Anti-tumor activity of a novel compound-CDF is mediated by regulating miR-21, miR-200, and PTEN in pancreatic cancer

PLoS One. 2011 Mar 9;6(3):e17850. doi: 10.1371/journal.pone.0017850.

Abstract

Background: The existence of cancer stem cells (CSCs) or cancer stem-like cells in a tumor mass is believed to be responsible for tumor recurrence because of their intrinsic and extrinsic drug-resistance characteristics. Therefore, targeted killing of CSCs would be a newer strategy for the prevention of tumor recurrence and/or treatment by overcoming drug-resistance. We have developed a novel synthetic compound-CDF, which showed greater bioavailability in animal tissues such as pancreas, and also induced cell growth inhibition and apoptosis, which was mediated by inactivation of NF-κB, COX-2, and VEGF in pancreatic cancer (PC) cells.

Methodology/principal findings: In the current study we showed, for the first time, that CDF could significantly inhibit the sphere-forming ability (pancreatospheres) of PC cells consistent with increased disintegration of pancreatospheres, which was associated with attenuation of CSC markers (CD44 and EpCAM), especially in gemcitabine-resistant (MIAPaCa-2) PC cells containing high proportion of CSCs consistent with increased miR-21 and decreased miR-200. In a xenograft mouse model of human PC, CDF treatment significantly inhibited tumor growth, which was associated with decreased NF-κB DNA binding activity, COX-2, and miR-21 expression, and increased PTEN and miR-200 expression in tumor remnants.

Conclusions/significance: These results strongly suggest that the anti-tumor activity of CDF is associated with inhibition of CSC function via down-regulation of CSC-associated signaling pathways. Therefore, CDF could be useful for the prevention of tumor recurrence and/or treatment of PC with better treatment outcome in the future.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Animals
  • Antigens, Neoplasm / metabolism
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cell Adhesion Molecules / metabolism
  • Cell Aggregation / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Clone Cells
  • Curcumin / analogs & derivatives*
  • Curcumin / pharmacology*
  • Curcumin / therapeutic use
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Drug Resistance, Neoplasm / drug effects
  • Epithelial Cell Adhesion Molecule
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Hyaluronan Receptors / metabolism
  • Mice
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • NF-kappa B / metabolism
  • Neoplasm Invasiveness
  • Neoplasm Proteins / metabolism
  • PTEN Phosphohydrolase / genetics*
  • PTEN Phosphohydrolase / metabolism
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Cell Adhesion Molecules
  • Epithelial Cell Adhesion Molecule
  • Hyaluronan Receptors
  • MIRN200 microRNA, human
  • MIRN21 microRNA, human
  • MicroRNAs
  • NF-kappa B
  • Neoplasm Proteins
  • RNA, Messenger
  • Deoxycytidine
  • gemcitabine
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Curcumin