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Chemical Compound Review

BIM-9     3-[3-[4-(1-methylindol-3-yl)- 2,5-dioxo...

Synonyms: CHEMBL6291, AG-K-37651, SureCN1567017, BSPBio_001077, KBioGR_000417, ...
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Disease relevance of Bisindolylmaleimide 11b

  • Therefore, we examined the effects of three inhibitors of protein kinase C, CGP 41251, RO 31-8220, and calphostin C, on human glioblastoma cells [1].
  • Here we have examined the effects of two PKC inhibitors, staurosporine and the more selective agent Ro 31-8220, on IL1 responses in the murine thymoma line EL4.NOB-1 [2].
  • Treatment of human melanoma cells with the selective PKC inhibitor Ro-31-8220 resulted in a significant increase of cell proliferation as measured by (3)H-thymidine incorporation and a fluorometric microassay [3].
  • The MAP kinase response to UTP was partially blocked by pertussis toxin (67+/-3% inhibition) and by the PKC inhibitor Ro 31-8220 (10 microm; 45+/-5% inhibition), indicating the possible involvement of both Gi/Go protein and Gq protein-dependent pathways in the overall response to UTP [4].
  • Ro 31-8220, in particular, might be a useful agent for the treatment of human brain tumors [5].

High impact information on Bisindolylmaleimide 11b

  • PKD activation was completely abrogated by exposure of the cells to the protein kinase C inhibitors GF I and Ro 31-8220 [6].
  • PSP was also specifically phosphorylated in permeabilized platelets after cellular stimulation by phorbol esters or thrombin and this phosphorylation was blocked by the PKC inhibitor Ro-31-8220 [7].
  • In contrast, PAF activates eosinophils independent of Gi by a mechanism that is abolished by Ro 31-8220, a selective protein kinase C inhibitor [8].
  • The specific protein kinase C inhibitor, Ro 31-8220, was without effect, whereas the unspecific inhibitors, staurosporine and calphostin C, abolished the shear stress-induced production of NO [9].
  • PKD activation induced by NT was abrogated by treatment of PANC-1 cells with PKC inhibitors GF-1 and Ro 31-8220 [10].

Chemical compound and disease context of Bisindolylmaleimide 11b


Biological context of Bisindolylmaleimide 11b

  • The staurosporine analog, Ro-31-8220, induces apoptosis independently of its ability to inhibit protein kinase C [14].
  • Interestingly, proliferation of the Bcl-2-over-expressing cells was still sensitive to the presence of Ro-31-8220, suggesting that the inhibitory effects of Ro-31-8220 on viability and cell proliferation were mediated by different mechanisms [14].
  • Moreover, the ability of Ro-31-8220 to induce apoptotic activation was completely inhibited by the over-expression of the apoptotic suppressor gene, Bcl-2, in the cells [14].
  • However, the biological effects of the Bis compounds were different: Bis-I and Bis-II had no observable effects on either cell survival or proliferation; Bis-III inhibited cell proliferation but not survival, whereas Ro-31-8220 induced apoptosis [14].
  • Effects of both agonists on intra- and extracellular release were inhibited by the protein kinase C (PKC) inhibitor, Ro-31-8220, and PKC down-regulation by preincubation with TPA [15].

Anatomical context of Bisindolylmaleimide 11b

  • In this report we describe the effects of the Bis analogs, Bis-I, Bis-II, Bis-III and Ro-31-8220 on the survival and proliferation of HL-60 cells, which have been widely used as a model cell system for studying the biological roles of PKC [14].
  • In studies of glucose transport, inhibition of immunoprecipitated PKC-zeta enzyme activity in vitro by both the PKC-zeta pseudosubstrate and RO 31-8220 correlated well with inhibition of insulin-stimulated glucose transport in intact adipocytes [16].
  • Bombesin-mediated PKD activation was prevented by treatment of Swiss 3T3 cells with the protein kinase C inhibitors GF 1092030X and Ro 31-8220 [17].
  • Ro-31-8220, a pan-protein kinase C (PKC) inhibitor, and Go6976, a classical PKC inhibitor, blunted LPS-induced HO-1 mRNA expression in monocytes and THP-1 cells [18].
  • Significantly, pretreatment of Swiss 3T3 fibroblasts with 1 microM phorbol 12-myristate 13-acetate for 24 h, or with the selective protein kinase C inhibitor Ro-31-8220, reduced LPA-stimulated phosphorylation of Tiam1 by approximately 75% [19].

