, resulted in poor xenograft tumor growth, with average tumor volumes 40% smaller than controls.
Conclusions
These data collectively demonstrate that NF?B signaling is important for medulloblastoma tumor growth, and that inhibition can reduce tumor size and viability in vivo. We discuss the implications of NF?B signaling on the approach to managing patients with medulloblastoma in order to improve clinical outcomes.
Background:
Medulloblastoma is largely a cancer of children, with 75-80% of cases diagnosed in individuals younger than fifteen years; some are diagnosed in infancy [1-3]. It is a very aggressive and invasive cancer which spreads primarily via cerebral spinal fluid to metastasize anywhere in the leptomeninges, or, in advanced disease, hematogenously to invade any body part. It is suspected to arise from cerebellar granule cell precursors [1,4] based on its primitive neuronal histology and location in the midline posterior fossa. Survival is achievable in many children, dependent on a number of factors, yet recurrence holds a dismal prognosis [3]. Current understanding of the biology of medulloblastoma cannot fully provide an explanation for medulloblastoma occurrence, proliferative properties, migratory activity, or chemotherapy resistance.
Article at:
http://www.biomedcentral.com/1471-2407/11/136
THE BIOLOGY OF NUCLEAR FACTOR KAPPA BETA (NFkB) IN
HEALTH AND PATHOLOGY in Research World, Carlos Kusano Bucalen Ferrari, Biomedical Research Group, Institute of Biological and
Health Sciences (ICBS), “Campus Universitário do
Araguaia”, “Universidade Federal de Mato Grosso”
(UFMT), Barra do Garças, MT, Brazil., July 2011
ABSTRACT:
This paper reviewed the molecular roles of NFkB in cell survival, disease, and death.
By activating FOXO, nuclear transcription factor-2 (Nrf-2), and mitogen-activated
protein kinase (MAPK) signaling mechanisms, NF?B mediates cell survival
mechanisms which guarantee cell viability against pathogenic stimuli. On the other
hand, NF?B could also modulate pathogenic signaling pathways leading to cell
degeneration, aging, disease and death. This dual role of NF?B should be considered
into development of novel strategies for tumor killing in cancer patients, or for the
preservation of brain neurons in Alzheimer’s disease.
Conclusion:
[b]Modulating NF?B cell pathways is essential to control cancer growth, aging process and
improve cell survival of important target tissues and organs. Future therapies should explore the
multiple pathways triggered by NF?B in cell proliferation and death.
Article at:
http://www.researchersworld.com/vol2/issue3/Paper_6.pdf
NUCLEAR FACTOR KAPPA-B i OMIM (OMIM is a comprehensive, authoritative compendium of human genes and genetic phenotypes that is freely available and updated daily. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, under the direction of Dr. Ada Hamosh. Its official home is omim.org.), no author, no date
Description:
NFKB has been detected in numerous cell types that express cytokines, chemokines, growth factors, cell adhesion molecules, and some acute phase proteins in health and in various disease states. NFKB is activated by a wide variety of stimuli such as cytokines, oxidant-free radicals, inhaled particles, ultraviolet irradiation, and bacterial or viral products. Inappropriate activation of NF-kappa-B has been linked to inflammatory events associated with autoimmune arthritis, asthma, septic shock, lung fibrosis, glomerulonephritis, atherosclerosis, and AIDS. In contrast, complete and persistent inhibition of NF-kappa-B has been linked directly to apoptosis, inappropriate immune cell development, and delayed cell growth.
Link at:
http://www.omim.org/entry/164011
Manipulation of the nuclear factor-kappaB pathway and the innate immune response by viruses in Oncogene, 2006, J Hiscott1,2,3, T-L A Nguyen1,2, M Arguello1,2, P Nakhaei1,2 and S Paz1,2, 1Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, McGill University, Montreal, Canada, 2Department of Microbiology & Immunology, McGill University, Montreal, Canada, 3Department of Medicine and Oncology, McGill University, Montreal, Canada
Abstract:
"Viral and microbial constituents contain specific motifs or pathogen-associated molecular patterns (PAMPs) that are recognized by cell surface- and endosome-associated Toll-like receptors (TLRs). In addition, intracellular viral double-stranded RNA is detected by two recently characterized DExD/H box RNA helicases, RIG-I and Mda-5. Both TLR-dependent and -independent pathways engage the IkappaB kinase (IKK) complex and related kinases TBK-1 and IKKalt epsilon. Activation of the nuclear factor kappaB (NF-kappaB) and interferon regulatory factor (IRF) transcription factor pathways are essential immediate early steps of immune activation; as a result, both pathways represent prime candidates for viral interference. Many viruses have developed strategies to manipulate NF-kappaB signaling through the use of multifunctional viral proteins that target the host innate immune response pathways. This review discusses three rapidly evolving areas of research on viral pathogenesis: the recognition and signaling in response to virus infection through TLR-dependent and -independent mechanisms, the involvement of NF-kappaB in the host innate immune response and the multitude of strategies used by different viruses to short circuit the NF-kappaB pathway."
Article at:
http://www.nature.com/onc/journal/v25/n51/full/1209941a.html
Inhibition of Nuclear Factor Kappa B (NF-B):
An Emerging Theme in Anti-Inflammatory Therapies in Molecular Interventions, Fulvio D'Acquisto, PhD, Michael J. May, PhD and Sankar Ghosh, PhD, Section of Immunobiology and Department of Molecular Biophysics and Biochemistry Howard Hughes Medical Institute Yale University School of Medicine New Haven, CT, February 2002
Abstract"
"The application of anti-inflammatory therapies began thousands of years ago with the use of readily available natural resources. It is only recently, however, that the cellular and molecular mechanisms of inflammation have been appreciated sufficiently to design anti-inflammatory strategies with limited side effects. For example, salicylates and glucocorticoids, two widely used anti-inflammatory drug classes, are now known to inhibit the activation of NF-?B, a transcription factor that regulates the inducible expression of a wide range of proinflammatory mediators. New generations of NF-?B–targeting anti-inflammatory agents that are specific, efficacious, and cost-effective may therefore complement or replace current therapies. In this review, we describe various classes of NF-?B inhibitors and discuss important unresolved issues regarding their use."
Article at:
http://triggered.stanford.clockss.org/ServeContent?rft_id=info:doi/10.1124/mi.2.1.22
What Is Nuclear Factor-Kappa Beta? in Life Extension Magazine, By Julius G. Goepp, MD, Julius G. Goepp, MD, is a pediatrician with additional certification in pediatric emergency medicine. He received his MD from the University of Maryland and is currently Senior Consultant at Lupine Creative Consulting, Inc., in Rochester, NY.July 2006
Excerpts:
"Simply put, NFkB is a protein that acts as a switch to turn inflammation on and off in the body. Scientists describe NFkB as a “smoke sensor” that detects dangerous threats like free radicals and infectious agents. In response to these threats, NFkB “turns on” the genes that produce inflammation. As we age, NFkB expression in the body increases, provoking widespread chronic inflammation and setting the stage for diseases ranging from atherosclerosis and diabetes to Alzheimer’s. The knowledge of this simple fact should motivate us to counteract NFkB’s deleterious effects and thus guard against many of the diseases commonly associated with aging."
