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Journal of Neuro-Oncology

, Volume 103, Issue 2, pp 207–219 | Cite as

Novel chemo-sensitizing agent, ERW1227B, impairs cellular motility and enhances cell death in glioblastomas

  • Liya Yuan
  • Tracy C. Holmes
  • R. Edward Watts
  • Chaitan Khosla
  • Tom J. Broekelmann
  • Robert Mecham
  • Hong Zheng
  • Enrique W. Izaguirre
  • Keith M. Rich
Laboratory Investigation - Human/Animal Tissue

Abstract

Glioblastomas display variable phenotypes that include increased drug-resistance associated with enhanced migratory and anti-apoptotic characteristics. These shared characteristics contribute to failure of clinical treatment regimens. Identification of novel compounds that promote cell death and impair cellular motility is a logical strategy to develop more effective clinical protocols. We recently described the ability of the small molecule, KCC009, a tissue transglutaminase (TG2) inhibitor, to sensitize glioblastoma cells to chemotherapy. In the current study, we synthesized a series of related compounds that show variable ability to promote cell death and impair motility in glioblastomas, irrespective of their ability to inhibit TG2. Each compound has a 3-bromo-4,5-dihydroisoxazole component that presumably reacts with nucleophilic cysteine thiol residues in the active sites of proteins that have an affinity to the small molecule. Our studies focused on the effects of the compound, ERW1227B. Treatment of glioblastoma cells with ERW1227B was associated with both down-regulation of the PI-3 kinase/Akt pathway, which enhanced cell death; as well as disruption of focal adhesive complexes and intracellular actin fibers, which impaired cellular mobility. Bioassays as well as time-lapse photography of glioblastoma cells treated with ERW1227B showed cell death and rapid loss of cellular motility. Mice studies with in vivo glioblastoma models demonstrated the ability of ERW1227B to sensitize tumor cells to cell death after treatment with either chemotherapy or radiation. The above findings identify ERW1227B as a potential novel therapeutic agent in the treatment of glioblastomas.

Keywords

Focal adhesive complexes Glioblastomas ERW1227B Cell death Drug-resistance Cellular motility 

Notes

Acknowledgments

This work is supported by grants from ABC2 Foundation (K.M.R.), the Stanford Center for Children’s Brain Tumors (C.K.), and support from Alvine Pharmaceuticals. K.M.R. and C.K. have a financial interest with Alvine Pharmaceuticals. We thank Ms. Bethany Kassebaum for her help with the radiation studies; and Mr. Cameron Ball for his assistance in analyzing the time-lapse imaging data. Time-lapse imaging (TiLa) code was created by the Computational Imaging Group at the University of Kansas Medical Center, under the direction of Drs. C. Little, B. Rongish, and A. Czirok. Dr. Czirok devised the original code for image acquisition and processing, which has been further developed and modified by Alan Petersen, Michael Filla, and Dr. Evan Zamir. A current version of this open source code is available from the Computational Imaging Group upon request (clittle@kumc.edu).

Supplementary material

Supplementary material 1 (AVI 118423 kb)

Supplementary material 2 (AVI 112723 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Liya Yuan
    • 1
  • Tracy C. Holmes
    • 5
  • R. Edward Watts
    • 5
  • Chaitan Khosla
    • 5
  • Tom J. Broekelmann
    • 2
  • Robert Mecham
    • 2
  • Hong Zheng
    • 3
  • Enrique W. Izaguirre
    • 4
  • Keith M. Rich
    • 1
    • 4
  1. 1.Department of Neurological SurgeryWashington University School of MedicineSt. LouisUSA
  2. 2.Department of Cell BiologyWashington University School of MedicineSt. LouisUSA
  3. 3.Division of DermatologyWashington University School of MedicineSt. LouisUSA
  4. 4.Department of Radiation OncologyWashington University School of MedicineSt. LouisUSA
  5. 5.Departments of Chemistry and Chemical EngineeringStanford UniversityStanfordUSA

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