Preclinical Studies of Celastrol and Acetyl Isogambogic Acid in Melanoma

Sanford-Burnham Medical Research Institute, لا هویا, California, United States
Clinical Cancer Research (Impact Factor: 8.72). 12/2007; 13(22 Pt 1):6769-78. DOI: 10.1158/1078-0432.CCR-07-1536
Source: PubMed


Sensitize melanomas to apoptosis and inhibit their growth and metastatic potential by compounds that mimic the activities of activating transcription factor 2 (ATF2)-driven peptides.
Small-molecule chemical library consisting of 3,280 compounds was screened to identify compounds that elicit properties identified for ATF2 peptide, including (a) sensitization of melanoma cells to apoptosis, (b) inhibition of ATF2 transcriptional activity, (c) activation of c-Jun NH(2)-terminal kinase (JNK) and c-Jun transcriptional activity, and (d) inhibition of melanoma growth and metastasis in mouse models.
Two compounds, celastrol (CSL) and acetyl isogambogic acid, could, within a low micromolar range, efficiently elicit cell death in melanoma cells. Both compounds efficiently inhibit ATF2 transcriptional activities, activate JNK, and increase c-Jun transcriptional activities. Similar to the ATF2 peptide, both compounds require JNK activity for their ability to inhibit melanoma cell viability. Derivatives of CSL were identified as potent inducers of cell death in mouse and human melanomas. CSL and a derivative (CA19) could also efficiently inhibit growth of human and mouse melanoma tumors and reduce the number of lung metastases in syngeneic and xenograft mouse models.
These studies show for the first time the effect of CSL and acetyl isogambogic acid on melanoma. These compounds elicit activities that resemble the well-characterized ATF2 peptide and may therefore offer new approaches for the treatment of this tumor type.

