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.
Highlights
Carcinoma of the exocrine pancreas remains among one of the deadliest solid tumors in humans
We propose that N-myristoyltransferase 1 (NMT1) is a novel regulator of cilia formation and tris DBA palladium a novel inhibitor of cilia formation and metastasis in pancreatic cancer
Given that melanoma and pancreatic carcinoma share some common genetic and signaling features, including loss of p16Ink4a, predisposing to melanoma and pancreatic carcinoma, we evaluated the effect of tris DBA treatment in pancreatic carcinoma
Summary
Carcinoma of the exocrine pancreas remains among one of the deadliest solid tumors in humans. Factors that contribute to the high degree of mortality are late detection, when distant metastases are present, anatomical location making definitive surgery difficult, and advanced age. Over 90% of pancreatic adenocarcinomas exhibit mutations in Kras, which is currently undruggable [1, 2]. Surgery and radiation alone are insufficient to control the disease. Chemotherapy is commonly used, with gemcitabine and folfirinox being the mainstays of therapy [3]. Additional studies have attempted to increase the success of therapy of pancreatic adenocarcinoma. The use of hedgehog inhibitors to block signaling and desmoplasia resulted in decreased desmoplasia, but with no clinical benefit [4]. Novel therapies are urgently needed for this common and lethal cancer [5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
