TLN-4601 suppresses growth and induces apoptosis of pancreatic carcinoma cells through inhibition of Ras-ERK MAPK signaling Public Deposited

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Creator
  • Fiordalisi, James J
    • Affiliation: School of Medicine, Department of Radiation Oncology, N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Gourdeau, Henriette
    • Other Affiliation: Thallion Pharmaceuticals Inc., 7150 Alexander-Fleming, Montreal QC, H4S 2C8 Canada
  • Cox, Adrienne
    • Affiliation: School of Medicine, Department of Radiation Oncology, Department of Pharmacology, N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Der, Channing
    • Affiliation: School of Medicine, Department of Pharmacology, N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Falardeau, Pierre
    • Other Affiliation: Thallion Pharmaceuticals Inc., 7150 Alexander-Fleming, Montreal QC, H4S 2C8 Canada
  • Campbell, Paul M
    • Affiliation: School of Medicine, Department of Pharmacology, N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Boufaied, Nadia
    • Other Affiliation: Thallion Pharmaceuticals Inc., 7150 Alexander-Fleming, Montreal QC, H4S 2C8 Canada
Abstract
  • Abstract Background TLN-4601 is a structurally novel farnesylated dibenzodiazepinone discovered using Thallion's proprietary DECIPHER® technology, a genomics and bioinformatics platform that predicts the chemical structures of secondary metabolites based on gene sequences obtained by scanning bacterial genomes. Our recent studies suggest that TLN-4601 inhibits the Ras-ERK MAPK pathway post Ras prenylation and prior to MEK activation. The Ras-ERK MAPK signaling pathway is a well-validated oncogenic cascade based on its central role in regulating the growth and survival of cells from a broad spectrum of human tumors. Furthermore, RAS isoforms are the most frequently mutated oncogenes, occurring in approximately 30% of all human cancers, and KRAS is the most commonly mutated RAS gene, with a greater than 90% incidence of mutation in pancreatic cancer. Results To evaluate whether TLN-4601 interferes with K-Ras signaling, we utilized human pancreatic epithelial cells and demonstrate that TLN-4601 treatment resulted in a dose- and time-dependent inhibition of Ras-ERK MAPK signaling. The compound also reduced Ras-GTP levels and induced apoptosis. Finally, treatment of MIA PaCa-2 tumor-bearing mice with TLN-4601 resulted in antitumor activity and decreased tumor Raf-1 protein levels. Conclusion These data, together with phase I/II clinical data showing tolerability of TLN-4601, support conducting a clinical trial in advanced pancreatic cancer patients.
Date of publication
Identifier
  • doi:10.1186/1750-2187-5-18
  • 21044336
Resource type
  • Article
Rights statement
  • In Copyright
Rights holder
  • Paul M Campbell et al.; licensee BioMed Central Ltd.
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Journal title
  • Journal of Molecular Signaling
Journal volume
  • 5
Journal issue
  • 1
Page start
  • 18
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1750-2187
Bibliographic citation
  • Journal of Molecular Signaling. 2010 Nov 02;5(1):18
Access
  • Open Access
Publisher
  • BioMed Central Ltd
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