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Available from: Ze’ev Ronai, Mar 07, 2015
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    • "Lactacystin, a metabolite of Streptomyces , irreversibly and specifi cally inhibits the chymotrypsin-and trypsinlike activities of proteasomes but, unlike MG132, does not 494 K. Stankova et al. inhibit other cellular proteases such as calpain, cathepsin B, chymotrypsin, trypsin and papain (Fenteany et al. 1995, Wang et al. 1998). Recently, celastrol, a quinine methide triterpene , derived from plants of the Celastreceae family, has also been shown to inhibit the chymotrypsin-like activity of the proteasome and to induce apoptosis in both in vitro and in vivo cancer models (Yang et al. 2006, Abbas et al. 2007). Celastrol has been well known as a natural remedy in the form of the plant it comes from, Tripterygium wilfordii , in traditional Chinese medicine for hundreds of years for its anti-infl ammatory and antioxidant properties, fundamental to the medical application of the compound in the treatment of autoimmune diseases, asthma and chronic infl ammation. "
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    ABSTRACT: Purpose: The study aimed to analyze the impact of the proteasome inhibitors MG132 (N-carbobenzyoxyl-L-leucyl-L-leucyl-L-leucinal), lactacystin and celastrol on manganese superoxide dismutase (MnSOD), catalase and glutathione-S-transferase-π (GST-π), and on the heat shock protein 70 (Hsp70) in human peripheral blood mononuclear cells (PBMC), exposed to ionizing radiation. Materials and methods: Changes in protein levels were analyzed by Western blot. Cellular viability, proteasome activity, level of oxidative stress and apoptosis were determined by standard colorimetric and fluorescence assays. Results: MG132 and lactacystin induced an increase in the intracellular levels of Hsp70. MnSOD was up-regulated by MG132 and celastrol, and GST-π was up-regulated by MG132 and lactacystin. Notably, the proteasome inhibitors significantly modified the protein levels in the irradiated cells and dramatically reduced the intracellular pool of oxidative species. The combined effect of radiation and proteasome inhibition was a dose-dependent up-regulation of the antioxidant enzymes and Hsp70. Conclusions: All three proteasome inhibitors showed antioxidant effects in PBMC and up-regulated the antioxidant enzymes MnSOD, catalase and GST-π and the stress protein Hsp70, modifying the early radiation response, and conferring protection against the effects of ionizing radiation.
    Full-text · Article · Mar 2013 · International Journal of Radiation Biology
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    • "Although celastrol, as a natural inhibitor of the proteasome and NF-κB activity, can induce apoptosis in a variety of tumor cell lines, including U937 cells, human prostate cancer cell lines, HL-60 cells, and human melanoma cells,12,14,17,18 the effects of celastrol on retinoblastoma are still not clear. Furthermore, the poor water solubility of celastrol limits its in vivo application. "
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    ABSTRACT: Celastrol, a Chinese herbal medicine, has shown antitumor activity against various tumor cell lines. However, the effect of celastrol on retinoblastoma has not yet been analyzed. Additionally, the poor water solubility of celastrol restricts further therapeutic applications. The goal of this study was to evaluate the effect of celastrol nanoparticles (CNPs) on retinoblastoma and to investigate the potential mechanisms involved. Celastrol-loaded poly(ethylene glycol)-block-poly(ɛ-caprolactone) nanopolymeric micelles were developed to improve the hydrophilicity of celastrol. The 2-(2-methoxy-4- nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulf-ophenyl)-2H tetrazolium monosodium salt (WST-8) assay was used to determine the inhibitory effect of CNPs on SO-Rb 50 cell proliferation in vitro. Immunofluorescence was used to evaluate the apoptotic effect of CNPs on nuclear morphology, and flow cytometry was used to quantify cellular apoptosis. The expression of Bcl-2, Bax, NF-κB p65, and phospo-NF-κB p65 proteins was assessed by Western blotting. A human retinoblastoma xenograft model was used to evaluate the inhibitory effects of CNPs on retinoblastoma in NOD-SCID mice. Hematoxylin and eosin staining was used to assess the apoptotic effects of CNPs on retinoblastoma. CNPs inhibit the proliferation of SO-Rb 50 cells in a dose- and time-dependent manner with an IC(50) of 17.733 μg/mL (celastrol-loading content: 7.36%) after exposure to CNPs for 48 hours. CNPs induce apoptosis in SO-Rb 50 cells in a dose-dependent manner. The expression of Bcl-2, NF-κB p65, and phospo-NF-κB p65 proteins decreased after exposure to CNPs 54.4 μg/mL for 48 hours. Additionally, the Bax/Bcl-2 ratio increased, whereas the expression of Bax itself was not significantly altered. CNPs inhibit the growth of retinoblastoma and induce apoptosis in retinoblastoma cells in mice. CNPs inhibit the growth of retinoblastoma in mouse xenograft model by inducing apoptosis in SO-Rb 50 cells, which may be related to the increased Bax/Bcl-2 ratio and the inhibition of NF-κB. CNPs may represent a potential alternative treatment for retinoblastoma.
    Preview · Article · May 2012 · International Journal of Nanomedicine
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    • "As root extract or purified compound, its remarkable anti-inflammatory ability has been demonstrated in animal models of different inflammatory diseases including asthma [2], Crohn's disease [3], and neurodegenerative disorders [4], [5]. Purified celastrol showed anticancer activity, in vivo in various tumor models of melanoma [6], prostate [7] and breast [8] cancer, as well as in vitro on leukemic cell lines [9], [10], [11], suggesting its use as a cancer therapeutic. "
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    ABSTRACT: Celastrol, an active compound extracted from the root of the Chinese medicine "Thunder of God Vine" (Tripterygium wilfordii), exhibits anticancer, antioxidant and anti-inflammatory activities, and interest in the therapeutic potential of celastrol is increasing. However, described side effects following treatment are significant and require investigation prior to initiating clinical trials. Here, we investigated the effects of celastrol on the adult murine hematopoietic system. Animals were treated daily with celastrol over a four-day period and peripheral blood, bone marrow, spleen, and peritoneal cavity were harvested for cell phenotyping. Treated mice showed specific impairment of the development of B cells and erythrocytes in all tested organs. In bone marrow, these alterations were accompanied by decreases in populations of common lymphoid progenitors (CLP), common myeloid progenitors (CMP) and megakaryocyte-erythrocyte progenitors (MEP). These results indicate that celastrol acts through regulators of adult hematopoiesis and could be used as a modulator of the hematopoietic system. These observations provide valuable information for further assessment prior to clinical trials.
    Full-text · Article · Apr 2012 · PLoS ONE
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