Protein Kinase C Translocation by Modified Phorbol Esters with Functionalized Lipophilic Regions

Bertolini, Thomas M.; Giorgione, Jennifer R.; Harvey, Daniel F.; Newton, Alexandra C.

doi:10.1021/jo030029w

Cited by 34 publications

(34 citation statements)

References 42 publications

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“…The overall result, therefore, could be partial agonism at the level of the in vivo PKCs. The plausibility of this partial association with membranes was previously shown (51). In addition, Wada et al reported (29) that a phorbol ester with a hydrophilic 12-ester chain could inhibit the activation of PKC-␣ by PMA.…”

Section: Discussionmentioning

confidence: 68%

Characterization of the Interaction of Ingenol 3-Angelate with Protein Kinase C

et al. 2004

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Ingenol 3-angelate (I3A) is one of the active ingredients in Euphorbia peplus, which has been used in traditional medicine. Here, we report the initial characterization of I3A as a protein kinase C (PKC) ligand. I3A bound to PKC-␣ in the presence of phosphatidylserine with high affinity; however, under these assay conditions, little PKC isoform selectivity was observed. PKC isoforms did show different sensitivity and selectivity for down-regulation by I3A and phorbol 12-myristate 13-acetate (PMA) in WEHI-231, HOP-92, and Colo-205 cells. In all of the three cell types, I3A inhibited cell proliferation with somewhat lower potency than did PMA. In intact CHO-K1 cells, I3A was able to translocate different green fluorescent protein-tagged PKC isoforms, visualized by confocal microscopy, with equal or higher potency than PMA. PKC-␦ in particular showed a different pattern of translocation in response to I3A and PMA. I3A induced a higher level of secretion of the inflammatory cytokine interleukin 6 compared with PMA in the WEHI-231 cells and displayed a marked biphasic dose-response curve for the induction. I3A was unable to cause the same extent of association of the C1b domain of PKC-␦ with lipids, compared with PMA or the physiological regulator diacylglycerol, and was able to partially block the association induced by these agents, measured by surface plasmon resonance. The in vitro kinase activity of PKC-␣ induced by I3A was lower than that induced by PMA. The novel pattern of behavior of I3A makes it of great interest for further evaluation.

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Section: Discussionmentioning

confidence: 68%

Characterization of the Interaction of Ingenol 3-Angelate with Protein Kinase C

et al. 2004

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“…a, TSLP was indeed induced in all settings. Croton oil, which contains phorbol esters, was particularly potent, but shaving, SDS and tape stripping were also effective. The induction of TSLP mRNA was rapid, but still detectable after 18 h. Intriguingly, this mild irritation affecting approximately 20% of the murine skin area was sufficient to initiate a systemic TSLP response.…”

Section: Resultsmentioning

confidence: 99%

Thymic stromal lymphopoietin induction by skin irritation is independent of tumour necrosis factor-α, but supported by interleukin-1

et al. 2015

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Thymic stromal lymphopoietin is a general responder to disrupted skin homeostasis and may have a role in triggering the alarm system of the skin. TSLP induction is rapid, transient and driven by a mechanism that does not involve TNF-α, but partially relies on the evolutionarily ancient IL-1 system. The irritated skin secretes TSLP into the circulatory system. TSLP regulation varies between species.

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“…Such phorbol ester lipophilic domain is thought to be responsible for redistributing a phorbolprotein complex to the plasma membrane. 174 Biotransformation of phorbol esters by intestinal bacteria has been successfully achieved. 175 …”

Section: Tumor Promotionmentioning

confidence: 99%

Traditional uses, chemistry and pharmacology of Croton species (Euphorbiaceae)

Salatino¹,

Salatino²,

Negri³

2007

J. Braz. Chem. Soc.

396

320

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Croton é um gênero de Euphorbiaceae com cerca de 1300 espécies, amplamente distribuídas em regiões tropicais do Novo e Velho Mundos. Várias espécies há muito tempo desempenham papel importante nos usos tradicionais de plantas medicinais na África, Ásia e América do Sul. Tais usos incluem tratamento de câncer, constipação intestinal, diarréia e outros problemas digestivos, diabetes, feridas externas, febre, hipercolesterolemia, hipertensão, inflamação, vermes intestinais, malária, dor, úlceras e obesidade. Várias espécies de Croton têm um látex vermelho que contém, em algumas espécies, pró-antocianidinas e/ou alcalóides. Os alcalóides de Croton são a taspina ou substâncias relacionadas a benzilisoquinolinas. Os diterpenos são muito comuns em Croton, correspondendo a clerodanos, cembranóides, halimanos, cauranos, labdanos, ésteres do forbol, traquilobanos e sarcopetalanos. Algumas espécies são aromáticas, devido à presença de óleos voláteis. Representantes de novas classes de substâncias (fenilbutanóides, alcalóides glutarimidínicos e diterpenos sarcopetalanos) têm sido isoladas de espécies de Croton. Enquanto laticíferos têm sido descritos em espécies de Croton, até o momento não há estudos anatômicos sobre estruturas secretoras de óleos voláteis. Parece haver afinidades químicas no gênero relacionadas à geografia, agrupando espécies com (i) cauranos e/ou labdanos, (ii) traquilobanos e (iii) alcalóides. Os ensaios farmacológicos freqüentemente vêm corroborando os usos tradicionais de espécies de Croton. Grande parte dos ensaios farmacológicos trata do clerodano trans-desidrocrotonina, envolvendo uma grande diversidade de efeitos, incluindo hipolipidêmico, hipoglicêmico, antiestrogênico e anticâncer. Efeitos citotóxicos também vêm sendo observados em ensaios com alcalóides (taspina) e com diterpenóides secocaurenos, labdanos e cembranóides. Vários outros efeitos de substâncias de Croton têm sido relatados, incluindo anti-hipertensivos, antiinflamatórios, antimaláricos, antimicrobianos, antiespasmódicos, antiulcerogênicos, antivirais e mio-relaxantes.Croton is a genus of Euphorbiaceae comprising around 1,300 species, widespread in tropical regions of the Old and New Worlds. Several species have a long role in the traditional use of medicinal plants in Africa, Asia and South America. Popular uses include treatment of cancer, constipation, diabetes, digestive problems, dysentery, external wounds, fever, hypercholesterolemia, hypertension, inflammation, intestinal worms, malaria, pain, ulcers and weight-loss. Several species of Croton have a red sap, in some species containing proanthocyanidins and/or alkaloids. The latter may be taspine or some of several benzylisoquinoline-like compounds. Diterpenes are very common in Croton, corresponding to clerodanes, cembranoid, halimanes, kauranes, labdanes, phorbol esters, trachylobanes and sarcopetalanes. Some species are aromatic due to the possession of volatile oils. Representatives of new classes of compounds (phenylbutanoids, glutarimide alkaloids, sarcopetalane diterpen...

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Protein Kinase C Translocation by Modified Phorbol Esters with Functionalized Lipophilic Regions

Cited by 34 publications

References 42 publications

Characterization of the Interaction of Ingenol 3-Angelate with Protein Kinase C

Characterization of the Interaction of Ingenol 3-Angelate with Protein Kinase C

Thymic stromal lymphopoietin induction by skin irritation is independent of tumour necrosis factor-α, but supported by interleukin-1

Traditional uses, chemistry and pharmacology of Croton species (Euphorbiaceae)

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