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


METHODS
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 membrane-based signaling molecules. Tris DBA showed potent antitumor activity in vivo against melanoma.


CONCLUSIONS
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.
Bhandarkar
Sulochana S
SS
Department of Dermatology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Bromberg
Jacqueline
J
Carrillo
Carol
C
Selvakumar
Ponniah
P
Sharma
Rajendra K
RK
Perry
Betsy N
BN
Govindarajan
Baskaran
B
Fried
Levi
L
Sohn
Allie
A
Reddy
Kalpana
K
Arbiser
Jack L
JL
D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009942:Organometallic Compounds / Q000494:pharmacology; D010165:Palladium / Q000494:pharmacology
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; C532099:tris(dibenzylideneacetone)dipalladium; D010165:Palladium; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase
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