Investigations with the selective PKC inhibitor chelerythrine on human basophils

Stebut, Esther von; Amon, Ulrich; Herbert, Jean‐Marc; Wolff, Helmut H.

doi:10.1007/bf02007765

Cited by 11 publications

(6 citation statements)

References 7 publications

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“…For example, rat liver alanine aminotransferase is inhibited by adduct formation between thiol groups of the enzyme and the iminium bond of chelerythrine (16). Chelerythrine also inhibits taxol-mediated polymerization of rat brain tubulin (32), histone kinase activity using partially purified PKC from the rat lacrimal gland (33), pyrogen-induced expression of tissue factor in endothelial cells, histamine release induced by aggregation of IgE-receptor on human basophils (34,35), Na ϩ ,K ϩ ,2Cl Ϫ cotransporter in Ehrlich mouse ascites tumor cells (36), and invasion of metastatic human follicular thyroid cancer (37). We have recently found that angoline and chelerythrine inhibit 7,12-dimethylbenz(a)anthracene-induced preneoplastic lesion formation in mouse mammary gland organ culture by approximately 60% at a test concentration of 10 M (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Angoline and Chelerythrine, Benzophenanthridine Alkaloids That Do Not Inhibit Protein Kinase C

Lee¹,

Qing²,

Mar³

et al. 1998

Journal of Biological Chemistry

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Starting with an extract derived from the stem of Macleaya cordata (Papaveraceae) that was active in the process of inhibiting phorbol 12,13-dibutyrate binding to partially purified protein kinase C (PKC), the benzophenanthridine alkaloid angoline was isolated and identified. This discovery appeared in context, as a related benzophenanthridine alkaloid, chelerythrine, has been reported to mediate a variety of biological activities, including potent and selective inhibition of protein kinase C (PKC). However, in our studies, angoline was not observed to function as a potent inhibitor of PKC. Moreover, we were unable to confirm the reported inhibitory activity of chelerythrine. In a comprehensive series of studies performed with various PKC isozymes derived from a variety of mammalian species, neither chelerythrine nor angoline inhibited activity with high potency. To the contrary, chelerythrine stimulated PKC activity in the cytosolic fractions of rat and mouse brain in concentrations up to 100 M. In addition, chelerythrine and angoline did not inhibit [ 3 H]phorbol 12,13-dibutyrate binding to the regulatory domain of PKC at concentrations up to 40 g/ml, and no significant alteration of PKC-␣, -␤, or -␥ translocation was observed with human leukemia (HL-60) cells in culture. Further, chelerythrine did not inhibit 12-O-tetradecanoylphorbol 13-acetate-induced ornithine decarboxylase activity with cultured mouse 308 cells, but angoline was active in this capacity with an IC 50 value of 1.0 g/ml. A relatively large number of biological responses have been reported in studies conducted with chelerythrine, and alteration of PKC activity has been considered as a potential mechanism of action. In light of the current report, mechanisms independent of PKC inhibition should be considered as responsible for these effects.

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Section: Discussionmentioning

confidence: 99%

Angoline and Chelerythrine, Benzophenanthridine Alkaloids That Do Not Inhibit Protein Kinase C

Lee¹,

Qing²,

Mar³

et al. 1998

Journal of Biological Chemistry

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“…Activation of JNK and p38 is mediated by upstream kinases, MEKK1 and MKK4, and regulates apoptosis. Chelerythrine is known to display a variety of biological activities, such as inhibition of taxol-mediated polymerization of rat brain tubulin (47) and histamine release induced by aggregation of the IgE receptors on human basophils (34). Chelerythrine is also shown to stimulate protein phosphorylation in the mitochondrial fraction of rat retina (35).…”

Section: Dominant-negative Mutants Of Mekk1 Mkk4 Jnk1 and P38 Blocmentioning

confidence: 99%

Activation of p38 and c-Jun N-terminal Kinase Pathways and Induction of Apoptosis by Chelerythrine Do Not Require Inhibition of Protein Kinase C

