Tris DBA palladium is highly effective against growth and metastasis of pancreatic cancer in an orthotopic model
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Begoña Díaz4,5, Katherine T. Ostapoff6,7, Jason E. Toombs6,7, Jason Lo1,2,3, Michael Y. Bonner1,2,3, Adam Curatolo8,9, Volkan Adsay10, Rolf A. Brekken6,7, Jack L. Arbiser1,2,3
1Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA
2Atlanta Veterans Administration Medical Center, Atlanta, GA, USA
3Winship Cancer Institute, Atlanta, GA, USA
4Tumor Microenvironment and Metastasis Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
5Division of Medical Oncology and Hematology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
6Department of Surgery, Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA
7Department of Pharmacology, Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA
8Vascular Biology Program, Department of Surgery, Children’s Hospital Boston, Boston, MA, USA
9Karp Family Research Laboratories, Harvard Medical School, Boston, MA, USA
10Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
Jack L. Arbiser, email: [email protected]
Keywords: pancreatic cancer, tris DBA palladium, NMT1, metastasis, chemotaxis
Received: March 24, 2016 Accepted: May 19, 2016 Published: July 09, 2016
Pancreatic carcinoma ranks among the most lethal of human cancers. Besides late detection, other factors contribute to its lethality, including a high degree of chemoresistance, invasion, and distant metastases. Currently, the mainstay of therapy involves resection of local disease in a minority of patients (Whipple procedure) and systemic gemcitabine. While systemic chemotherapy has some benefit, even with optimal treatment, the five year survival after diagnosis is dismal. Thus, treatment of pancreatic carcinoma remains a tremendous unmet need.
The organometallic compound tris DBA palladium is a potent inhibitor of N-myristoyltransferase 1 (NMT1), an enzyme that catalyzes the transfer of myristate to protein substrates. This compound is highly effective in vivo against murine models of melanoma with both mutant and wild type b-RAF genotypes. Based upon the signaling similarities between melanoma and pancreatic carcinoma, we evaluated the efficacy of tris DBA palladium in vitro and in vivo against pancreatic carcinoma. We found that tris DBA palladium decreased proliferation and colony formation of pancreatic cancer cells in vitro. In an orthotopic mouse model, tris DBA palladium was highly active in inhibiting growth, ascites production, and distant metastases in vivo. Furthermore, tris DBA palladium impaired chemotaxis and inhibited cilia formation in Pan02 cells in a NMT1-dependent manner. We propose that NMT1 is a novel regulator of cilia formation and tris DBA palladium a novel inhibitor of cilia formation and metastasis in pancreatic cancer. Thus, further evaluation of tris DBA palladium for the treatment of pancreatic cancer is warranted.
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