"NFkB is an instigating factor that unleashes inflammatory responses in chronic disease conditions. For example, NFkB can signal our cells to continue to multiply long past their normal life span, which can promote cancer. Furthermore, NFkB can further spark the smoldering inflammation that damages joint tissues, thereby provoking crippling arthritic conditions. NFkB likewise plays a role in spurring inflammation in the nervous system, which can set the stage for the onset of various neurological disorders. Scientists believe that NFkB-induced inflammation in the airways may play a role in asthma."
"One of NFkB’s most lethal functions is inducing cancer in our bodies. Scientists are finding that, in addition to its central role in producing inflammation, NFkB plays an equally prominent and related role in the development of cancer."
"The NFkB system has emerged as the central actor in the link between inflammation and cancer. NFkB affects both malignant and non-malignant tumor cells. In malignant cells, it turns on genes that create resistance to apoptotic cell death and DNA damage, in effect promoting cancer development by rendering cells capable of reproducing, even when they are exposed to pharmaceutical anti-cancer agents. In non-malignant tumor cells, NFkB turns on genes that produce factors to stimulate blood vessel formation, in support of rapid tumor enlargement and progression. Finally, byproducts produced by NFkB stimulation can also damage DNA, thereby contributing to the very earliest stages of tumor initiation."
"The ubiquitous presence of NFkB throughout the inflammation-cancer cycle suggests that the next breakthroughs in cancer treatment will likely center on the inhibition of NFkB and its actions. As scientists learn more about NFkB and the complex systems that regulate it, they also learn more about the wide array of substances that can inhibit its dangerous actions. For example, the anti-inflammatory drug ibuprofen inhibits not only the COX-2 enzyme but also NFkB,12 and has a well-established safety record. This drug, as well as many natural inhibitors of NFkB, will therefore play an important role in controlling the inflammatory components of tumor formation and growth."
"Because the NFkB system is also involved in producing healthy immune responses, there are concerns about its long-term inhibition. While NFkB seems to be most profoundly involved in cancer at the stages of promotion and progression,8,14 it may be possible to use inhibitors for relatively short periods. Another potential use for such inhibitors would be in combination with chemotherapy or radiation treatments, as a means of controlling the associated inflammation and enhancing the effects of those treatments"
"Summary
Scientists have discovered that by controlling our DNA, nuclear factor-kappa beta (NFkB) plays a central role in determining our health and longevity. By integrating signals of inflammation, NFkB appears to be the common link between such diverse conditions as heart disease, cancer, and arthritis."
RECENT FINDINGS ON NFkB AND DISEASE:
"In recent years, numerous studies have shed light on the disease-promoting effects of NFkB and the benefits of quieting its activity in the body. For instance, recent studies indicate that NFkB plays a role in the following conditions:
Autoimmune joint disease: NFkB plays a crucial role in both rheumatoid arthritis and systemic lupus erythematosus, according to Spanish researchers.2 These two autoimmune conditions are known to produce severe joint pain and deterioration, as well as other symptoms that dramatically impair quality of life. Effective therapies to block NFkB may positively modulate these disease processes.
Hepatitis C: Infection with the hepatitis C virus is a growing cause of liver disease and liver cancer, and (unlike hepatitis B) there is no vaccine to protect against this deadly threat. In early 2006, Japanese scientists determined that NFkB plays a key role in the process by which the hepatitis C virus leads to the proliferation of human liver cancer cells.3
Inflammatory bowel disease: Crohn’s disease is an inflammatory bowel disease associated with symptoms such as severe abdominal pain, diarrhea, weight loss, and rectal bleeding. Recently, scientists noted that therapies that improve the symptoms and pathological signs of Crohn’s disease may work by decreasing levels of NFkB.4
Survival after heart attack: The death of heart muscle due to a blocked coronary artery is known as a heart attack. If the heart cannot adequately repair itself after such an attack, a common result is heart failure, in which the heart muscle cannot pump enough blood to meet the body’s needs. New findings from 2006 suggest that blocking NFkB may support cardiac muscle healing and prevent heart failure following heart attack.5
Prostate cancer: Zinc has long been known for its role in supporting healthy prostate function. Research from 2006 suggests that NFkB may provide the link between zinc and protection against prostate cancer. Zinc supplementation suppresses NFkB’s signaling effects, and researchers believe this may help prevent the metastasis of malignant prostate cancer cells.6
Diabetes: Insulin resistance in muscle tissues is a key factor in type II diabetes. In a recent investigation, researchers studied the muscle tissue of people with type II diabetes and found signs of increased NFkB activity. Reducing NFkB through exercise training in these individuals led to improvements in blood sugar metabolism.7"
Article at:
http://www.lef.org/magazine/mag2006/jul2006_report_nuclear_01.htm
The NF-?B-independent functions of IKK subunits in immunity and cancer in Cell Symposia, Trends in Cell Biology, Alain Chariotemail'
Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), GIGA-Signal Transduction, Laboratory of Medical Chemistry, CHU, Sart-Tilman, University of Liege, Belgium, 2009
Summary:
"The I?B kinase (IKK) complex is involved in transcriptional activation by phosphorylating the inhibitory molecule I?Ba, a modification that triggers its subsequent degradation, enabling activation of nuclear factor kappa B (NF-?B). Importantly, recent reports indicate that multiple cytoplasmic and nuclear proteins distinct from the NF-?B and I?B proteins are phosphorylated by the catalytic subunits of the IKK complex, IKKa or IKKß. Here, I describe how IKK subunits can have crucial roles in allergy, inflammation and immunity by targeting proteins such as SNAP23 and IRF7, but also in cancer by phosphorylating key molecules such as p53, TSC1 and FOXO3a through NF-?B-independent pathways. Thus, these recent findings considerably widen the biological roles of these kinases and suggest that a full understanding of the biological roles of IKKa and IKKß requires an exhaustive characterization of their substrates.
Article at:
http://www.cell.com/trends/cell-biology/abstract/S0962-8924(09)00134-2?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0962892409001342%3Fshowall%3Dtrue?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0962892409001342%3Fshowall%3Dtrue
The diverse and complex roles of NF-?B subunits in cancer in Nature Reviews Cancer, Neil D. Perkins, February 2012
Abstract:
It is only recently that the full importance of nuclear factor-?B (NF-?B) signalling to cancer development has been understood. Although much attention has focused on the upstream pathways leading to NF-?B activation, it is now becoming clear that the inhibitor of NF-?B kinases (IKKs), which regulate NF-?B activation, have many independent functions in tissue homeostasis and normal immune function that could compromise the clinical utility of IKK inhibitors. Therefore, if the NF-?B pathway is to be properly exploited as a target for both anticancer and anti-inflammatory drugs, it is appropriate to reconsider the complex roles of the individual NF-?B subunits
Article at:
http://www.nature.com/nrc/journal/v12/n2/full/nrc3204.html
CNBC biotech & pharma reporter Meg Tirrell talks to Richard Pazdur, the FDA's cancer czar about how far we've come in cancer treatment, breakthrough designations and if chemotherapy will soon be a thing of the past.
