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Primary and liver metastasis-derived cell lines from KrasG12D; Trp53R172H; Pdx-1 Cre animals undergo apoptosis in response to triptolide.

AbstractOBJECTIVES:
Pancreatic cancer has a 5-year survival rate of less than 5%, partly because of limited chemotherapeutic options, thereby highlighting the need for novel therapies. Triptolide, a diterpene triepoxide that was derived from a Chinese herb, has shown great promise in preclinical testing against pancreatic cancer using immunocompromised animals.
RESULTS:
In this study, we tested the ability of triptolide to induce cell death in cell lines derived from a primary tumor and adjacent liver metastases of immunocompetent animals (Kras, Trp53, Pdx-1 Cre [KPC]). Both cell lines were more aggressive in their ability to form tumors when compared with other pancreatic cancer cell lines and showed constitutive activation of the nuclear factor κ-light-chain-enhancer of activated B cells pathway. Triptolide induced apoptotic cell death in both cell lines, as evidenced by decreased cell viability as well as increased caspase 3/7 activity, annexin V positivity, and increased terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positivity in tumors from KPC animals treated with Minnelide. In addition, triptolide decreased levels of HSP70, its transcription factor HSF1, as well as the antiapoptotic proteins Bcl-xL, Bcl-2, and Mcl-1, which are known to be up-regulated in pancreatic cancer.
CONCLUSIONS:
The ability of triptolide to cause cell death in cell lines derived from immunocompetent animals further validates its potential as a novel agent against pancreatic cancer.
AuthorsVeena Sangwan, Sulagna Banerjee, Kelsey M Jensen, Zhiyu Chen, Rohit Chugh, Vikas Dudeja, Selwyn M Vickers, Ashok K Saluja
JournalPancreas (Pancreas) Vol. 44 Issue 4 Pg. 583-9 (May 2015) ISSN: 1536-4828 [Electronic] United States
PMID25875797 (Publication Type: Evaluation Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents, Alkylating
  • Biomarkers, Tumor
  • Diterpenes
  • Epoxy Compounds
  • Phenanthrenes
  • triptolide
Topics
  • Animals
  • Antineoplastic Agents, Alkylating (pharmacology, therapeutic use)
  • Apoptosis (drug effects)
  • Biomarkers, Tumor (metabolism)
  • Cell Line, Tumor
  • Diterpenes (pharmacology, therapeutic use)
  • Epoxy Compounds (pharmacology, therapeutic use)
  • Immunocompetence
  • Mice
  • Mice, Transgenic
  • Pancreatic Neoplasms (drug therapy, immunology)
  • Phenanthrenes (pharmacology, therapeutic use)

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