Associations of Bisindolylmaleimide 11b with other chemical compounds

  • Inhibition of protein kinase C with Ro 31-8220 nearly abolished the effects of PMA, but had no effect on either pervanadate-induced protein tyrosine phosphorylation or amylase secretion [20].
  • Bryostatin 1-induced PKD activation was markedly attenuated by treatment of cells with the PKC inhibitors bisindolylmaleimide I and Ro 31-8220 [21].
  • The down-regulatory effect of C(2)-ceramide on type I collagen mRNA levels was abrogated by protein kinase C inhibitors H7, staurosporine, and Ro-31-8220 and potently inhibited by a combination of MEK1,2 inhibitor PD98059 and p38 inhibitor SB203580 [22].
  • Using a protein tyrosine kinase inhibitor, herbimycin A, or a protein kinase C inhibitor, Ro-31-8220, we found that the anti-CD38-induced Erk-2 activation is both protein tyrosine kinase and protein kinase C dependent [23].
  • Furthermore, inhibition of U46619-induced platelet aggregation by Ro 31-8220 was relieved by activation of the G(i) pathway by selective activation of either the P2T(AC) receptor or the alpha(2A)-adrenergic receptor [24].

Gene context of Bisindolylmaleimide 11b

  • In the presence of forskolin, Ro 31-8220 loses its ability to block UTP-stimulated ERK activation [25].
  • The increase in inositol phosphates induced by bFGF, EGF, or bombesin was significantly enhanced by Ro-31-8220, an inhibitor of protein kinase C (PKC), suggesting that PtdIns(4,5)P2-hydrolyzing phospholipase is coupled to the receptors for these agonists but that the response is down-regulated by PKC [26].
  • Inhibition of 1) p70 S6 kinase by rapamycin, 2) protein kinase B by Akt inhibitor, or 3) protein kinase C by Ro-31-8220, the potential downstream targets of PI3K for activation of gIV-PLA(2), had no effect on AA release or LTC(4) secretion caused by fMLP [27].
  • The protein kinase C (PKC) inhibitors RO 31-8220, Gö 6976, and a pseudosubstrate peptide inhibitor of atypical PKCs attenuated arachidonic acid release, cPLA(2) phosphorylation, and NF-kappaB activation induced by TNF-alpha or IL-1beta, thus indicating atypical PKCs in cPLA(2) regulation and transcription factor activation [28].
  • Protein kinase C (PKC) inhibitors (staurosporine or Ro 31-8220) also inhibited IFN-gamma-induced response [29].

