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Chemical Compound Review

AG-H-28996     1-[6-[(3-ethanoyl-2,4,6- trihydroxy-5...

Synonyms: AG-K-50754, KBioGR_000420, KBioSS_000420, CBiol_002045, CTK7F5758, ...
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Disease relevance of rottlerin

  • Furthermore, the glioma cell line U373, which expresses endogenous PKCdelta, underwent apoptosis in response to etoposide, and the apoptotic response was blocked by the PKCdelta inhibitor rottlerin [1].
  • Data suggest that rottlerin affects mitochondrial function independent of PKC delta, thereby sensitizing cells to TRAIL, and that mitochondria constitute an important target in overcoming inherent resistance to TRAIL in colon carcinomas [2].
  • The effects of PMA on MAPK phosphorylation and glioblastoma cell proliferation were reduced by BIM, rottlerin, the MEK inhibitor U0126, and PKCdelta and c-Src siRNAs [3].
  • We selectively blocked the activity of PKC isoforms by using GF 109203X or rottlerin and demonstrated that this inhibition largely decreased lytic KSHV reactivation by TPA [4].
  • METHODS: In this report we compared the effect of staurosporine, Bis II, Gö 6976, rottlerin, and pertussis toxin on histamine release from human basophils mediated by the following stimuli: HrHRF, polyclonal human anti-IgE antibody, and antigen, as well as the IgE-independent stimulus, FMLP [5].

High impact information on rottlerin

  • This COL1A1 segment imparted rottlerin sensitivity to a heterologous promoter [6].
  • In vitro nuclear transcription assays and transient transfections with COL1A1 promoter deletion constructs demonstrated that rottlerin profoundly reduced COL1A1 transcription and that this effect required a 129-bp promoter region encompassing nucleotides -804 to -675 [6].
  • Furthermore, the PKCdelta/PKC inhibitor rottlerin prevented the effects induced by phorbol 12-myristate 13-acetate and human neutrophil elastase, suggesting that PKCdelta and PKC are involved in Duox1 activation [7].
  • In VASP(-/-) platelets, the enhancement of filopodia generation, actin polymerization, and platelet aggregation by rottlerin is ablated [8].
  • Cotreatment with rottlerin, a PKCdelta-specific inhibitor, completely blocks NSC606985-induced mitochondrial DeltaPsim loss and caspase-3 activation, while the inhibition of caspase-3 by z-DEVD-fluoromethyl ketone (Z-DEVD-fmk) only partially attenuates PKCdelta activation and apoptosis [9].

Chemical compound and disease context of rottlerin


Biological context of rottlerin

  • Pretreatment of these cells with the PKC-delta inhibitor rottlerin prevented the thrombin-induced phosphorylation of p38 MAP kinase, suggesting that p38 MAP kinase signals downstream of PKC-delta [14].
  • Both the PKC delta inhibitor rottlerin and ectopic expression of a dominant negative form of PKC delta independently restored SRE-dependent transcription and immediate-early gene expression in senescent cells [15].
  • The biological significance of these findings is implicated by the finding that rottlerin, a selective PKCtheta inhibitor, blocked FasL induction by anti-CD3 or PMA plus ionomycin stimulation and, consequently, protected human Jurkat T cells and the mouse T cell hybridoma A1.1 from activation-induced cell death [16].
  • DNA damage-induced SAPK activation was attenuated by (i) treatment with rottlerin, (ii) expression of a kinase-inactive PKCdelta(K-R) mutant, and (iii) down-regulation of PKCdelta by small interfering RNA (siRNA) [17].
  • Pretreatment with the PKC delta-selective inhibitor rottlerin or transfection with an antisense PKC delta oligonucleotide inhibited PMA-induced cIAP-2 expression, whereas cotransfection with a PKC delta plasmid induced cIAP-2 promoter activity, which, taken together, identifies a role for PKC delta in cIAP-2 induction [18].