5 minute Video at:
http://video.cnbc.com/gallery/?video=3000280678
Why inflammation leads to a leaky blood-brain barrier: MicroRNA-155 in Science Daily, June 2, 2014, Federation of American Societies for Experimental Biology
Summary:
"Until now, scientists have not known exactly how inflammation weakens the blood-brain barrier, allowing toxins and other molecules access to the brain. A new research report solves this mystery by showing that a molecule, called 'microRNA-155,' is responsible for cleaving epithelial cells to create microscopic gaps that let material through."
Excerpt:
"This study has the potential to be a game-changer in terms of how we treat neurological conditions and how we deliver drugs to the brain," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "Since it was first discovered, the Blood-Brain Barrier has always been a touch elusive. Now, after careful analysis, we are learning exactly how our bodies keep our brains safe and that microRNA-155 is a key player."
Article at:
http://www.sciencedaily.com/releases/2014/06/140602104749.htm
TAK1 promotes ovarian cancer aggressiveness through activation of NF-kB pathway posted at Hong Kong University Scholars Hub, Cai, Chunhui, 2013, The University of Hong Kong (Pokfulam, Hong Kong)
Abstract:
Ovarian cancer is one of the most deadly female malignancies. Despite advances in the treatment of ovarian cancer for the past decade, the cure rate of this disease is moderately improved. Emerging evidence suggests the molecular personalized therapeutic approach become popular for human cancer treatment. The nuclear factor-kappa B (NF-?B) signaling pathway has been shown to play multiple roles in cancer progression such as anti-apoptosis, cell cycle, angiogenesis and metastasis. This study attempted to characterize the functional roles of transforming growth factor (TGF)-ß-activating kinase 1 (TAK1) in the activation of NF-?B signaling. Importantly, this study provided evidence showing the significance of TAK1-NF-?B signaling axis in ovarian cancer aggressiveness during omental metastasis.
Using quantitative RT-PCR and immunohistochemical analyses, TAK1 was frequently up-regulated and was significantly associated with high-grade (P=0.001), lymph node and distant metastasis (P=0.025), as well as a tendency toward advanced stage ovarian cancers (P=0.08). Functionally, enforced expression of TAK1 could augment cell proliferation, colony formation, anchorage-independent growth ability and migration/invasion in ovarian cancer cells. Conversely, repression of TAK1 expression by genetically or pharmaceutical approach abrogated these tumorigenic capacities including tumor growth in vivo. Furthermore, co-treatment of (5Z) -7-Oxozeaenol could sensitize ovarian cancer cells to cisplatin-induced cell apoptosis, indicating TAK1 is also involved in chemoresistance. Mechanistically, using Western blotting and NF-?B -reporter luciferase analyses, the elevation of TAK1 phosphorylation at Ser412 but not Thr184/187 was found to associate with the activation of NF-?B in ovarian cancer cells solely. A series of functional studies with genetic and pharmaceutical alterations revealed that the increased TAK1 Ser412 phosphorylation was required for exerting the ovarian cancer cell oncogenesis. Omental metastasis is the common phenomenon observed in most of advanced-stage ovarian cancer. Using omentum conditioned medium (OCM), the findings of this study showed that the omentum tissue was able to secrete numerous factors including chemokines such as GRO-a and IL8 in activating TAK1-NF-?B signaling cascade, which thereby induced increased oncogenic capacities in cell growth, migration and invasion. Taken together, this study suggests that TAK1-NF-?B signaling axis is indispensable for promoting oncogenesis of ovarian cancer and targeting this pathway may be a promising personalized cancer therapeutic approach in ovarian cancer.
Article at:
http://hub.hku.hk/handle/10722/193410
”NF-kB, a key player in breast cancer development.”, Seminar by Prof. Junichiro Inoue., Okinawa Institute of Science and Technology, Wednesday, April 9, 2014
Abstract:
"Patients with triple-negative breast cancer (TNBC), which lacks expression of the oestrogen receptor, the progesterone receptor and ERBB2, have the highest rates of early relapse when compared with patients with other breast cancer subtypes. The basal-like subtype, a subgroup of TNBC, exhibits a high level of constitutive NF-kB activation, which led us to hypothesize that NF-kB may regulate its cancer stem cell (CSC) population. We would like to show that constitutive and induced NF-kB activation played a positive role in CSC maintenance and propose a new model, in which the NF-kB activation in non-CSCs increases expression of soluble or membrane-bound ligands, which act in trans to stimulate CSCs leading to expansion of CSC population. Collectively, our results strongly suggest that NF-kB plays a non-cell-autonomous role in regulating CSC populations of basal-like breast cancers by forming intratumoral microenvironments."
Article at:
https://groups.oist.jp/csu/event/seminar-prof-junichiro-inoue-%E2%80%9Dnf-kb-key-player-breast-cancer-development%E2%80%9D
New drug target found for lung cancer in Science Daily, February 16, 2012, Salk Institute for Biological Studies
Article:
"Drugs targeting an enzyme involved in inflammation might offer a new avenue for treating certain lung cancers, according to a new study by scientists at the Salk Institute for Biological Studies.
The scientists discovered that blocking the activity of the enzyme IKK2, which helps activate the body's inflammation response, slowed the growth of tumors in mice with lung cancer and increased their lifespan.
The findings, reported February 12 in Nature Cell Biology, suggest that drugs that hinder the ability of the enzyme to command cellular activity might prove effective as lung cancer therapies.
"Lung cancer is one of most lethal cancers and prognosis for patients is often poor, with only about 15 percent surviving more than 5 years," says Inder Verma, Salk's American Cancer Society Professor of Molecular Biology and lead author of the paper. "We developed a new method of initiating lung cancer in mice, which has properties associated with human lung cancer, and used this model to identify the role of this enzyme in cancer proliferation. We believe that this research could one day lead to therapies that improve the outlook for lung cancer patients."
Scientists have long known that there is a link between cancer and inflammation, the body's first line of defense against infection. Some of the same biochemical players that protect the body by controlling the inflammation response of cells can also be hijacked by genetic mutations involved in the development of cancer.
To better understand how these normally helpful components of the immune system are put to nefarious tasks in cancer cells, Verma and his colleagues developed a new method of inducing non-small-cell lung cancer in mice. This type accounts for as much as 80 percent of all lung cancer cases.
The researchers used a modified virus to insert genetic mutations into cells lining the mice's lungs, causing the animals to develop tumors. This laid the groundwork for studies on the molecular causes of this specific cancer type that would be impossible in humans.
They then turned their attention to a protein complex, NF-KB, that initiates the inflammation response to infection by orchestrating a cell's genetic activity. Malfunctioning regulation of NF-KB has been linked to various types of cancer, including lung cancer, but due to its many functions in the cell, drugs that directly target NF-KB would likely cause severe side effects.
To get around this limitation, the Salk researchers focused on IKK2, an enzyme that spurs NF-KB's activity in response to stress. When they blocked IKK2 activity in the mice with lung cancer, the mice had smaller tumors and lived longer, suggesting that the enzyme is necessary for NF-KB to stimulate tumor growth.
"Now that we understand IKK2 is required for NF-KB to promote tumor growth, we hope to find ways to target its activity with drugs," says Yifeng Xia, a postdoctoral researcher in Verma's lab and first author on the paper. "Systemically and chronically blocking IKK2 activity is too toxic to be used in chemotherapy, but we might be able to target another molecule in the signaling pathway by which IKK2 regulates tumor growth."
