Dasatinib synergizes with doxorubicin to block growth, migration, and invasion of breast cancer cells

Br J Cancer. 2009 Jul 7;101(1):38-47. doi: 10.1038/sj.bjc.6605101. Epub 2009 Jun 9.

Abstract

Background: Src family kinases control multiple cancer cell properties including cell cycle progression, survival, and metastasis. Recent studies suggest that the Src inhibitor dasatinib blocks these critical cancer cell functions.

Methods: Because the molecular mechanism of action of dasatinib in breast cancers has not been investigated, we evaluated the effects of dasatinib as a single agent and in combination with the commonly used chemotherapeutic doxorubicin, on the proliferation, viability, and invasive capacity of breast cancer cells lines earlier categorised as dasatinib-sensitive (MDA-MB-231) and moderately resistant (MCF7 and T47D). We also tested the effects of these drugs on the actin cytoskeleton and associated signalling pathways.

Results: The cell lines tested varied widely in sensitivity to growth inhibition (IC(50)=0.16-12.3 microM), despite comparable Src kinase inhibition by dasatinib (IC(50)=17-37 nM). In the most sensitive cell line, MDA-MB-231, dasatinib treatment induced significant G(1) accumulation with little apoptosis, disrupted cellular morphology, blocked migration, inhibited invasion through Matrigel (P<0.01), and blocked the formation of invadopodia (P<0.001). Importantly, combination treatment with doxorubicin resulted in synergistic growth inhibition in all cell lines and blocked the migration and invasion of the highly metastatic, triple-negative MDA-MB-231 cell line.

Conclusion: The observed synergy between dasatinib and doxorubicin warrants the re-evaluation of dasatinib as an effective agent in multi-drug regimens for the treatment of invasive breast cancers.

Publication types

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

MeSH terms

  • Actins / metabolism
  • Antibiotics, Antineoplastic / administration & dosage
  • Antibiotics, Antineoplastic / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Growth Processes / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cytoskeleton / drug effects
  • Cytoskeleton / metabolism
  • Cytoskeleton / pathology
  • Dasatinib
  • Doxorubicin / administration & dosage*
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • G1 Phase / drug effects
  • Humans
  • Neoplasm Invasiveness
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / administration & dosage
  • Pyrimidines / pharmacology*
  • Thiazoles / administration & dosage
  • Thiazoles / pharmacology*
  • Tubulin / metabolism
  • src-Family Kinases / antagonists & inhibitors

Substances

  • Actins
  • Antibiotics, Antineoplastic
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Thiazoles
  • Tubulin
  • Doxorubicin
  • src-Family Kinases
  • Dasatinib