Antitumor effects of Dasatinib on laryngeal squamous cell carcinoma in vivo and in vitro

Eur Arch Otorhinolaryngol. 2013 Mar;270(4):1397-404. doi: 10.1007/s00405-013-2394-3. Epub 2013 Feb 13.

Abstract

A novel drug named Dasatinib is a highly potent ATP-competitive orally active dual Src/Abl kinase inhibitor with anti-proliferative activity against solid tumors and CML (chronic myeloid leukaemia) cell lines. Dasatinib has been shown to have preclinical activity against human prostate, breast, pancreatic, lung, and head and neck cancer. To determine whether Dasatinib can inhibit the growth of laryngeal squamous cell carcinoma, in the present study, we investigated the antitumor effect of Dasatinib on Hep-2 cells. Hep-2 cells were treated with different concentrations of Dasatinib for different time. Cell proliferation, cell cycle distribution, and cell apoptosis were evaluated using MTT assay, flow cytometry, and fluorescent microscopy. It was found that Dasatinib exhibited significant efficacy in growth inhibition, cell cycle arrest at G0/G1 phase, and apoptosis induction in a dose- and time-dependent manner. Measuring the modulation of regulators in the cell cycle, apoptosis and signal transductions by western blot analysis showed that the effect of Dasatinib was due to suppression of the expression of Bax, Bcl-2, Caspase-3, and Caspase-8. Moreover, in vivo studies were performed in a nude mouse xenograft model, the new prescription (DDP + Dasatinib) was better than DDP alone in terms of therapeutic efficacy. In conclusion, the antitumor effect of Dasatinib on Hep-2 cells was due to the induction of cell cycle arrest as well as apoptosis. The possible mechanisms underlying the action might be attributed to the suppression of Src phosphorylation. This investigation suggests a potential clinical application of Dasatinib for the treatment of laryngeal cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Apoptosis / drug effects*
  • Blotting, Western
  • Carcinoma, Squamous Cell / pathology*
  • Cell Cycle / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / pathology
  • Cisplatin / pharmacology
  • Dasatinib
  • Dose-Response Relationship, Drug
  • Flow Cytometry
  • Humans
  • In Vitro Techniques
  • Laryngeal Neoplasms / pathology*
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrimidines / therapeutic use*
  • Rats
  • Thiazoles / therapeutic use*

Substances

  • Protein Kinase Inhibitors
  • Pyrimidines
  • Thiazoles
  • Cisplatin
  • Dasatinib