Analytical, diagnostic and therapeutic context of Bisindolylmaleimide 11b


  1. Disorders in cell circuitry associated with multistage carcinogenesis: exploitable targets for cancer prevention and therapy. Weinstein, I.B., Begemann, M., Zhou, P., Han, E.K., Sgambato, A., Doki, Y., Arber, N., Ciaparrone, M., Yamamoto, H. Clin. Cancer Res. (1997) [Pubmed]
  2. Staurosporine, but not Ro 31-8220, induces interleukin 2 production and synergizes with interleukin 1alpha in EL4 thymoma cells. Mahon, T.M., Matthews, J.S., O'Neill, L.A. Biochem. J. (1997) [Pubmed]
  3. Proliferation of human melanoma cells is under tight control of protein kinase C alpha. Krasagakis, K., Lindschau, C., Fimmel, S., Eberle, J., Quass, P., Haller, H., Orfanos, C.E. J. Cell. Physiol. (2004) [Pubmed]
  4. Human adenosine A1 receptor and P2Y2-purinoceptor-mediated activation of the mitogen-activated protein kinase cascade in transfected CHO cells. Dickenson, J.M., Blank, J.L., Hill, S.J. Br. J. Pharmacol. (1998) [Pubmed]
  5. Growth inhibition induced by Ro 31-8220 and calphostin C in human glioblastoma cell lines is associated with apoptosis and inhibition of CDC2 kinase. Begemann, M., Kashimawo, S.A., Lunn, R.M., Delohery, T., Choi, Y.J., Kim, S., Heitjan, D.F., Santella, R.M., Schiff, P.B., Bruce, J.N., Weinstein, I.B. Anticancer Res. (1998) [Pubmed]
  6. Protein kinase D (PKD) activation in intact cells through a protein kinase C-dependent signal transduction pathway. Zugaza, J.L., Sinnett-Smith, J., Van Lint, J., Rozengurt, E. EMBO J. (1996) [Pubmed]
  7. Human platelets contain SNARE proteins and a Sec1p homologue that interacts with syntaxin 4 and is phosphorylated after thrombin activation: implications for platelet secretion. Reed, G.L., Houng, A.K., Fitzgerald, M.L. Blood (1999) [Pubmed]
  8. Pertussis toxin shows distinct early signalling events in platelet-activating factor-, leukotriene B4-, and C5a-induced eosinophil homotypic aggregation in vitro and recruitment in vivo. Teixeira, M.M., Giembycz, M.A., Lindsay, M.A., Hellewell, P.G. Blood (1997) [Pubmed]
  9. Intracellular pH and tyrosine phosphorylation but not calcium determine shear stress-induced nitric oxide production in native endothelial cells. Ayajiki, K., Kindermann, M., Hecker, M., Fleming, I., Busse, R. Circ. Res. (1996) [Pubmed]
  10. Neurotensin induces protein kinase C-dependent protein kinase D activation and DNA synthesis in human pancreatic carcinoma cell line PANC-1. Guha, S., Rey, O., Rozengurt, E. Cancer Res. (2002) [Pubmed]
  11. Induction of apoptosis in glioblastoma cells by inhibition of protein kinase C and its association with the rapid accumulation of p53 and induction of the insulin-like growth factor-1-binding protein-3. Shen, L., Glazer, R.I. Biochem. Pharmacol. (1998) [Pubmed]
  12. Tyrosine phosphorylation of a 34-kDa protein induced by cross-linking a novel glycosylphosphatidylinositol-anchored glycoprotein (GPI-80) on human neutrophils that may regulate their adherence and migration. Yu, Y., Araki, Y., Sendo, F. IUBMB Life (2000) [Pubmed]
  13. Rehmannia glutinosa induces glial cell line-derived neurotrophic factor gene expression in astroglial cells via cPKC and ERK1/2 pathways independently. Yu, H., Oh-Hashi, K., Tanaka, T., Sai, A., Inoue, M., Hirata, Y., Kiuchi, K. Pharmacol. Res. (2006) [Pubmed]
  14. The staurosporine analog, Ro-31-8220, induces apoptosis independently of its ability to inhibit protein kinase C. Han, Z., Pantazis, P., Lange, T.S., Wyche, J.H., Hendrickson, E.A. Cell Death Differ. (2000) [Pubmed]
  15. Regulation of phospholipase D in L6 skeletal muscle myoblasts. Role of protein kinase c and relationship to protein synthesis. Thompson, M.G., Mackie, S.C., Thom, A., Palmer, R.M. J. Biol. Chem. (1997) [Pubmed]
  16. Protein kinase C-zeta as a downstream effector of phosphatidylinositol 3-kinase during insulin stimulation in rat adipocytes. Potential role in glucose transport. Standaert, M.L., Galloway, L., Karnam, P., Bandyopadhyay, G., Moscat, J., Farese, R.V. J. Biol. Chem. (1997) [Pubmed]
