title: Preclinical studies of celastrol and acetyl isogambogic acid in melanoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Signal Transduction Program, Cancer Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Sabiha
authors.initials: S
authors.lastname: Abbas
authors.forename: Anindita
authors.initials: A
authors.lastname: Bhoumik
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.forename: Stefan
authors.initials: S
authors.lastname: Vasile
authors.forename: Stan
authors.initials: S
authors.lastname: Krajewski
authors.forename: Nicholas D P
authors.initials: ND
authors.lastname: Cosford
authors.forename: Ze'ev A
authors.initials: ZA
authors.lastname: Ronai
mesh_terms: D051698:Activating Transcription Factor 2 / Q000037:antagonists & inhibitors; D000818:Animals; D045744:Cell Line, Tumor; D002867:Chromones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D053978:Pentacyclic Triterpenes; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054852:Small Molecule Libraries / Q000737:chemistry; D014158:Transcription, Genetic; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D051698:Activating Transcription Factor 2; D002867:Chromones; D053978:Pentacyclic Triterpenes; D016755:Proto-Oncogene Proteins c-jun; D054852:Small Molecule Libraries; D014315:Triterpenes; C526110:acetyl isogambogic acid; D048670:MAP Kinase Kinase 4; C050414:celastrol