Breast Cancer Research and Treatment

, Volume 132, Issue 2, pp 391–409

KX-01, a novel Src kinase inhibitor directed toward the peptide substrate site, synergizes with tamoxifen in estrogen receptor α positive breast cancer

  • Muralidharan Anbalagan
  • Latonya Carrier
  • Seth Glodowski
  • David Hangauer
  • Bin Shan
  • Brian G. Rowan
Preclinical study

Abstract

KX-01 is the first clinical Src inhibitor of the novel peptidomimetic class that targets the peptide substrate site of Src providing more specificity toward Src kinase. The present study was designed to evaluate the effects of KX-01 as a single agent and in combination with tamoxifen (TAM) on cell growth and apoptosis of ERα positive breast cancer in vitro and in vivo. Flow cytometry demonstrated that KX-01 induced cell cycle arrest in G2/M phase. Immunofluorescent staining for mitotic phase markers and TUNEL staining indicated that cells had arrested in the mitotic phase and mitotic arrested cells were undergoing apoptosis. KX-01 induced nuclear accumulation of cyclin B1, and activation of CDK1, MPM2, and Cdc25C that is required for progression past the G2/M checkpoint. Apoptosis resulted from activation of caspases 6, 7, 8, and 9. Combinational index analysis revealed that combinations of KX-01 with TAM resulted in synergistic growth inhibition of breast cancer cell lines. KX-01 combined with TAM resulted in decreased ERα phosphorylation at Src-regulated phosphorylation sites serines 118 and 167 that were associated with reduced ERα transcriptional activity. Orally administered KX-01 resulted in a dose dependent growth inhibition of MCF-7 tumor xenografts, and in combination with TAM exhibited synergistic growth inhibition. Immunohistochemical analysis revealed that combinational treatment reduced angiogenesis, and ERα signaling in tumors compared to either drug alone that may underlie the synergistic tumor growth inhibition. Combinations of KX-01 with endocrine therapy present a promising new strategy for clinical management of ERα positive breast cancer.

Keywords

Breast cancer Src kinase inhibitor KX-01 Tamoxifen Preclinical Synergy 

Supplementary material

10549_2011_1513_MOESM1_ESM.pdf (1.4 mb)
Supplementary material 1 (PDF 1483 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Muralidharan Anbalagan
    • 1
  • Latonya Carrier
    • 1
  • Seth Glodowski
    • 1
  • David Hangauer
    • 2
  • Bin Shan
    • 3
  • Brian G. Rowan
    • 1
  1. 1.Department of Structural and Cellular BiologyTulane University School of MedicineNew OrleansUSA
  2. 2.Kinex Pharmaceuticals LLCState University of New York at BuffaloBuffaloUSA
  3. 3.Department of MedicineTulane University School of MedicineNew OrleansUSA

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