The researchers also showed that Timp-1, a gene involved in regulating cell growth, carries orders from NF-KB to tell lung cancer cells to proliferate. When they suppressed the expression of the gene, the mice with lung cancer had smaller tumors and survived longer.
"The next step is to develop antibodies or other types of drugs that can neutralize Timp-1 to abolish its pro-proliferation role in lung cancer," says Xia.
The Salk scientists now hope to develop a mouse model of small cell lung cancer, a more aggressive form of the disease that's been linked to smoking. They will then test whether the potential drug targets they discovered in this study would be relevant for this more deadly cancer.
The other authors on the paper were Reuben J. Shaw, a professor in Salk's Molecular and Cell Biology Laboratory; Salk postdoctoral researcher, Narayana Yeddula, and pathologist, Mathias Leblanc; Eugene Ke, of University of California, San Diego; and Yonghui Zhang and Eric Oldfield, of the University of Illinois at Urbana-Champaign.
The study was funded by the Ellison Medical Foundation, H.N. and Frances C. Berger Foundation, Ipsen/Biomeasure, Sanofi Aventis, Leducq Foundation, National Institutes of Health, Merieux Foundation, Prostate Cancer Foundation and the U.S. Department of Defense."
Article at:
http://www.sciencedaily.com/releases/2012/02/120216094728.htm
GSK misses survival endpoint with Tykerb-Herceptin pairing in Fierce Pharma, June 1, 2014 | By Carly Helfand
Excerpt:
"When it comes to improving disease-free survival in HER2-positive early breast cancer patients, two isn't better than one, GlaxoSmithKline ($GSK) found--at least, not when those two are Tykerb and Roche ($RHHBY) cancer giant Herceptin. As Glaxo announced at ASCO on Sunday, a Phase III study of the pair missed that primary endpoint, failing to outdo Herceptin on its own.
GSK SVP of Oncology R&D Dr. Rafael Amado
In the 8,000-plus-patient study, dubbed ALTTO, 86% of women treated with Herceptin as an adjuvant therapy lived for four years without their cancer returning and 88% of women receiving a Herceptin-Tykerb combo reached that mark--a non-statistically significant difference. In women receiving Herceptin followed by Tykerb, the 4-year disease-free survival rate came out to 87%.
"While it is disappointing that ALTTO did not meet its primary endpoint, we now have a tremendous amount of information that will help to further our knowledge of the biology of this disease and inform future studies in HER2-positive breast cancer in the adjuvant setting," Dr. Rafael Amado, GSK's SVP of oncology R&D, said in a statement.
Article at:
http://www.fiercepharma.com/story/gsk-misses-survival-endpoint-tykerb-herceptin-pairing/2014-06-01#ixzz33VEOhjs6
Metformin and NF-kB inhibitors combine to attack cancer cells in Oncology Times UK Edition, News in Brief, no author cited, October 2011
Article:
"Research published in Nature Cell Biology in September shows how blocking a key controller of energy production in cancer cells – NF-kB – and treating them with a diabetes drug, metformin, effectively starves cancer cells.For cancer cells to divide and grow quickly, they need to produce energy rapidly by breaking down glucose through glycolysis.By doing this they generate the energy and raw materials needed to create new cells. The researchers found that this switching is controlled by a protein complex called NF-kB, which controls the balance between different types of energy generation.When glucose supplies run short, NF-kB moves energy generation to an alternative process that doesn’t rely on glucose. But blocking NF-kB in cancer cells leaves them unable to make this switch and so they ultimately die.By targeting this protein complex, the researchers showed they could kill bowel cancer cells in the lab. To mimic the effect of glucose starvation, the researchers first treated the cancer cells with a molecule that blocks NF-kB, but alone has no effect on survival. However, when combined with metformin, which blocks alternative methods of energy production, they effectively besiege the cancer cells so that they starve and die.Professor Guido Franzoso, lead researcher based at Imperial College London, said: ‘This is the first time that NF-kB has been shown to control how cells generate energy. We already knew that NF-kB plays a role in cancer. It is part of a family of regulators that control the immune and inflammation responses and have been shown to promote the disease.‘Inhibitors of NF-kB are currently used in the clinic to treat cancer patients but have had limited success, due to their side-effects. We hope that we can now start exploring the possibility of combining them with metformin as a double hit to increase their effectiveness against cancer.’Dr Julie Sharp, senior science information manager at Cancer Research UK, said: ‘Cancer cells need a rapid supply of energy to grow and divide and understanding how they generate energy is an exciting area of research. [b]By blocking energy production, effectively starving the cells, researchers have revealed a new way to selectively attack cancer cells leaving normal cells unharmed.’"
Article at:
http://journals.lww.com/oncotimesuk/Fulltext/2011/10000/Metformin_and_NF_kB_inhibitors_combine_to_attack.12.aspx
Modulators of HIF1a and NFkB in cancer treatment: is it a rational approach for controlling malignant progression? in Frontiers Journal Pharmaceuticals, Marco Tafani1,2, Bruna Pucci2, Andrea Russo3, Luana Schito4, Laura Pellegrini2,5, Giulietta A. Perrone6, Lidia Villanova2,7, Luisa Salvatori8, Linda Ravenna8, Elisa Petrangeli1,8 and Matteo A. Russo1,2*, 1Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
2Laboratory of Molecular and Cellular Pathology – Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana, Rome, Italy, 3Department of Surgical Pathology, Istituti di Ricovero e Cura a Carattere Scientifico Istituto Regina Elena, Rome, Italy
4Vascular Program, Institute of Cellular Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
5John A. Burns School of Medicine, University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA
6UOC of Pathologic Anatomy, San Filippo Neri Hospital, Rome, Italy
7Division of Endocrinology, Gerontology, and Metabolism, Department of Medicine, Stanford University, Stanford, CA, USA
8Institute of Molecular Biology and Pathology, Consiglio Nazionale delle Ricerche, Rome, Italy, February 2013
Excerpt:
"HIF1a and NFkB are two transcription factors very frequently activated in tumors and involved in tumor growth, progression, and resistance to chemotherapy. In fact, HIF1a and NFkB together regulate transcription of over a thousand genes that, in turn, control vital cellular processes such as adaptation to the hypoxia, metabolic reprograming, inflammatory reparative response, extracellular matrix digestion, migration and invasion, adhesion, etc. Because of this wide involvement they could control in an integrated manner the origin of the malignant phenotype. Interestingly, hypoxia and inflammation have been sequentially bridged in tumors by the discovery that alarmin receptors genes such as RAGE, P2X7, and some TLRs, are activated by HIF1a; and that, in turn, alarmin receptors strongly activate NFkB and proinflammatory gene expression, evidencing all the hallmarks of the malignant phenotype. Recently, a large number of drugs have been identified that inhibit one or both transcription factors with promising results in terms of controlling tumor progression. In addition, many of these molecules are natural compounds or off-label drugs already used to cure other pathologies. Some of them are undergoing clinical trials and soon they will be used alone or in combination with standard anti-tumoral agents to achieve a better treatment of tumors with reduction of metastasis formation and, more importantly, with a net increase in survival. This review highlights the central role of HIF1a activated in hypoxic regions of the tumor, of NFkB activation and proinflammatory gene expression in transformed cells to understand their progression toward malignancy. Different molecules and strategies to inhibit these transcription factors will be reviewed. Finally, the central role of a new class of deacetylases called Sirtuins in regulating HIF1a and NFkB activity will be outlined."