  17. Bombesin, vasopressin, endothelin, bradykinin, and platelet-derived growth factor rapidly activate protein kinase D through a protein kinase C-dependent signal transduction pathway. Zugaza, J.L., Waldron, R.T., Sinnett-Smith, J., Rozengurt, E. J. Biol. Chem. (1997) [Pubmed]
  18. Lipopolysaccharide-induced heme oxygenase-1 expression in human monocytic cells is mediated via Nrf2 and protein kinase C. Rushworth, S.A., Chen, X.L., Mackman, N., Ogborne, R.M., O'Connell, M.A. J. Immunol. (2005) [Pubmed]
  19. Lysophosphatidic acid induces threonine phosphorylation of Tiam1 in Swiss 3T3 fibroblasts via activation of protein kinase C. Fleming, I.N., Elliott, C.M., Collard, J.G., Exton, J.H. J. Biol. Chem. (1997) [Pubmed]
  20. Pervanadate stimulates amylase release and protein tyrosine phosphorylation of paxillin and p125(FAK) in differentiated AR4-2J pancreatic acinar cells. Feick, P., Gilhaus, S., Schulz, I. J. Biol. Chem. (1998) [Pubmed]
  21. Bryostatin 1 induces biphasic activation of protein kinase D in intact cells. Matthews, S.A., Pettit, G.R., Rozengurt, E. J. Biol. Chem. (1997) [Pubmed]
  22. Activation of extracellular signal-regulated kinase 1/2 inhibits type I collagen expression by human skin fibroblasts. Reunanen, N., Foschi, M., Han, J., Kahari, V.M. J. Biol. Chem. (2000) [Pubmed]
  23. CD38 ligation results in activation of the Raf-1/mitogen-activated protein kinase and the CD3-zeta/zeta-associated protein-70 signaling pathways in Jurkat T lymphocytes. Zubiaur, M., Izquierdo, M., Terhorst, C., Malavasi, F., Sancho, J. J. Immunol. (1997) [Pubmed]
  24. Molecular mechanism of thromboxane A(2)-induced platelet aggregation. Essential role for p2t(ac) and alpha(2a) receptors. Paul, B.Z., Jin, J., Kunapuli, S.P. J. Biol. Chem. (1999) [Pubmed]
  25. A2B adenosine and P2Y2 receptors stimulate mitogen-activated protein kinase in human embryonic kidney-293 cells. cross-talk between cyclic AMP and protein kinase c pathways. Gao, Z., Chen, T., Weber, M.J., Linden, J. J. Biol. Chem. (1999) [Pubmed]
  26. Stimulation of phospholipase D by epidermal growth factor requires protein kinase C activation in Swiss 3T3 cells. Yeo, E.J., Exton, J.H. J. Biol. Chem. (1995) [Pubmed]
  27. Activation of group IV cytosolic phospholipase A2 in human eosinophils by phosphoinositide 3-kinase through a mitogen-activated protein kinase-independent pathway. Myou, S., Leff, A.R., Myo, S., Boetticher, E., Meliton, A.Y., Lambertino, A.T., Liu, J., Xu, C., Munoz, N.M., Zhu, X. J. Immunol. (2003) [Pubmed]
  28. Atypical lambda/iota PKC conveys 5-lipoxygenase/leukotriene B4-mediated cross-talk between phospholipase A2s regulating NF-kappa B activation in response to tumor necrosis factor-alpha and interleukin-1beta. Anthonsen, M.W., Andersen, S., Solhaug, A., Johansen, B. J. Biol. Chem. (2001) [Pubmed]
  29. Interferon-gamma-induced epithelial ICAM-1 expression and monocyte adhesion. Involvement of protein kinase C-dependent c-Src tyrosine kinase activation pathway. Chang, Y.J., Holtzman, M.J., Chen, C.C. J. Biol. Chem. (2002) [Pubmed]
  30. Activation of platelet-activating factor (PAF) receptor stimulates nitric oxide (NO) release via protein kinase C-alpha in HEC-1B human endometrial epithelial cell line. Dearn, S., Rahman, M., Lewis, A., Ahmed, Z., Eggo, M.C., Ahmed, A. Mol. Med. (2000) [Pubmed]
  31. Effect of protein kinase C inhibitors and 2,3-butanedione monoxime on the long-term hypothermic preservation of isolated rat hearts. Fagbemi, O.S., Northover, B.J. Clin. Sci. (1996) [Pubmed]
  32. Failure to activate caspase 3 in phorbol ester-resistant leukemia cells is associated with resistance to apoptotic cell death. Choi, Y.J., Park, J.W., Woo, J.H., Kim, Y.H., Lee, S.H., Lee, J.M., Kwon, T.K. Cancer Lett. (2002) [Pubmed]
  33. Vasoconstriction in rat isolated mesentery and small intestine in response to various activators of protein kinase C. Northover, A.M., Northover, B.J. Agents Actions (1994) [Pubmed]
  34. Evidence for protein kinase involvement in long-term postsynaptic excitation of intrinsic primary afferent neurons in the intestine. Nguyen, T.V., Stebbing, M.J., Clerc, N., Kawai, M., Harvey, J.R., Furness, J.B. Autonomic neuroscience : basic & clinical. (2004) [Pubmed]
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