12 New Necrosis Signaling Pathway Inhibitors
New Necrosis signaling pathway inhibitors
Necrosis is the premature death of cells in living tissue and can be caused by external factors to the cell or tissue, such as infection, toxins, cancer, infarction, poisons, ROS (Reactive Oxygen Species), inflammation or trauma.
Historically, cell death has been subdivided into regulated (apoptosis, aka programmed cell death) and unregulated (necrosis) forms. While apoptosis has always been recognized to be a pathway of highly coordinated signaling events which is a naturally occurring cause of cellular death and can often provide beneficial effects to the organism.
Necrosis is morphologically characterized by a gain in cell volume (oncosis), swelling of organelles, plasma membrane rupture and subsequent loss of intracellular contents.
Necrosis or necrotic cell death is almost always detrimental and can be fatal. Currently, necrotic pathways are poorly defined and are still largely identified in negative terms by the absence of apoptotic or autophagic markers.
Biochemically it is characterized by loss of regulation in ion homeostasis, random digestion of DNA & ultimately postlytic of DNA fragmentation. Physiologically, necrosis affects groups of contiguous cells, phagocytosis by macrophages and significant inflammatory immune response.
AG-126: Tyrphostin AG 126, reduces LPS-induced tyrosine phosphorylation of p42MAPK Tyrphostin AG126 prevented the PCW-inducible phosphorylation of p42/p44(MAPK), potently blocked cytokine release and drastically reduced the bioavailable TNFα. AG-126 or TNFα-specific siRNA) were used to block apoptotic and necrotic death signaling.
Chetomin: Chetomin, Inhibitor of tumor growth, anti-bacterial agent and demonstrates potent immunosuppressive properties. Chetomin, an inhibitor of hypoxia-inducible factors (HIF).Shown to attenuate hypoxia-induced transcription in vitro (IC50= 20 mM) and < 10 nM in inhibiting secreted and cellular VEGF, respectively, in Hep38 cells) and inhibit tumor growth by inducing necrosis in vivo.
DMNQ: DMNQ is a Redox-cycling agent that induces intracellular superoxide anion formation and, depending on the concentration, induces cell proliferation, apoptosis or necrosis. DMNQ does not react with free thiol groups, is non-alkylating and adduct-forming in contrast to other quinones. Thus, DMNQ is a valuable tool for the generation of reactive oxygen species (ROS) in order to study the role of ROS in cell toxicity, apoptosis and necrosis.
CYCLOSPORIN A: Cyclosporin A isolated from Fusarium Solani. Potent immunosuppressor. Inhibits nitric oxide (NO) synthesis induced by interleukin 1α, LPS, and TNFα. Cyclosporin A-cyclophilin complexes block calcineurin (protein phosphatase 2B), a key enzyme in T cell activation. Also an inhibitor of the mitochondrial permeability transition pore (MPTP) and preventor of necrosis in several models
MYRISTOLEIC ACID METHYL ESTER MYRISTOLEIC Acid is a cytotoxic fruit extract. It induces apoptosis and necrosis in human prostate cancer cells. The methyl ester form increases its hydrophobicity.
IM-54: IM-54 is an indolylmaleimide derivative which, at 1 μM, inhibits necrotic cell death induced by Hydrogen peroxide in promyelocytic leukemia HL-60 cells. It does not prevent etoposide-induced apoptosis and does not inhibit protein kinase C or S6 kinase 1.
Necrosis Inhibitor-2, NecroX-2, a cell permeable necrosis inhibitor, with antioxidant activity. It localizes mostly in mitochondra. Selectively blocks oxidative stress-induced necrotic cell death. (0.1μM Necrosis inhibitor 2 prevented ˜50% cell death in H9C2 cells exposed to 400 μM t-BuOOH for 2 hours LDH assay used). Does not protect against staurosporine or etoposide induced apoptosis. Protects cells against cold shock, hypoxia and oxidative stress in vitro.Ref: H.J. Kim et al. Arch. Pharm. Res. 33. 1813 (2010).
Necrosis Inhibitor-5, NecroX-5, is a cell-permeable necrosis inhibitor with antioxidant activity. It localizes mostly in mitochondria. Selectively blocks oxidative stress-induced necrotic death (0.1 μM Necrosis Inhibitor 5, prevented ˜50% cell death in H9C2 cells exposed to 400μM t-BuOOH for 2 hours LDH assay used). Does not protect against staurosporine or Etoposide-induce apoptosis.Protects cells against cold shock, hypoxia and oxidative stress in vitro, as well as, CCL4- induced acute liver and chronic liver fibrosis in rodent models.H.J. Kim et al. Arch. Pharm. Res. 33. 1813 (2010).
PJ-34: PJ-34 is a potent, water soluble poly (ADP-ribose) polymerase (PARP) inhibitor (EC50=20nM) compared to (EC50=200μM )of the prototypical PARP inhibitor 3-aminobenzamide. Inhibits induced cell necrosis (EC50=20nM). Has significant, dose dependent,anti-inflammatory effects in a variety of localInflammation models and provides cardioprotection by decreasing myocardial infarct size.
Sterigmatocystin: Sterigmatocystin is a mycotoxin that inhibits DNA synthesis. Induces sister chromatid exchanges in bone marrow cells of mice. Causes necrosis.
ST-638: Tyrphostin ST-638, is a tyrosine kinase inhibitor (IC50= 370 nM). It suppresses tyrosine phosphorylation induced by tumor necrosis factor-α and phorbol myristate acetate in neutrophils and by angiotensin II in cardiac fibroblasts. Also shown to inhibit phospholipase D activity in human neutrophils.
Thaxtomin: Phytotoxin. Causes plant cell necrosis at nanomolar concentrations. Demonstrated to be produced by bacterial nitric oxide synthases (NOS).The complete Novel Necrosis & Necroptosis Pathway Reagents E-Booklet
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Detailed description of fuctionality.
Detailed description of Necroptosis pathways .
Identification of Necroptosis downstream mechanisms
Applications of Small Molecule Necrosis Inhibitors
Complete listing of Reagents and Chemical Structure.