Article at:
http://journal.frontiersin.org/Journal/10.3389/fphar.2013.00013/abstract
Role of NF-KB in Loss of Skeletal Muscle Mass in Cancer Cachexia and its Therapeutic Targets in the American Journay of Cancer Biology, Daya S. Srivastava, Dhara B. Dhaulakhandi, 2013
Abstract"
"Cancer cachexia is a type of cancer metabolic syndrome characterized by wasting of energy storage tissue of the body such as loss of skeletal muscle or fat body mass. It is one of the most common forms of cachexia. Researchers have shown that around 50%–80% cancer patients are cachectic and about 22% cancer related deaths are due to cachexia.Recent evidences confirm that skeletal muscle loss is induced by different mediator based mechanisms such as cytokines, tumor-derived factors, TNF-alpha receptors, androgen receptors, negative modulator of growth factors, and ubiquitin-proteasome pathways. These mediators interact with their unique receptors on skeletal muscles and activate nuclear factor-kappa-B (NF-?B) which is a transcription factor essential for atrophy based muscle protein degradation. Inhibition of NF-?B ameliorates cancer-induced muscle loss are suggestive of a new set of drug targets for clinical intervention in cancer cachexia. Here we summarize the recent advances concerning involvement of NF-?B in loss of skeletal muscle mass in cancer cachexia and its therapeutic targets. Future experimental efforts may focus on discovering of new drugs that act as potential therapeutic targets in cancer cachexia against the myriad of signaling pathways to precisely understand the mechanisms of loss of skeletal muscle mass and adipose tissue which could demonstrates significant improvement in treatment outcome, functional status and quality of life of the patients."
Article at:
http://www.ivyunion.org/index.php/ajcb/article/view/201300117
Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls, This work was supported by grants from the NIH and AACR (M.K.), and Agence Nationale pour la Recherche, Association pour la Recherche sur le Cancer, Belgian InterUniversity Attraction Pole, Ministère de la Recherche/Cancéropole IdF, et Université Paris Descartes (V.B.)., Baud Véronique, IC, Institut Cochin CNRS : UMR8104, INSERM : U567, Université Paris Descartes - Paris V, FR , Karin Michael, Laboratory of gene regulation and signal transduction University of California, San Diego, US
Excerpts:
"Abstract
Preface
NF-?B transcription factors play a key role in many physiological processes, such as innate and adaptive immune responses, cell
proliferation, cell death, and inflammation. It has become clear that aberrant regulation of NF-?B and the signaling pathways that
control its activity are involved in cancer development and progression, as well as in resistance to chemo- and radiotherapy. This review discusses recent cancer-genetics and cancer-genome evidence for the involvement of NF-?B in human cancer, and discusses the therapeutic potential and benefit of targeting NF-?B in cancer and the possible complications and pitfalls of such an approach."
"Multiple myeloma and genetic abnormalities in NF-?B pathways
The most dramatic and broad example for genetic alterations that lead to activation of NF-?B in cancer was recently identified through the application of oncogenomics in multiple myeloma (MM). MM is a B cell neoplasia that accounts for 1% of all cancers and more than 10% of total hematological malignancies. MM is mainly characterized by unrestrained accumulation of antibody-secreting plasma B cells in the bone marrow, attributed to loss of apoptosis control and cell-cycle deregulation40–42. The bone marrow microenvironment has also been shown to contribute to the pathogenesis and progression of MM43. Despite advances in chemotherapy and stem cell transplantation, which have improved survival rates, MM remains an incurable disease. Thus, new treatment approaches are needed to improve the outcome of MM therapy and provide patients with longer disease-free survival. Of all the different signaling pathways constitutively
activated in primary MM cells, NF-?B has recently emerged as one of the most important drivers of the tumor-promoting machinery."
"The discovery of genetic alterations that lead to constitutive NF NF-?B activition in one fifth of MM patients strikes a strong rationale for the use of NF-?B inhibitors as single-agent therapeutics in this malignancy. It also supports the idea that genomic technology should become an integral part of prospective clinical trials, helping identify which molecularly defined subsets of patients will preferentially respond to NF-?B inhibition. Indeed, a major challenge for cancer researchers and clinicians is how to identify those patients that are most
likely to benefit from IKKß or NF-?B inhibition"
Article at:
http://hal.inria.fr/docs/00/35/23/49/PDF/inserm-00352349_edited.pdf
Peptides genetically selected for NF-?B activation cooperate with oncogene Ras and model carcinogenic role of inflammation in Proceedings of the National Academy of Sciences of the United States of America, PNAS, Proceedings of the National Academy of Sciences,
Venkatesh Natarajana,1,2, Andrei P. Komarovb,1, Thomas Ippolitoa, Kyle Bonneaub, Alex A. Chenchikb, and Andrei V. Gudkova,2,
aDepartment of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263; and bCellecta, Inc., Mountain View, CA 94043, December 2013
Abstract:
"Significance
Despite general acceptance of the link between chronic inflammation and cancer, the precise molecular mechanisms underlying the cancer-promoting effects of inflammation remain undefined. Inducible transcription factor NF-?B is the key regulator of inflammation, which is commonly deregulated in cancer cells to become constitutively active. Whether this deregulation contributes to malignant transformation was the main question addressed in this study. We isolated a series of genetic elements encoding artificial intracellular proteins capable of constitutive activation of NF-?B, named NF-?B–activating selectable peptides (NASPs), and demonstrated that all of them had carcinogenic activity in conventional cellular models. Specifically, NASPs made normal rodent cells susceptible to malignant transformation by oncogene Ras, which cannot do it on its own. This result defines chronically active NF-?B as an oncogene."
Article at:
http://www.pnas.org/content/early/2014/01/09/1311945111
The role of NF-?B pathway in cancer inflammation of esophageal squamous carcinoma in ASC University 2013 Gastrointestinal Cancers Symposium, Ching Tzao, Li-Yuan Cheng, Chien-Chih Chang, Guang-Huan Sun; Division of Thoracic Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Department of Immunology and Microbiology, National Defense Medical Center, Taipei, Taiwan; Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, held 2014
Abstract:
Background: Chronic inflammation plays an important role in tumorigenesis and tumor progression in human cancers. We aim to investigate the role of NF-kB in cancer inflammation of esophageal squamous cell carcinoma (ESCC). Methods: To generate M2-polarized macrophages, cells of human U937 monocyte cell line were treated with phorbol myristate acetate (PMA, 50 ng/ml) for 6 hours, and then cultured with PMA plus Th2 cytokines, IL-4 (20 ng/ml) and IL-13 (20 ng/ml), for another 18 hours. M2 phenotype was verified by flow cytometry and by cytokine profiling using enzyme-linked immunosorbent assay (ELISA). After co-culture with M2 macrophages, transcription nuclear factor-kB (NF-kB) activity was measured using quantitative polymerase chain reaction (Q-PCR), followed by reconfirmation with Western blot analysis for IkBa in KYSE-170 and -510 ESCC cell lines (kindly provided by Dr. Yutaka Shimada at Kyoto University, Japan). A selective inhibitor to NF-kB, Bay11-7082, was used to treat ESCC cell lines co-cultured with M2 macrophages, followed by cell proliferation, migration, invasion assays and vascular endothelial growth factor (VEGF) secretion by ELISA. The effect of Bay11-7082 (5 mg/kg) against growth of ESCC tumor was tested in xenografted tumors. Results: PMA plus Th2 cytokines treatment promoted differentiation of U937 cells into M2 macrophages. When treated with Bay11-7082, proliferation, migration, invasion and induction of VEGF expression was significantly inhibited in M2 macrophage co-cultured ESCC cells with a down-regulation of IkBa expression. Tumor growth was significantly increased in M2 macrophage co-cultured ESCC cells compared to that of the non-co-cultured controls, which was significantly retarded by treatment with Bay11-7082. Conclusions: NF-kB pathway was activated in ESCC cell lines co-cultured with M2 macrophages with an increase in cell proliferation, cell motility and angiogenic factor in vitro and tumor growth in vivo, which were significantly suppressed by a NF-kB inhibitor, Bay11-7082. These results suggest a role of M2 macrophage in promoting aggressiveness of ESCC cells, possibly through an activation of NF-kB pathway that may serve as a potential therapeutic target for ESCC."
