Tris DBA palladium is highly effective against growth and metastasis of pancreatic cancer in an orthotopic model

Begoña Díaz, Katherine T. Ostapoff, Jason E. Toombs, Jason Lo, Michael Y. Bonner, Adam Curatolo, Volkan Adsay, Rolf A. Brekken, Jack L. Arbiser

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)51569-51580
Number of pages12
JournalOncotarget
Volume7
Issue number32
DOIs
StatePublished - Aug 1 2016

Fingerprint

Palladium
Pancreatic Neoplasms
Neoplasm Metastasis
Growth
Cilia
gemcitabine
Melanoma
Organometallic Compounds
Myristic Acid
Chemotaxis
Therapeutics
tris(dibenzylideneacetone)dipalladium
Ascites
Genotype
Drug Therapy
Survival
Pancreatic Carcinoma
Enzymes
glycylpeptide N-tetradecanoyltransferase
Neoplasms

Keywords

  • Chemotaxis
  • Metastasis
  • NMT1
  • Pancreatic cancer
  • Tris DBA palladium

ASJC Scopus subject areas

  • Oncology

Cite this

Díaz, B., Ostapoff, K. T., Toombs, J. E., Lo, J., Bonner, M. Y., Curatolo, A., ... Arbiser, J. L. (2016). Tris DBA palladium is highly effective against growth and metastasis of pancreatic cancer in an orthotopic model. Oncotarget, 7(32), 51569-51580. https://doi.org/10.18632/oncotarget.10514

Tris DBA palladium is highly effective against growth and metastasis of pancreatic cancer in an orthotopic model. / Díaz, Begoña; Ostapoff, Katherine T.; Toombs, Jason E.; Lo, Jason; Bonner, Michael Y.; Curatolo, Adam; Adsay, Volkan; Brekken, Rolf A.; Arbiser, Jack L.

In: Oncotarget, Vol. 7, No. 32, 01.08.2016, p. 51569-51580.

Research output: Contribution to journalArticle

Díaz, B, Ostapoff, KT, Toombs, JE, Lo, J, Bonner, MY, Curatolo, A, Adsay, V, Brekken, RA & Arbiser, JL 2016, 'Tris DBA palladium is highly effective against growth and metastasis of pancreatic cancer in an orthotopic model', Oncotarget, vol. 7, no. 32, pp. 51569-51580. https://doi.org/10.18632/oncotarget.10514
Díaz, Begoña ; Ostapoff, Katherine T. ; Toombs, Jason E. ; Lo, Jason ; Bonner, Michael Y. ; Curatolo, Adam ; Adsay, Volkan ; Brekken, Rolf A. ; Arbiser, Jack L. / Tris DBA palladium is highly effective against growth and metastasis of pancreatic cancer in an orthotopic model. In: Oncotarget. 2016 ; Vol. 7, No. 32. pp. 51569-51580.
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