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Author Notes:

Jack L Arbiser, Department of Dermatology, Emory University School of Medicine, WMB 5309, 101 Woodruff Circle, Atlanta, GA 30322, Tel (404) 727-5063, Fax (404) 727-0923, Email: jarbise@emory.edu.

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Research Funding:

JLA was supported by the grant RO1 AR47901and P30 AR42687 Emory Skin Disease Research Core Center Grant from the National Institutes of Health; as well as a Veterans Administration Merit Award and funding from the Jamie Rabinowitch-Davis and Minsk Foundations.

RKS is supported by Canadian Institutes of Health Research, Canada; Grant Number: MOP-36484.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • ACTIVATED PROTEIN-KINASE
  • KAPPA-B ACTIVITY
  • PHASE-II TRIAL
  • METASTATIC MELANOMA
  • MALIGNANT-MELANOMA
  • CONSTITUTIVE ACTIVATION
  • INDUCED APOPTOSIS
  • BRAF MUTATIONS
  • CELL LINES
  • ANGIOGENESIS

Tris (Dibenzylideneacetone) dipalladium, a N-myristoyltransferase-1 inhibitor, is effective against melanoma growth in vitro and in vivo

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Journal Title:

Clinical Cancer Research

Volume:

Volume 14, Number 18

Publisher:

, Pages 5743-5748

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Purpose: Melanoma is a solid tumor that is notoriously resistant to chemotherapy, and its incidence is rapidly increasing. Recently, several signaling pathways have been shown to contribute to melanoma tumorigenesis, including constitutive activation of mitogen-activated protein kinase, Akt, and Stat-3. The activation of multiple pathways may account in part for the difficulty in treatment of melanoma. In a recent screen of compounds, we found that an organopalladium compound, Tris (dibenzylideneacetone) dipalladium (Tris DBA), showed significant antiproliferative activity against melanoma cells. Studies were carried out to determine the mechanism of action of Tris DBA. Experimental Design: Tris DBA was tested on efficacy on proliferation of human and murine melanoma cells. To find the mechanism of action of Tris DBA, we did Western blot and gene array analyses. The ability of Tris DBA to block tumor growth in vivo was assessed. Results: Tris DBA has activity against B16 murine and A375 human melanoma in vivo. Tris DBA inhibits several signaling pathways including activation of mitogen-activated protein kinase, Akt, Stat-3, and S6 kinase activation, suggesting an upstream target. Tris DBA was found to be a potent inhibitor of N-myristoyltransferase-1, which is required for optimal activity of membranebased signaling molecules. Tris DBA showed potent antitumor activity in vivo against melanoma. Conclusion: Tris DBA is thus a novel inhibitor of N-myristoyltransferase-1 with significant antitumor activity and is well tolerated in vivo. Further preclinical evaluation of Tris DBA and related complexes is warranted.

Copyright information:

© 2008 American Association for Cancer Research.

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