Article at:
http://meetinglibrary.asco.org/content/104922-133
New roles for the RelA(p65) NF-kB subunit in cancer at Cancer Research UK, Neil Perkins research projects, Newcastle University
Medical School, Newcastle Upon Tyne NE2 4HH, United Kingdom
Funding period: 01 June 2011 to 31 May 2016, Funding scheme: Biological Sciences Committee (BSC) Programme Grants
Funding committee: Science Committee
Abstract:
Background:
Aberrant regulation of the Nuclear Factor kappa B (NF-kB) transcription factor family, together with their activators, the IkB kinases (IKK), plays a critical role in tumorigenesis and the response of cancer cells to therapy. As a consequence, there is much interest in the development of drugs that target the NF-kB pathway, while many treatments currently in clinical use are thought to exert at least part of their effect though inhibition or modulation of NF-kB/IKK signaling. A comprehensive understanding of the NF-kB/IKK pathway is therefore not only required for the development of accurate models of tumorigenesis but also for future cancer drug discovery.
Two major objectives of our research have been to investigate the function of NF-kB following different forms of DNA-damage and to understand how NF-kB activity is integrated with tumour suppressors. A theme emerging from these studies has been the importance of context and post-translational modifications for NF-kB activity.
We have argued that the activities of parallel signaling pathways have a critical role in determining NF-kB dependent transcriptional output and propose that models in which NF-kB activity is always tumour promoting are too simplistic. Rather, tumour suppressors can act to keep the oncogenic activities of NF-kB in check with their loss during tumour development being required to unleash NF-kB's anti apoptotic and pro-metastatic activities in malignant cancer cells.
Aims & objectives:
We have recently discovered new pathways through which the RelA(p65) NF-kB subunit can contribute to tumorigenesis and the response to cancer therapies. In the next quinquennium we will use these as the basis for a programme of research to:
Investigate NF-kB function after DNA damage and define the mechanisms through which the RelA subunit regulates DNA repair through non-transcriptional mechanisms.
Dissect the mitochondrial and non-mitochondrial pathways through which NF-kB regulates energy production and metabolism
Methods:
We will use molecular and cell biological techniques as well as the creation of new mouse models, to determine the physiological role of RelA in these processes and define their significance during tumorigenesis.
How the results of this research will be used:
Our proposal will advance our knowledge of the mechanisms by which NF-kB regulates two key events in cancer cell biology, DNA repair and mitochondrial activity. This will open up new directions of clinically relevant research, with the potential to enhance the use of both current and future anti-cancer drugs.
Article at:
http://www.cancerresearchuk.org/science/research/who-and-what-we-fund/browse-by-location/newcastle/newcastle-university/grants/12750-new-roles-for-the-relap65
NFLAMMATION, CANCER AND CANCER STEM CELLS in Entre Mediterraneen de Medecine Moleculaire, Jean Francois Peyron-Team Leader, 2013
Excerpt:
"Team4 “Inflammation, Cancer, Cancer Stem Cells“ (Head : Jean-Francois Peyron) is studying intracellular signaling pathways that transmit activation, proliferation and survival signals during inflammation and tumorigenesis. This fundamental and pre-clinical research, backed by the use of pertinent murine models, aims at the discovery of future therapeutical targets.
Our research is following two axis :
1- the molecular dissection of the role of the NF-kappaB transcription factor during the different steps of tumorigenesis.
2- The study of the self-renewal capacity of cancer stem cells.
NF-kB in carcinogenesis :
Oncogenic abnormal NF-kB activation is important for cancer initiation and progression by inducing genes that support proliferation, resistance to apoptosis and treatments, metastasis. We previously showed that pharmacological inhibition of NF-kB decrease the survival of numerous types of cancer cells and potentiates the apoptotic effect of chemotherapeutic drugs.
Our goal is to determine at a molecular level, the contribution of NF-kB to the transforming activity of the Bcr-abl oncogene in Chronic Myeloid Leukemia (CML). We previously showed that NF-kB inhibition in vitro induced apoptosis of leukemic cells and bypass imatinib resistance to to the T315I mutation of Bcr-abl. Besides, we are searching for the molecular intermediates between Bcr-abl and NF-kB, in order to identify new potential therapeutical targets.
We are studying in vivo the contribution of NF-kB to tumorigenesis in a murine model of PTEN invalidation in T cells (cre-lox) that leads to a T lymphoma. Using a transcriptomic approach, we are searching for NF-kB target genes that participates to transformation and will characterize their mode of action.
NF-kB is involved in tumor resistance to treatments. We have isolated a CPT11 topoisomerase inhibitor-resistant variant of the HT29 colon cancer cell line that displays abnormal constitutive NF-kB activation. We are searching the NF-kB target genes that mediate this resistance.
NF-kB is a molecular link between chronic inflammation and transformation. We are characterizing the biological and molecular components from the Saccharomyces boulardii (Sb) probiotic that could be responsible for the anti-inflammatory and protective effects of Sb because of their inhibition of intracellular signaling pathway including NF-kB during enterohemorrhagic E Coli infection. The participation of alterations in the integrity of the intestinal epithelial barrier is studied during irritable bowel syndrome.
Article at:
http://www.unice.fr/c3m/EN/Equipe4.html
Role of NF-?B in Human Malignancies at The Miyamoto Lab, University of Wisconsin, Madison, no author, no date
Posting:
"Numerous studies over the last several decades have been dedicated to understanding how oncogenes (cancer inducing genes) and tumor suppressors (cancer preventing genes) modulate cancer development. Their findings suggest the concept that malignant behaviors may develop by a process of normal cells acquiring autonomy from multiple regulatory signals via genetic or epigenetic alterations of signaling pathways. Thus, malignant cancer cells often display a set of six or seven alterations, referred to as “acquired capabilities”. Each of these attributes could in principle provide a drug target and combined targeting of different acquired capabilities may be required to effectively eradicate cancer cells in each patient. The critical issue is to determine which dysregulated signaling pathways are controlling these attributes in specific types of human cancers. Ideally, this information needs to be defined in individual cancer patients in order to maximally tailor therapy.