Anatomical context of rottlerin

  • Similar to the situation in splenic B cells, rottlerin inhibits BCR and PMA stimulation of NF-kappaB in 70Z/3 cells [19].
  • However, after 15-min incubation with rottlerin, mitochondrial membrane potential (Delta psi m) was dramatically reduced in RKO cells, and, in cells subsequently treated with TRAIL, rapid apoptosis was evident within 8 h [2].
  • In contrast, a PKCdelta inhibitor, rottlerin, had an opposite effect on cell clustering and caused dissociation of cell junctions [20].
  • Furthermore, lysate-derived PKCdelta from activated monocytes phosphorylated p47phox in a rottlerin-sensitive manner [21].
  • Signaling via both the TCR and CD28 is required for optimal activation of the multisubunit IkappaB kinase (IKK) complex in primary human T lymphocytes; this activation could be inhibited by a Ca(2+)-independent PKC isoform inhibitor, rottlerin [22].

Associations of rottlerin with other chemical compounds


Gene context of rottlerin

  • Interestingly, both rottlerin and EGF induced substantial increases in phospholipase D (PLD) activity, which is commonly elevated in response to mitogenic stimuli [27].
  • Furthermore, rottlerin, an inhibitor of protein kinase Cdelta (PKCdelta) and calmodulin kinase III, abrogated the up-regulation at both protein and mRNA levels [28].
  • Expression of a dominant negative PKC delta mutant (PKC delta-KR) or pretreatment of cells with rottlerin, a chemical PKC delta inhibitor, attenuated TNF-alpha- and phorbol ester-induced transcription from the IL-8 promoter [29].
  • The inhibition of PKCdelta by rottlerin did not affect the activation of p38 MAPK by arsenate [28].
  • The later JNK1 activation and apoptotic progression are also prevented by co-treatments of cells with rottlerin, a PKC-delta inhibitor or z-VAD-fmk, a pan caspase inhibitor [30].