Mandlekar

Tan

et al. 2000

Journal of Biological Chemistry

101

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Chelerythrine, a natural benzophenanthridine alkaloid, has been reported to mediate a variety of biological activities, including inhibition of protein kinase C (PKC). Here we report that chelerythrine induced timeand dose-dependent activation of JNK1 and p38 in HeLa cells, which was mediated the upstream kinases, MEKK1 and MKK4. However, treatment with two other potent and selective PKC inhibitors, GF-109203X and Gö 6983, or down-regulation of PKC activity by prolonged treatment with phorbol 12-myristate 13-acetate had no effect on JNK1 and p38 activities. Furthermore, under the conditions where JNK1 and p38 were activated, we did not observe any significant inhibitory effect of chelerythrine on the activities of PKC isozymes present in HeLa cells. Interestingly, pretreatment with the antioxidants, N-acetyl-L-cysteine, dithiothreitol, and glutathione, impaired chelerythrine-induced JNK1 and p38 activation. In addition, chelerythrine induced apoptosis that was blocked by the antioxidants and the dominant-negative mutants of MEKK1, MKK4, JNK1, and p38. Together, these results uncover a novel biochemical property of chelerythrine, i.e. activation of MEKK1-and MKK4-dependent JNK1 and p38 pathways through an oxidative stress mechanism, which mediate the induction of apoptosis, but are independent of PKC inhibition.

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“…The possibility must be considered that presently unknown kinases may be the targets responsible for the results obtained in this study. For example, chelerythrine is currently claimed to be selective for PKC (Herbert et al, 1990), but the nature of its inhibition, which is via the catalytic domain which is homologous with other protein kinases (Von Stebut et al, 1994) may render it potentially less selective. Indeed, chelerythrine has been observed to have a paradoxical stimulatory effect on the phosphorylation of a 20 kDa protein (Lombardini, 1995).…”

Section: Discussionmentioning

confidence: 99%

Differential effects of protein kinase C inhibitors on chemokine production in human synovial fibroblasts

Jordan

Watson

Yoshimura

et al. 1996

British J Pharmacology

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1 Rheumatoid arthritis is associated with the accumulation and activation of selected populations of inflammatory cells within the arthritic joint. One putative signal for this process is the production, by resident cells, of a group of inflammatory mediators known as the chemokines. 2 The chemokines interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1) and RANTES (regulated on activation normal T-cell expressed and presumably secreted) are target-cell specific chemoattractants produced by synovial fibroblasts in response to stimulation with interleukin-la (IL-la) or tumour necrosis factor a (TNFa). The signalling pathways involved in their production are not well defined. We therefore used four different protein kinase C inhibitors to investigate the role of this kinase in the regulation of chemokine mRNA and protein expression in human cultured synovial fibroblasts. 3 The non-selective PKC inhibitor, staurosporine (1-300 nM) significantly increased the production of IL-la-induced IL-8 mRNA and protein. A specific PKC inhibitor, chelerythrine chloride (0.1-3 gM), also caused a small concentration-dependent increase in IL-8 mRNA and protein production. In contrast, 3-[1-[3-(amidinothio)propyl]-3-indoly]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione methanesulphonate (Ro 31-8220) and 2[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(lH-indol-3-yl)-maleimide (GF 109203X), two selective PKC inhibitors of the substituted bisindolylmaleimide family had a concentration-dependent biphasic effect on IL-la or TNFa-induced chemokine expression. At low concentrations they caused a stimulation in chemokine production, which was especially evident at the mRNA level. At higher concentrations both inhibited IL-la or TNFa-induced chemokine mRNA and protein production. Ro 31-8220 was 10 fold more potent than GF 109203X, with an IC50 of 1.6+0.08 ,M (mean+s.e.mean, n=4) for IL-la induced IL-8 production. Ro 31-8220 also inhibited the expression of IL-la or TNFa-induced MCP-1 and RANTES mRNA with a similar potency. 4 The stimulatory effect of staurosporine is discussed in relation to the known poor selectivity of this inhibitor for PKC. It is proposed that activation of an isoform of PKC, possibly PKC epsilon or zeta, which is inhibited by higher concentrations of the bisinodolylmaleimides, plays a role in the regulation of chemokine expression induced by IL-la or TNFa in synovial cells. 5 The inhibition of chemokine production by bisindolylmaleimide compounds heralds a novel approach for future anti-inflammatory therapies.

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Investigations with the selective PKC inhibitor chelerythrine on human basophils

Cited by 11 publications

References 7 publications

Angoline and Chelerythrine, Benzophenanthridine Alkaloids That Do Not Inhibit Protein Kinase C

Angoline and Chelerythrine, Benzophenanthridine Alkaloids That Do Not Inhibit Protein Kinase C

Activation of p38 and c-Jun N-terminal Kinase Pathways and Induction of Apoptosis by Chelerythrine Do Not Require Inhibition of Protein Kinase C

Differential effects of protein kinase C inhibitors on chemokine production in human synovial fibroblasts

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