We are currently investigating the mechanisms of dysregulated, constitutive (always “on”) activation of NF-kB in several different human cancer types. In particular, we are currently focusing our efforts to understand NF-kB activation mechanisms in two hematologic malignancies, multiple myeloma (MM) and mantle cell lymphoma (MCL), both are lethal diseases and can be difficult to treat. Constitutive NF-kB activity can be detected in a very high percentage (~80% or more) of patient-derived cancer samples but the mechanisms behind this activity are unclear. We also learned that “normal” stromal cells associated with multiple myeloma cells further increase NF-kB activation in myeloma cells to augment drug resistance. Therefore, not only cancer cells but also normal “microenvironment” cell types appear to promote cancer cell resistance. In collaboration with clinical colleagues and bioengineering experts, we are developing new methodologies (e.g., miniaturized “microchannels”) that enable the analysis of precious patient samples with different anti-cancer drugs to learn the mechanism of NF-kB activity and how to modulate such an activity in these cells. We are also aiming to learn what other signaling pathways are altered in these cells as they become resistant to different combinations of cancer drugs. Finally, we are screening chemical compounds to identify potential candidates for new anticancer drugs targeting resistant pathways. Ultimately, we want to develop a strategy to screen individual patient samples to help tailor personalized treatments."
Posting at:
http://miyamotolab.wisc.edu/index.php/research/role-of-nf-kb-in-human-malignancies
Celastrol induces apoptosis of gastric cancer cells by miR-146a inhibition of NF-?B activity in Cancer Cell International 2013,, Min Sha, Jun Ye, Li-xin Zhang, Zheng-yun Luan and Ya-bao Chen*, Institute of Clinical medicine, Taizhou people’s Hospital affiliated of Nantong University of medicine, 210 Yingchun, Taizhou, Jiangsu Province, 225300, China
Celastrol is a remedial ingredient isolated from the root extracts of Tripterygium Wilfordi (Thunder of God vine) and Celastrus Regelii. In in vitro and in vivo animal experiments, celastrol exhibits antioxidant,[2] anti-inflammatory,[3][4] anticancer,[5][6][7][8] and insecticidal [9] activities. Celastrol, also known as tripterine, is a pentacyclic triterpenoid and belongs in the family of quinone methides.(Wikipedia)
IMPORTANT REFERENCE NOT CITED IN ARTICLE: Michael Mullan, Roskamp Institute:
Reduction of ß-amyloid pathology by celastrol in a transgenic mouse model of Alzheimer's disease
Daniel Paris,corresponding author1 Nowell J Ganey,1 Vincent Laporte,1 Nikunj S Patel,1 David Beaulieu-Abdelahad,1 Corbin Bachmeier,1 Amelia March,1 Ghania Ait-Ghezala,1 and Michael J Mullan1
1The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA
corresponding authorCorresponding author.
Daniel Paris: dparis@rfdn.org; Nowell J Ganey: jganey@rfdn.org; Vincent Laporte: vlaporte@rfdn.org; Nikunj S Patel: npatel@rfdn.org; David Beaulieu-Abdelahad: dbeaulieu@rfdn.org; Corbin Bachmeier: cbachmeier@rfdn.org; Amelia March: amarch@rfdn.org; Ghania Ait-Ghezala: gaitghezala@rfdn.org; Michael J Mullan: mmullan@rfdn.org
Received December 17, 2009; Accepted March 8, 2010.
Article at:
http://pubmedcentralcanada.ca/pmcc/articles/PMC2841120/
Abstract:
Background
Celastrol, a plant triterpene, is known to play important role in inhibiting proliferation and inducing apoptosis of gastric cancer cells. In the present study, the mechanism of celastrol on gastric cancer cells apoptosis was examined.
Methods
We assessed effect of celastrol on NF-?B signaling pathway in gastric cancer cells using western blot and luciferase reporter assay. The real-time PCR was used to evaluate the effect of celastrol on miR-146a expression, and miR-146a mimic to evaluate whether over-expression of miR-146a can affect NF-?B activity. Finally, the effect of miR-146a on celastrol-induced anti-tumor activity was assessed using miR-146a inhibitor.
Results
Celastrol decreased gastric cancer cells viability in a dose-dependent. Celastrol also reduced I?B phosphorylation, nuclear P65 protein levels and NF-?B activity. Furthermore, Celastrol could increase miR-146a expression and up-regulation of miR-146a expression could suppress NF-?B activity. More important, down-regulation of miR-146a expression can reverse the effect of celastrol on NF-?B activity and apoptosis in gastric cancer cells.
Conclusions
In this study, we demonstrated that the effect of celastrol on apoptosis is due to miR-146a inhibition of NF-?B activity.
Article at:
http://www.cancerci.com/content/13/1/50
NF-kB in Colorectal Cancer, May 2013
My comments:
Article or excerpts cannot be copied and pasted so you have to see article by using the link:
http://link.springer.com/article/10.1007%2Fs00109-013-1045-x#page-2
Bottom Line:
"leading cause of morbidity worldwide, responsible for half a million deaths annually."
"NF-kB plays an important roll in pathogenesis of colorectal cancer."
"NF-kB is a target for therapeutic intervention."
Article at:
http://link.springer.com/article/10.1007%2Fs00109-013-1045-x#page-2
Overview of NFkB signaling in Abcam Discover More (Biotech Co), By C. Hooper, King’s College London, MRC Centre for Neurodegenerative Research, Institute of Psychiatry, no date
Excerpt:
"The role of NFkB signaling in disease
Asthma is a chronic inflammatory disorder. The pathogenesis of asthma involves the persistent expression of pro-inflammatory cytokines, chemokines and other such inflammatory mediators. Many of these genes contain the kB site for NFkB within their promoters, suggesting that NFkB plays a vital role in asthma (Yamamoto and Gaynor 2001; Christman et al., 2000). Indeed, increased NFkB activity has been observed in the airways of asthmatic patients (Hart et al., 1998). NFkB is also implicated in inflammatory bowel disease such as Crohn’s disease and ulcerative colitis (Neurath et al., 1998; Schreiber et al., 1998). NFkB activation is evident in biopsies from such patients and treatment of patients with steroids decreases NFkB activity in biopsies as well as reducing the clinical symptoms of disease. Furthermore, NFkB is involved in the pathophysiology of the autoimmune disorder rheumatoid arthritis (RA). NFkB itself is upregulated in RA and cytokines such as TNFa that activate NFkB are elevated in the synovial fluid of patients with RA (Feldmann et al., 1996; Roman-Blas and Jimenez 2006).
In addition to the roles that NFkB plays in inflammatory diseases, constitutive activation of the NFkB pathway is involved in some forms of cancer such as leukemia, lymphoma, colon cancer and ovarian cancer (Rayet and Gelinas 1999). Mutations that can lead to such tumors include those that inactivate IkB proteins as well as amplifications and rearrangements of genes encoding the NFkB transcription factor subunits. However, more commonly it is thought that changes in the upstream pathways that lead to NFkB activation become deregulated in cancer.
