Preclinical studies of celastrol and acetyl lsogambogic acid in melanoma

Sanford-Burnham Medical Research Institute, لا هویا, California, United States
Clinical Cancer Research (Impact Factor: 8.19). 12/2007; 13(22 Pt 1):6769-78. DOI: 10.1158/1078-0432.CCR-07-1536
Source: PubMed

ABSTRACT 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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    • "TNF-a, IL-1b and IFN-c induced expression of ECAM, ICAM-1, VCAM-1 and E-Selectin was inhibited by celastrol at very low concentrations [35]. Pre-clinical studies using celastrol in combination with acetyl isogambogic acid in the treatment of melanoma has shown to be effective [36]. In murine brain endothelial cells, celastrol has been shown to inhibit TNF-a and IFN-c induced expression of iNOS and VCAM-1 expression and NO production [25]. "
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