Analytical, diagnostic and therapeutic context of rottlerin


  1. Protein kinase Calpha and protein kinase Cdelta play opposite roles in the proliferation and apoptosis of glioma cells. Mandil, R., Ashkenazi, E., Blass, M., Kronfeld, I., Kazimirsky, G., Rosenthal, G., Umansky, F., Lorenzo, P.S., Blumberg, P.M., Brodie, C. Cancer Res. (2001) [Pubmed]
  2. Rottlerin sensitizes colon carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis via uncoupling of the mitochondria independent of protein kinase C. Tillman, D.M., Izeradjene, K., Szucs, K.S., Douglas, L., Houghton, J.A. Cancer Res. (2003) [Pubmed]
  3. Phorbol 12-myristate 13-acetate induces epidermal growth factor receptor transactivation via protein kinase Cdelta/c-Src pathways in glioblastoma cells. Amos, S., Martin, P.M., Polar, G.A., Parsons, S.J., Hussaini, I.M. J. Biol. Chem. (2005) [Pubmed]
  4. Role of protein kinase C delta in reactivation of Kaposi's sarcoma-associated herpesvirus. Deutsch, E., Cohen, A., Kazimirsky, G., Dovrat, S., Rubinfeld, H., Brodie, C., Sarid, R. J. Virol. (2004) [Pubmed]
  5. Pharmacologic regulation of histamine release by the human recombinant histamine-releasing factor. Bheekha-Escura, R., Chance, S.R., Langdon, J.M., MacGlashan, D.W., MacDonald, S.M. J. Allergy Clin. Immunol. (1999) [Pubmed]
  6. Role of protein kinase C-delta in the regulation of collagen gene expression in scleroderma fibroblasts. Jimenez, S.A., Gaidarova, S., Saitta, B., Sandorfi, N., Herrich, D.J., Rosenbloom, J.C., Kucich, U., Abrams, W.R., Rosenbloom, J. J. Clin. Invest. (2001) [Pubmed]
  7. Dual oxidase 1-dependent MUC5AC mucin expression in cultured human airway epithelial cells. Shao, M.X., Nadel, J.A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  8. PKC{delta} regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation. Pula, G., Schuh, K., Nakayama, K., Nakayama, K.I., Walter, U., Poole, A.W. Blood (2006) [Pubmed]
  9. Nanomolar concentration of NSC606985, a camptothecin analog, induces leukemic-cell apoptosis through protein kinase Cdelta-dependent mechanisms. Song, M.G., Gao, S.M., Du, K.M., Xu, M., Yu, Y., Zhou, Y.H., Wang, Q., Chen, Z., Zhu, Y.S., Chen, G.Q. Blood (2005) [Pubmed]
  10. Inhibition of protein kinase Calpha enhances anticancer agent-induced loss of anchorage-independent growth regardless of protection against apoptosis by Bcl-2. Huigsloot, M., Tijdens, R.B., van de Water, B. Mol. Pharmacol. (2003) [Pubmed]
  11. Coadministration of sorafenib with rottlerin potently inhibits cell proliferation and migration in human malignant glioma cells. Jane, E.P., Premkumar, D.R., Pollack, I.F. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  12. Activation of protein kinase C-delta attenuates kainate-induced cell death of cortical neurons. Jung, Y.S., Lee, B.K., Park, H.S., Shim, J.K., Kim, S.U., Lee, S.H., Baik, E.J., Moon, C.H. Neuroreport (2005) [Pubmed]
  13. The PKC delta inhibitor, rottlerin, induces apoptosis of haematopoietic cell lines through mitochondrial membrane depolarization and caspases' cascade. Liao, Y.F., Hung, Y.C., Chang, W.H., Tsay, G.J., Hour, T.C., Hung, H.C., Liu, G.Y. Life Sci. (2005) [Pubmed]
  14. Protein kinase C-delta regulates thrombin-induced ICAM-1 gene expression in endothelial cells via activation of p38 mitogen-activated protein kinase. Rahman, A., Anwar, K.N., Uddin, S., Xu, N., Ye, R.D., Platanias, L.C., Malik, A.B. Mol. Cell. Biol. (2001) [Pubmed]
  15. Protein kinase C delta blocks immediate-early gene expression in senescent cells by inactivating serum response factor. Wheaton, K., Riabowol, K. Mol. Cell. Biol. (2004) [Pubmed]
  16. Protein kinase ctheta cooperates with calcineurin to induce Fas ligand expression during activation-induced T cell death. Villalba, M., Kasibhatla, S., Genestier, L., Mahboubi, A., Green, D.R., Altman, A. J. Immunol. (1999) [Pubmed]
  17. Activation of SAPK/JNK signaling by protein kinase Cdelta in response to DNA damage. Yoshida, K., Miki, Y., Kufe, D. J. Biol. Chem. (2002) [Pubmed]
