Physalin B, a novel inhibitor of the ubiquitin-proteasome pathway, triggers NOXA-associated apoptosis

Vandenberghe, Isabelle; Créancier, Laurent; Vispé, Stéphane; Annereau, Jean‐Philippe; Barret, Jean-Marc; Pouny, Isabelle; Samson, Arnaud; Aussagues, Yannick; Massiot, Georges; Ausseil, Frédéric; Bailly, Christian; Kruczynski, Anna

doi:10.1016/j.bcp.2008.05.031

Cited by 58 publications

(49 citation statements)

References 33 publications

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“…These results may lead to novel treatments of choroidal neovascularization, the major contributor to age-related macular degeneration and one of the leading causes of irreversible blindness in the Western hemisphere (256). Physalin B (463) has been identified recently as an inhibitor of the ubiquitin-mediated proteasome pathway in the DLD-1 human colon cancer cell line, producing an accumulation of ubiquitinated proteins and inhibiting TNFa-induced NF-kB activation (257). The antiangiogenic activity of this compound remains to be tested.…”

Section: Antiangiogenic 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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Section: Antiangiogenic 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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“…The natural compound physalin B has been reported as an indirect UPP inhibitor [13] . The effect of physalin B on the ALP was investigated here.…”

Section: Acta Pharmacologica Sinica Npgmentioning

confidence: 99%

“…Several studies have investigated the anticancer potential of P angulata, which showed that the organic extracts and some purified compounds possess cytotoxic activity against several tumor cell lines and sarcoma 180 tumor cells transplanted into mice [12] . The cytotoxicity of this plant has been attributed to the physalins, an inhibitor of the ubiquitin-proteasome pathway (UPP) [13] . The UPP and autophagy-lysosome pathway (ALP) are the two major systems for eukaryotic intracellular protein clearance that are functionally coupled to maintain homeo stasis [14,15] .…”

Section: Introductionmentioning

confidence: 99%

Physalin B not only inhibits the ubiquitin-proteasome pathway but also induces incomplete autophagic response in human colon cancer cells in vitro

Han

et al. 2015

Acta Pharmacol Sin

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Aim: To investigate the effects of physalin B insolated from Physalis divericata on human colon cancer cells in vitro and its anticancer mechanisms. Methods: Human HCT116 colon cancer cell line was tested. Cell viability and apoptosis were detected, and relevant proteins were measured using Western blot analyses. Autophagosomes were observed in stable GFP-LC3 HCT116 cells. Localization of autophagosomes and lysosomes was evaluated in GFP-LC3/RFP-LAMP1-co-transfected cells. Microtubules and F-actin microfilaments were observed with confocal microscope. Mitochondrial ROS (mito-ROS) was detected with flow cytometry in the cells stained with MitoSox dye. Results: Physalin B inhibited the viability of HCT116 cells with an IC 50 value of 1.35 μmol/L. Treatment of the cells with physalin B (2.5-10 μmol/L) induced apoptosis and the cleavage of PARP and caspase-3. Meanwhile, physalin B treatment induced autophagosome formation, and accumulation of LC3-II and p62, but decreased Beclin 1 protein level. Marked changes of microtubules and F-actin microfilaments were observed in physalin B-treated cells, which led to the blockage of co-localization of autophagosomes and lysosomes. Physalin B treatment dose-dependently increased the phosphorylation of p38, ERK and JNK in the cells, whereas the p38 inhibitor SB202190, ERK inhibitor U0126 or JNK inhibitor SP600125 could partially reduce physalin B-induced PARP cleavage and p62 accumulation. Moreover, physalin B treatment dose-dependently increased mito-ROS production in the cells, whereas the ROS scavenger NAC could reverse physalin B-induced effects, including incomplete autophagic response, accumulation of ubiquitinated proteins, changes of microtubules and F-actin, activation of p38, ERK and JNK, as well as cell death and apoptosis. Conclusion: Physalin B induces mito-ROS, which not only inhibits the ubiquitin-proteasome pathway but also induces incomplete autophagic response in HCT116 cells in vitro.

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“…Thus, the identification of bortezomib within the screen inadvertently served as an internal control in validating our experimental setup. In addition to its proteasome-inhibiting properties (57), physalin B has also been shown to have anti-inflammatory and other immunomodulatory activity (58). The proteasome-inhibiting activity of siomycin has been correlated with its role as an inhibitor of the transcription factor forkhead box M1 (FOXM1) (59)(60)(61).…”

Section: Resultsmentioning

confidence: 99%

Identification and Validation of Small Molecules That Enhance Recombinant Adeno-associated Virus Transduction following High-Throughput Screens

Nicolson

Hirsch

et al. 2016

J Virol

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While the recent success of adeno-associated virus (AAV)-mediated gene therapy in clinical trials is promising, challenges still face the widespread applicability of recombinant AAV(rAAV). A major goal is to enhance the transduction efficiency of vectors in order to achieve therapeutic levels of gene expression at a vector dose that is below the immunological response threshold. In an attempt to identify novel compounds that enhance rAAV transduction, we performed two high-throughput screens comprising 2,396 compounds. We identified 13 compounds that were capable of enhancing transduction, of which 12 demonstrated vector-specific effects and 1 could also enhance vector-independent transgene expression. Many of these compounds had similar properties and could be categorized into five groups: epipodophyllotoxins (group 1), inducers of DNA damage (group 2), effectors of epigenetic modification (group 3), anthracyclines (group 4), and proteasome inhibitors (group 5). We optimized dosing for the identified compounds in several immortalized human cell lines as well as normal diploid cells. We found that the group 1 epipodophyllotoxins (teniposide and etoposide) consistently produced the greatest transduction enhancement. We also explored transduction enhancement among single-stranded, self-complementary, and fragment vectors and found that the compounds could impact fragmented rAAV2 transduction to an even greater extent than single-stranded vectors. In vivo analysis of rAAV2 and all of the clinically relevant compounds revealed that, consistent with our in vitro results, teniposide exhibited the greatest level of transduction enhancement. Finally, we explored the capability of teniposide to enhance transduction of fragment vectors in vivo using an AAV8 capsid that is known to exhibit robust liver tropism. Consistent with our in vitro results, teniposide coadministration greatly enhanced fragmented rAAV8 transduction at 48 h and 8 days. This study provides a foundation based on the rAAV small-molecule screen methodology, which is ideally used for more-diverse libraries of compounds that can be tested for potentiating rAAV transduction. IMPORTANCEThis study seeks to enhance the capability of adeno-associated viral vectors for therapeutic gene delivery applicable to the treatment of diverse diseases. To do this, a comprehensive panel of FDA-approved drugs were tested in human cells and in animal models to determine if they increased adeno-associated virus gene delivery. The results demonstrate that particular groups of drugs enhance adeno-associated virus gene delivery by unknown mechanisms. In particular, the enhancement of gene delivery was approximately 50 to 100 times better with than without teniposide, a compound that is also used as chemotherapy for cancer. Collectively, these results highlight the potential for FDA-approved drug enhancement of adeno-associated virus gene therapy, which could result in safe and effective treatments for diverse acquired or genetic diseases.A deno-associated viral (AAV) vec...

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Physalin B, a novel inhibitor of the ubiquitin-proteasome pathway, triggers NOXA-associated apoptosis

Cited by 58 publications

References 33 publications

Withanolides and Related Steroids

Withanolides and Related Steroids

Physalin B not only inhibits the ubiquitin-proteasome pathway but also induces incomplete autophagic response in human colon cancer cells in vitro

Identification and Validation of Small Molecules That Enhance Recombinant Adeno-associated Virus Transduction following High-Throughput Screens

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