Physalins from Witheringia solanacea as Modulators of the NF-κB Cascade

Jacobo-Herrera, Nadia; Bremner, Paul; Márquez, Nieves; Gupta, Mahabir P.; Gibbons, Simon; Muñóz, Eduardo; Heinrich, Michael

doi:10.1021/np050225t

Cited by 52 publications

(52 citation statements)

References 22 publications

(47 reference statements)

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“…42 Similar NF-κB inhibitory activities have been reported with bortezomib. By analogy, it is likely that the NF-κB inhibitory activity of physalin B is derived from its interference with the proteasome pathway, as reported here.…”

Section: Fig 9 Chemical Structures Of Physalin B and C Isolated Fromsupporting

confidence: 60%

High-Throughput Bioluminescence Screening of Ubiquitin-Proteasome Pathway Inhibitors from Chemical and Natural Sources

Ausseil

Samson²,

Aussagues

et al. 2007

SLAS Discovery

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To discover original inhibitors of the ubiquitin-proteasome pathway, the authors have developed a cell-based bioluminescent assay and used it to screen collections of plant extracts and chemical compounds. They first established a DLD-1 human colon cancer cell line that stably expresses a 4Ubiquitin-Luciferase (4Ub-Luc) reporter protein, efficiently targeted to the ubiquitinproteasome degradation pathway. The assay was then adapted to 96-and 384-well plate formats and calibrated with reference proteasome inhibitors. Assay robustness was carefully assessed, particularly cell toxicity, and the statistical Z´ factor value was calculated to 0.83, demonstrating a good performance level of the assay. A total of 18,239 molecules and 15,744 plant extracts and fractions thereof were screened for their capacity to increase the luciferase activity in DLD-1 4Ub-Luc cells, and 21 molecules and 66 extracts inhibiting the ubiquitin-proteasome pathway were identified. The fractionation of an active methanol extract of Physalis angulata L. aerial parts was performed to isolate 2 secosteroids known as physalin B and C. In a cell-based Western blot assay, the ubiquitinated protein accumulation was confirmed after a physalin treatment confirming the accuracy of the screening process. The method reported here thus provides a robust approach to identify novel ubiquitin-proteasome pathway inhibitors in large collections of chemical compounds and natural products. (Journal of Biomolecular Screening 2007:106-116)

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Section: Fig 9 Chemical Structures Of Physalin B and C Isolated Fromsupporting

confidence: 60%

High-Throughput Bioluminescence Screening of Ubiquitin-Proteasome Pathway Inhibitors from Chemical and Natural Sources

Ausseil

Samson²,

Aussagues

et al. 2007

SLAS Discovery

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show abstract

“…In recent years, some known physalins have been found in Brachistus stramoniifolius (physalins B, F, and H) (134) (138). A total of 22 new physalins have been reported from Physalis species and several structures described previously have been revised.…”

Section: Physalins and Withaphysalinsmentioning

confidence: 99%

“…As observed with dexamethasone, physalins also decreased TNF-a concentration and enhanced the anti-inflammatory interleukin IL-10 concentration in tissues. Physalins B (463) and F (450) have been shown to inhibit TNF-a induced activation of NF-kB and either a 5,6 double bond or a 5b,6b-epoxide are required for activity; the 5a,6b-diol physalin D (313) is inactive (138).…”

Section: Anti-inflammatory Activitymentioning

confidence: 99%

Withanolides and Related Steroids

Misico

Nicotra

Oberti

et al. 2011

Progress in the Chemistry of Organic Natural Products Vol. 94

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“…[52] Jacobo-Herrera et al reported that physalins were modulators of the NF-kB cascade, and showed inhibitory activity on PMA-induced NF-kB activation. [53] From theses reports, the mechanism of GLI-mediated transcriptional inhibition by physalins might include a path of PKC inhibition.…”

Section: Inhibition Of Gli-mediated Expressionmentioning

confidence: 99%

Naturally Occurring Small‐Molecule Inhibitors of Hedgehog/GLI‐Mediated Transcription

Hosoya

Arai

Koyano³

et al. 2008

ChemBioChem

122

105

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The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. To search for Hh/GLI inhibitors, we screened for naturally occurring inhibitors of the transcriptional activator GLI1 by using a cell-based assay. We identified zerumbone (1), zerumbone epoxide (2), staurosporinone (9), 6-hydroxystaurosporinone (10), arcyriaflavin C (11) and 5,6-dihydroxyarcyriaflavin A (12) as inhibitors of GLI-mediated transcription. In addition, we isolated physalins F (17) and B (18) from Physalis minima, which are also potent inhibitors. These compounds also inhibited GLI2-mediated transactivation. Semiquantitative RT-PCR and Western blotting analysis further revealed that 1, 9, 17, and 18 decreased Hh-related component expressions. We also show that inhibitors of GLI-mediated transactivation reduce the level of the antiapoptosis Bcl2 expression. Finally, these identified compounds were cytotoxic to PANC1 pancreatic cancer cells, which express Hh/GLI components. These results strongly suggest that the cytotoxicity of the compounds to PANC1 cells correlates with their inhibition of GLI-mediated transcription.

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Physalins from Witheringia solanacea as Modulators of the NF-κB Cascade

Cited by 52 publications

References 22 publications

High-Throughput Bioluminescence Screening of Ubiquitin-Proteasome Pathway Inhibitors from Chemical and Natural Sources

High-Throughput Bioluminescence Screening of Ubiquitin-Proteasome Pathway Inhibitors from Chemical and Natural Sources

Withanolides and Related Steroids

Naturally Occurring Small‐Molecule Inhibitors of Hedgehog/GLI‐Mediated Transcription

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