Tris (dibenzylideneacetone) dipalladium, a N-myristoyltransferase-1 inhibitor, is effective against melanoma growth in vitro and in vivo Journal Article
| Authors: | Bhandarkar, S. S.; Bromberg, J.; Carrillo, C.; Selvakumar, P.; Sharma, R. K.; Perry, B. N.; Govindarajan, B.; Fried, L.; Sohn, A.; Reddy, K.; Arbiser, J. L. |
| Article Title: | Tris (dibenzylideneacetone) dipalladium, a N-myristoyltransferase-1 inhibitor, is effective against melanoma growth in vitro and in vivo |
| 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. © 2008 American Association for Cancer Research. |
| Keywords: | signal transduction; mitogen activated protein kinase; protein kinase b; s6 kinase; vasculotropin; controlled study; protein expression; unclassified drug; human cell; drug efficacy; nonhuman; antineoplastic agents; antineoplastic agent; cell proliferation; animal cell; mouse; animal; animals; mice; drug inhibition; stat3 protein; melanoma; in vivo study; antineoplastic activity; enzyme activation; in vitro study; drug screening; drug screening assays, antitumor; cell line, tumor; carcinogenesis; drug antagonism; drug mechanism; nude mouse; mice, nude; tumor cell line; melanoma cell; experimental melanoma; melanoma, experimental; neoplasm transplantation; organometallic compound; organometallic compounds; palladium; acyltransferase; cancer transplantation; protein n myristoyltransferase; protein n myristoyltransferase inhibitor; tris(dibenzylideneacetone)dipalladium; glycylpeptide n-tetradecanoyltransferase; acyltransferases |
| Journal Title: | Clinical Cancer Research |
| Volume: | 14 |
| Issue: | 18 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2008-09-15 |
| Start Page: | 5743 |
| End Page: | 5748 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-08-0405 |
| PUBMED: | 18794083 |
| PROVIDER: | scopus |
| PMCID: | PMC4423743 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 7" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Source: Scopus" |