Article at:
http://www.abcam.com/?pageconfig=resource&rid=11255&pid=10629
Developing Drugs Against a Master Regulator of Cancer Cell Behavior: Targeting NF-kB in article from Columbia University, The Center for Lymphoid Malignancies, no author, no date
Excerpts:
"[b]Overexpression of NF-?B has been observed in many malignancies, ranging from breast and ovarian cancer to a host of hematological malignancies. Because of its pivotal role in oncogenesis, NF-?B represents a focal point for an intense compound screening which would target and down-regulate it. Previous work by us and our collaborators reported the discovery of a unique class of benzensulfonamides capable of NF-?B down-regulation in two different and independent screening assays."
Article at:
http://www.cumc.columbia.edu/lymphoma/developing-drugs-against-master-regulator-of-cancer-cell-behavior-targeting-nf-kb#page-2
The NFkB pathway and endocrine-resistant breast cancer Conference Paper in Endochronology Journal, Y Zhou, S Eppenberger-Castori1
, U Eppenberger1 and C C Benz, Buck Institute for Age Research, Novato, California 94945, USA, 1 Stiftung Tumorbank Basel, Lo¨rracherstrasse 50, CH-4125 Riehen, Switzerland, 2005
Abstract:
"Endocrine therapy with an estrogen receptor (ER)-targeted antiestrogen, such as tamoxifen, or estrogen ablation by aromatese inhibitors is clinically indicated for the management of all forms of ER-positive breast cancer. However 30-50% of ER-positive breast cancer cases fail to benefit clinically from endocrine therapy alone, and recent molecular evidence suggests that 'crosstalk' pathways originating from activated receptor tyosine kinases and/or other roliferative and survival signals may be contributing to this endocrine resistance. Molecular identification and validation of candidate ER crosstalking pathways will likely lead to clinically important prognostic markers and targets for the application of novel therapeutics in combination with standard endocrine agents. This review focuses on a critical survival and proliferation pathway involving activation of nuclear factor-kB (NF-kB), a family of ubiquitously expressed transcription factors that for nearly two decades have been known to be critical regulators of mammalian immune and inflammatory responses, and more recently have been associated with chemotherapy resistance. With the demonstration that activation of NF-kB is absolutely required for normal mammary gland development, NF-kB invovement in human breast cancers was initially explored and linked in the development of hormone-independent(ER-negative) breast cancer. Newer clinical evidence now implicates NF-kB activation, particularly DNA-binding by the p50 subunit of NF-kB, as a potential prognostic marker capable of identifying high-risk subset of ER-positive, primary breast cancers destined for early relapse despite adjuvant endocrine therapy with tamoxifen. Furthermore, initial preclinical studies suggest that treatment strategies designed to prevent or interrupt activation of NF-kB in cell-line models of these more aggressive, ER-positive breast cancers can restore their sensitivity to such standard endocrine agents as tamoxifen.
Article at:
http://erc.endocrinology-journals.org/content/12/Supplement_1/S37.full.pdf
NF-?B as potential target in the treatment of melanoma in Journal of Translational Medicine, Gabriele Madonna1, Claudio Dansky Ullman2, Giusy Gentilcore1, Giuseppe Palmieri3 and Paolo Antonio Ascierto1*1 Unit of Medical Oncology and Innovative Therapy, Istituto Nazionale Tumori Fondazione, G. Pascale, Napoli, Italy
2 Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, USA
3 Institute of Biomolecular Chemistry-CNR, Sassari, Italy
Abstract:
"The RAS/MAP kinase pathway has attracted attention because activating mutations of the BRAF serine/threonine kinase was described in over 50% of melanomas. Very recently, selective and potent BRAF inhibitors have been developed. Several other signal transduction pathways have been found to be constitutively active or mutated in other subsets of melanoma tumors that are potentially targetable with new agents. Among these, NF?B is another pathway that melanoma tumors use to achieve survival, proliferation and resistance to apoptosis. Inhibition of NF-?B activation appears to be a very promising option for anti-cancer therapies."
Article at:
http://www.translational-medicine.com/content/10/1/53#
What You Need to Know About the Fraudulent Nature of the Pharmaceutical Investment Business With Disease in Dr Rath Health Foundation, no author, no date
My comments:
Interesting perspective about the pharmaceutical business. Read both the "The Laws of the Pharmaceutical Business with Disease" and "The History of the Pharma-Cartel"
Link at:
http://www4.dr-rath-foundation.org/open_letters/pharma_laws_history.html
List of largest pharmaceutical settlements, Wikipedia
My Comments:
Interesting to see what 'Big Pharma' business entails--fraud? Worth taking a look see, this is what they got caught at.
Link at:
http://en.wikipedia.org/wiki/List_of_largest_pharmaceutical_settlements
Military Building Brain Chips to Treat PTSD in Newsmax Health, Nick Tate, Thursday, 29 May 2014
Article:
"The Pentagon is working to develop a new brain chip to help treat post-traumatic stress disorder in soldiers and veterans, the Defense One Website reports.
The innovation could bring sweeping changes to the way PTSD, as well as depression and anxiety, is treated for millions of Americans.
The Defense Advanced Research Projects Agency (DARPA) is working with scientists from the University of California-San Francisco, Lawrence Livermore National Lab, and Medtronic to create an implanted chip with electrodes extending into the brain to treat PTSD. The military hopes to have a prototype within five years and then plans to seek Food and Drug Administration approval.
The technology draws on a decade of research in treating disorders such as Parkinson's disease through a technique called deep brain stimulation. Low doses of electricity are pulsed into the brain in a way that is similar to how a defibrillator sends electricity to jumpstart a heart after cardiac arrest.
"DARPA is looking for ways to characterize which regions come into play for different conditions — measured from brain networks down to the single neuron level — and develop therapeutic devices that can record activity, deliver targeted stimulation, and most importantly, automatically adjust therapy as the brain itself changes," said Justin Sanchez, the DARPA program manager.
If it is successful, the research will produce new brain-monitoring capabilities that can help researchers better understand — and modify — the electrical patterns in the brain that signal anxiety, memory loss, and depression."
Article at:
http://www.newsmaxhealth.com/Health-News/brain-chips-treat-ptsd/2014/05/29/id/574045#ixzz33PaLBDfH
What do Americans spend fighting cancer? in CNBC Biotechs and Pharmaceuticals, Meg Tirrell, 30 May 2014
Excerpts:
"How many people get cancer?
Half of all men and a third of all women in the U.S. will develop cancer in their lifetimes. The median age of diagnosis is 66 years old.
This year, an estimated 1.67 million new cases of cancer will be diagnosed in the U.S., with prostate, breast and lung cancers being the most common types.
The World Health Organization says more than 30 percent of cancer deaths could be prevented by modifying behaviors. Tobacco use is the single most important risk factor for cancer, accounting for about 22 percent of cancer deaths globally
Other risk factors include being overweight or obese, eating too few fruits and vegetables, low levels of physical activity and alcohol use.
Fortunately, the five-year survival rate in the U.S. for cancers diagnosed between 2003 and 2009 is 68 percent. That's up from 49 percent for 1975 to 1977."
"The U.S. is expected to spend at least $158 Billion on medical expenses for cancer in 2020 up from $124.6 Billion in 2010."
"The global market for cancer drugs grew to $91 Billion in 2013, up from $71 Billion in 2008 and $37 Billion in 2003."
"The average cost per month of a branded cancer drug in the U.S. has risen to $10,000 from $5,000 a decade ago"
Article at:
http://www.cnbc.com/id/101718721