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.