Characterization and use of HapT1-derived homologous tumors as a preclinical model to evaluate therapeutic efficacy of drugs against pancreatic tumor desmoplasia

Sujit Suklabaidya, Biswajit Das, Syed Azmal Ali, Sumeet Jain, Sharada Swaminathan, Ashok K. Mohanty, Susen K. Panda, Pujarini Dash, Subhankar Chakraborty, Surinder K. Batra, Shantibhusan Senapati

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Desmoplasia in human pancreatic cancer (PC) promotes cancer progression and hinders effective drug delivery. The objectives of this study were to characterize a homologous orthotopic model of PC in Syrian golden hamster and investigate the effect of anti-fibrotic (pirfenidone), antioxidant (N-acetyl cysteine, NAC) and anti-addiction (disulfiram, DSF) drugs on desmoplasia and tumor growth in this model. The HapT1 PC cells when implanted orthotopically into hamsters formed tumors with morphological, cellular and molecular similarities to human PC. Protein profiling of activated hamster pancreatic stellate cells (ha-PSCs) revealed expression of proteins involved in fibrosis, cancer cells growth and metastasis. Pirfenidone, suppressed growth of HapT1 cells and the desmoplastic response in vivo; these effects were enhanced by co-administration of NAC. Disulfiram alone or in combination with copper (Cu) was toxic to HapT1 cells and PSCs in vitro; but co-administration of DSF and Cu accelerated growth of HapT1 cells in vivo. Moreover, DSF had no effect on tumor-associated desmoplasia. Overall, this study identifies HapT1-derived orthotopic tumors as a useful model to study desmoplasia and tumor-directed therapeutics in PC. Pirfenidone in combination with NAC could be a novel combination therapy for PC and warrants investigation in human subjects.

Original languageEnglish (US)
Pages (from-to)41825-41842
Number of pages18
JournalOncotarget
Volume7
Issue number27
DOIs
StatePublished - Jul 5 2016

Keywords

  • HapT1
  • desmoplasia
  • hamster homologous orthotopic model
  • pancreatic cancer
  • pancreatic stellate cells

ASJC Scopus subject areas

  • Oncology

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    Suklabaidya, S., Das, B., Ali, S. A., Jain, S., Swaminathan, S., Mohanty, A. K., Panda, S. K., Dash, P., Chakraborty, S., Batra, S. K., & Senapati, S. (2016). Characterization and use of HapT1-derived homologous tumors as a preclinical model to evaluate therapeutic efficacy of drugs against pancreatic tumor desmoplasia. Oncotarget, 7(27), 41825-41842. https://doi.org/10.18632/oncotarget.9729