Preclinical Studies of Celastrol and Acetyl Isogambogic Acid in Melanoma

Abstract

Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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.

ATF2 contributes to cisplatin resistance in non‐small cell lung cancer and celastrol induces cisplatin resensitization through inhibition of JNK/ATF2 pathway

“…13 In several cancer models, both in vitro and in vivo, Celastrol showed promising anticancer activity. It induces apoptosis in different cancer cells [14][15][16][17][18][19] and inhibits the growth of glioma, melanoma and prostate cancer in nude mice. 15,20,21 In addition, it synergistically enhances the cytotoxicity of ionizing radiation, gambogic acid, TRAIL/APO-2L and temozolomide.…”

“…It induces apoptosis in different cancer cells [14][15][16][17][18][19] and inhibits the growth of glioma, melanoma and prostate cancer in nude mice. 15,20,21 In addition, it synergistically enhances the cytotoxicity of ionizing radiation, gambogic acid, TRAIL/APO-2L and temozolomide. [22][23][24] Although several hypothetical cellular targets for celastrol have been reported, its mechanism of action has not been fully elucidated.…”

Celastrol Synergistically Enhances Temozolomide Cytotoxicity in Melanoma Cells

“…In the past decade, CEL has become the focus of numerous preclinical studies that have shown its potential for use in a wide range of conditions, from inflammatory diseases such as arthritis and Crohn's disease to neurologic diseases such as Alzheimer's and amyotrophic lateral sclerosis (14)(15)(16)(17). More recently, both in vitro and in vivo studies have yielded results suggesting that CEL may also be effective in the treatment of chemoresistant neoplasms including pancreatic cancer, glioma, and melanoma (18)(19)(20). Preclinical studies in melanoma have shown the ability of monotherapy CEL to inhibit melanoma cell growth and reduce the number and size of metastases that develop in nude mice (20).…”

“…More recently, both in vitro and in vivo studies have yielded results suggesting that CEL may also be effective in the treatment of chemoresistant neoplasms including pancreatic cancer, glioma, and melanoma (18)(19)(20). Preclinical studies in melanoma have shown the ability of monotherapy CEL to inhibit melanoma cell growth and reduce the number and size of metastases that develop in nude mice (20).…”

“…These results are in concordance with previous studies of CEL in melanoma cell lines that have also noted its inhibitory effects on NF-κB transcription. In one such study, a chemical library screen identified CEL as having the capacity to elicit similar effects as the proapoptotic ATF2 peptide (20). The authors were able to show a dose-dependent decrease in NF-κB transcription activity upon treatment of melanoma cell lines with CEL (20).…”