  18. Induction of cIAP-2 in human colon cancer cells through PKC delta/NF-kappa B. Wang, Q., Wang, X., Evers, B.M. J. Biol. Chem. (2003) [Pubmed]
  19. B-cell receptor- and phorbol ester-induced NF-kappaB and c-Jun N-terminal kinase activation in B cells requires novel protein kinase C's. Krappmann, D., Patke, A., Heissmeyer, V., Scheidereit, C. Mol. Cell. Biol. (2001) [Pubmed]
  20. Protein kinase C alpha/beta inhibitor Go6976 promotes formation of cell junctions and inhibits invasion of urinary bladder carcinoma cells. Koivunen, J., Aaltonen, V., Koskela, S., Lehenkari, P., Laato, M., Peltonen, J. Cancer Res. (2004) [Pubmed]
  21. Protein kinase C delta is required for p47phox phosphorylation and translocation in activated human monocytes. Bey, E.A., Xu, B., Bhattacharjee, A., Oldfield, C.M., Zhao, X., Li, Q., Subbulakshmi, V., Feldman, G.M., Wientjes, F.B., Cathcart, M.K. J. Immunol. (2004) [Pubmed]
  22. The physical association of protein kinase C theta with a lipid raft-associated inhibitor of kappa B factor kinase (IKK) complex plays a role in the activation of the NF-kappa B cascade by TCR and CD28. Khoshnan, A., Bae, D., Tindell, C.A., Nel, A.E. J. Immunol. (2000) [Pubmed]
  23. Methylglyoxal enhances cisplatin-induced cytotoxicity by activating protein kinase Cdelta. Godbout, J.P., Pesavento, J., Hartman, M.E., Manson, S.R., Freund, G.G. J. Biol. Chem. (2002) [Pubmed]
  24. Rottlerin is a mitochondrial uncoupler that decreases cellular ATP levels and indirectly blocks protein kinase Cdelta tyrosine phosphorylation. Soltoff, S.P. J. Biol. Chem. (2001) [Pubmed]
  25. Serotonin-induced MMP-13 production is mediated via phospholipase C, protein kinase C, and ERK1/2 in rat uterine smooth muscle cells. Shum, J.K., Melendez, J.A., Jeffrey, J.J. J. Biol. Chem. (2002) [Pubmed]
  26. Peroxisome proliferator-activated receptor gamma ligands inhibit mitogenic induction of p21(Cip1) by modulating the protein kinase Cdelta pathway in vascular smooth muscle cells. Wakino, S., Kintscher, U., Liu, Z., Kim, S., Yin, F., Ohba, M., Kuroki, T., Schönthal, A.H., Hsueh, W.A., Law, R.E. J. Biol. Chem. (2001) [Pubmed]
  27. Antagonistic effects of protein kinase C alpha and delta on both transformation and phospholipase D activity mediated by the epidermal growth factor receptor. Hornia, A., Lu, Z., Sukezane, T., Zhong, M., Joseph, T., Frankel, P., Foster, D.A. Mol. Cell. Biol. (1999) [Pubmed]
  28. Pathways of induction of peroxiredoxin I expression in osteoblasts: roles of p38 mitogen-activated protein kinase and protein kinase C. Li, B., Ishii, T., Tan, C.P., Soh, J.W., Goff, S.P. J. Biol. Chem. (2002) [Pubmed]
  29. Regulation of airway epithelial cell NF-kappa B-dependent gene expression by protein kinase C delta. Page, K., Li, J., Zhou, L., Iasvovskaia, S., Corbit, K.C., Soh, J.W., Weinstein, I.B., Brasier, A.R., Lin, A., Hershenson, M.B., Iasvoyskaia, S. J. Immunol. (2003) [Pubmed]
  30. The c-Jun N-terminal kinase 1 activity is differentially regulated by specific mechanisms during apoptosis. Ham, Y.M., Choi, J.S., Chun, K.H., Joo, S.H., Lee, S.K. J. Biol. Chem. (2003) [Pubmed]
  31. Induction of relaxin messenger RNA expression in response to prolactin receptor activation requires protein kinase C delta signaling. Peters, C.A., Maizels, E.T., Robertson, M.C., Shiu, R.P., Soloff, M.S., Hunzicker-Dunn, M. Mol. Endocrinol. (2000) [Pubmed]
  32. PKCdelta regulates endothelial basal barrier function through modulation of RhoA GTPase activity. Harrington, E.O., Shannon, C.J., Morin, N., Rowlett, H., Murphy, C., Lu, Q. Exp. Cell Res. (2005) [Pubmed]
  33. Potent stimulation of large-conductance Ca(2+)-activated K(+) channels by rottlerin, an inhibitor of protein kinase C-delta, in pituitary tumor (GH(3)) cells and in cortical neuronal (HCN-1A) cells. Wu, S.N., Wang, Y.J., Lin, M.W. J. Cell. Physiol. (2007) [Pubmed]
  34. Modulation of Na-K-2Cl cotransport by intracellular Cl(-) and protein kinase C-delta in Calu-3 cells. Liedtke, C.M., Papay, R., Cole, T.S. Am. J. Physiol. Lung Cell Mol. Physiol. (2002) [Pubmed]
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