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INHIBITORS 8
Triptolide - NF-kB Inhibitor
Triptolide, a diterpenoid isolated from the Chinese herb Tripterygium wilfordii hook F, has been used for centuries in traditional Chinese medicine to treat
immune-related disorders. Current knowledge regarding its mechanism of action is still limited. So far, triptolide is known to block the activation of NF-kB 6,
inhibit the heat shock response 7 and induce caspase activation 8 .
1. Pierce JW. et al., 1997. Novel Inhibitors of Cytokine-induced Ikappa Balpha Phosphorylation and Endothelial Cell Adhesion Molecule Expression Show Anti-inflammatory Effects in Vivo. J.
Biol. Chem., 272: 21096. 2. Phulwani NK. et al., 2008. TLR2 Expression in Astrocytes Is Induced by TNF-{alpha}- and NF-{kappa}B-Dependent Pathways. J. Immunol., 181: 3841-3849.
3. Méndez-Samperio P. et al., 2008. Mycobacterium bovis Bacillus Calmette-Guérin Induces CCL5 Secretion via the Toll-Like Receptor 2-NF-{kappa}B and -Jun N-Terminal Kinase Signaling
Pathways. Clin. Vaccine Immunol. 15: 277 - 283. 4 Sethi G. et al., 2007. Celastrol, a novel triterpene, potentiates TNF-induced apoptosis and suppresses invasion of tumor cells by inhibiting
NF-kB–regulated gene products and TAK1-mediated NF-B activation. Blood, 109: 2727 - 2735. 5. Jung HW. et al., 2007. Celastrol inhibits production of nitric oxide and proinflammatory
cytokines through MAPK signal transduction and NF-kappaB in LPS-stimulated BV-2 microglial cells. Exp Mol Med. 39(6):715-21. 6. Lee KY. et al., 1999. PG490 (triptolide) cooperates with
tumor necrosis factor-alpha to induce apoptosis in tumor cells. J Biol Chem. 274: 13451-13455. 7. Westerheide SD. et al., 2006. Triptolide, an Inhibitor of the Human Heat Shock Response
That Enhances Stress-induced Cell Death. J. Biol. Chem., 281: 9616 - 9622. 8. Carter BZ. et al., 2006. Triptolide induces caspase-dependent cell death mediated via the mitochondrial pathway
in leukemic cells. Blood 108: 630 - 7.
Mitogen-Activated Protein (MAP) Kinase Inhibitors
PD98059 - MAP Kinase Kinase Inhibitor
PD98059 is a potent and selective inhibitor of MAP kinase kinase (also known as MAPK/ERK kinase or MEK kinase) 1 . It mediates its inhibitory properties by
binding to the ERK-specific MAP kinase MEK, therefore preventing phosphorylation of ERK1/2 (p44/p42 MAPK) by MEK1/2.
PD0325901 - MEK Inhibitor
PD0325901 is a selective inhibitor of mitogen-activated protein kinase kinase (MEK), with potential antineoplastic activity 2 . MEK is a key component of the
RAS/RAF/MEK/ERK signaling pathway that is frequently activated in human tumors. This pathway plays also an important role in the self-renewing state of
embryonic stem cells. Treatment with PD0325901 has been shown to enhance reprogramming efficiencies of induced pluripotent stem cells 3 .
SB203580 - p38/RK MAP Kinase Inhibitor
SB203580 is a pyridinyl imidazole inhibitor widely used to elucidate the roles of p38 mitogen-activated protein (MAP) kinase 4 . SB203580 inhibits also the
phosphorylation and activation of protein kinase B (PKB, also known as Akt) 5 .
SP600125 - JNK Inhibitor
SP600125 is a potent, cell-permeable, selective and reversible inhibitor of c-Jun N-terminal kinase (JNK) 6 . It inhibits in a dose-dependent manner the phosphorylation
of JNK. JNK is a member of the mitogen-activated protein kinase (MAPK) family and plays an essential role in TLR-mediated inflammatory responses.
U0126 - MEK1 and MEK2 Inhibitor
U0126 is a selective inhibitor of the MAP kinase kinases, MEK1 and MEK2. It acts by inhibiting the kinase activity of MEK1/2 thus preventing the activation of
MAP kinases p42 and p44 which are encoded by the erk2 and erk1 genes respectively 7 .
1. Alessi DR. et al., 1995. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J. Biol. Chem. 270, 27489-27494. 2. Kohno M. &
Pouyssegur J. 2006. Targeting the ERK signaling pathway in cancer therapy. Ann Med. 38(3):200-11. 3. Lin T. et al., 2009. A chemical platform for improved induction of human iPSCs.
Nat Methods. 6(11):805-8. 4. Cuenda A. et al., 1995. SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett.
364:229-233. 5. Lali FV. et al., 2000.The pyridinyl imidazole inhibitor SB203580 blocks phosphoinositide-dependent protein kinase activity, protein kinase B phosphorylation, and retinoblastoma
hyperphosphorylation in interleukin-2-stimulated T cells independently of p38 mitogen-activated protein kinase. J Biol Chem. 275(10):7395-402. 6. Bennett BL. et al., 2001. SP600125, an
anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc. Natl. Acad. Sci. USA. 98:13681-13686. 7. Favata MF. et al., 1998. Identification of a novel inhibitor of mitogen-activated protein
kinase.J. Biol. Chem. 273(29):18623-32.
Phosphatidylinositol 3-Kinase (PI3K) Inhibitors
3-Methyladenine - PI3K inhibitor
3-Methyladenine is commonly used as a specific inhibitor of autophagic sequestration 1 . It blocks autophagy by inhibition of phosphatidylinositol 3-kinase
(PI3K) activity, an enzyme required for autophagy 2 .
LY294002 - PI3K Inhibitor
LY294002 is a potent, cell permeable inhibitor of PI3K that acts on the ATP binding site of the enzyme 3 . LY294002 is often used to study the role of PI3K
in apoptosis 4 and autophagy 2 .
Wortmannin - PI3K Inhibitor
Wortmannin is a cell-permeable, fungal metabolite that acts as a potent, selective and irrevesible inhibitor of PI3K 5 . Wortmannin has been used to determine
the involvement of PI3K in many cellular processes, such as apoptosis 4 , autophagy 2 and TLR signaling 6 .
1. Seglen PO. & Gordon PB., 1982. 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. PNAS. 1982 Mar;79(6):1889-92.
2. Blommaart EF. et al., 1997. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur. J. Biochem. 243: 240–246.
3. Vlahos CJ. et al., 1994. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J. Biol. Chem 69(7):5241-8. 4. Duronio V.,
2008. The life of a cell: apoptosis regulation by the PI3K/PKB pathway. Biochem J. 415(3):333-44. 5. Arcaro A. and Wymann MP., 1993. Wortmannin is a potent phosphatidylinositol 3-kinase
inhibitor: the role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses. Biochem. J. 296:297-301. 6. Fukao T and Koyasu S., 2003. PI3K and negative regulation of TLR signaling.
Trends Immunol 24: 358-363.
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