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 Izaguirre, Keith M. Rich

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)207-219
Number of pages13
JournalJournal of Neuro-Oncology
Volume103
Issue number2
DOIs
StatePublished - Jun 1 2011

Fingerprint

Glioblastoma
Cell Death
Drug Therapy
Photography
Therapeutics
Clinical Protocols
ERW1227B
Treatment Failure
Phosphatidylinositol 3-Kinases
Drug Resistance
Sulfhydryl Compounds
Biological Assay
Adhesives
Cysteine
Actins
Catalytic Domain
Down-Regulation
Radiation
Phenotype
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

Cite this

Yuan, L., Holmes, T. C., Watts, R. E., Khosla, C., Broekelmann, T. J., Mecham, R., ... Rich, K. M. (2011). Novel chemo-sensitizing agent, ERW1227B, impairs cellular motility and enhances cell death in glioblastomas. Journal of Neuro-Oncology, 103(2), 207-219. https://doi.org/10.1007/s11060-010-0379-2

Novel chemo-sensitizing agent, ERW1227B, impairs cellular motility and enhances cell death in glioblastomas. / Yuan, Liya; Holmes, Tracy C.; Watts, R. Edward; Khosla, Chaitan; Broekelmann, Tom J.; Mecham, Robert; Zheng, Hong; Izaguirre, Enrique; Rich, Keith M.

In: Journal of Neuro-Oncology, Vol. 103, No. 2, 01.06.2011, p. 207-219.

Research output: Contribution to journalArticle

Yuan, L, Holmes, TC, Watts, RE, Khosla, C, Broekelmann, TJ, Mecham, R, Zheng, H, Izaguirre, E & Rich, KM 2011, 'Novel chemo-sensitizing agent, ERW1227B, impairs cellular motility and enhances cell death in glioblastomas', Journal of Neuro-Oncology, vol. 103, no. 2, pp. 207-219. https://doi.org/10.1007/s11060-010-0379-2
Yuan, Liya ; Holmes, Tracy C. ; Watts, R. Edward ; Khosla, Chaitan ; Broekelmann, Tom J. ; Mecham, Robert ; Zheng, Hong ; Izaguirre, Enrique ; Rich, Keith M. / Novel chemo-sensitizing agent, ERW1227B, impairs cellular motility and enhances cell death in glioblastomas. In: Journal of Neuro-Oncology. 2011 ; Vol. 103, No. 2. pp. 207-219.
@article{f6b77ce74d434b389ec0c1e90944978f,
title = "Novel chemo-sensitizing agent, ERW1227B, impairs cellular motility and enhances cell death in glioblastomas",
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.",
author = "Liya Yuan and Holmes, {Tracy C.} and Watts, {R. Edward} and Chaitan Khosla and Broekelmann, {Tom J.} and Robert Mecham and Hong Zheng and Enrique Izaguirre and Rich, {Keith M.}",
year = "2011",
month = "6",
day = "1",
doi = "10.1007/s11060-010-0379-2",
language = "English (US)",
volume = "103",
pages = "207--219",
journal = "Journal of Neuro-Oncology",
issn = "0167-594X",
publisher = "Kluwer Academic Publishers",
number = "2",

}

TY - JOUR

T1 - Novel chemo-sensitizing agent, ERW1227B, impairs cellular motility and enhances cell death in glioblastomas

AU - Yuan, Liya

AU - Holmes, Tracy C.

AU - Watts, R. Edward

AU - Khosla, Chaitan

AU - Broekelmann, Tom J.

AU - Mecham, Robert

AU - Zheng, Hong

AU - Izaguirre, Enrique

AU - Rich, Keith M.

PY - 2011/6/1

Y1 - 2011/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=79959837759&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79959837759&partnerID=8YFLogxK

U2 - 10.1007/s11060-010-0379-2

DO - 10.1007/s11060-010-0379-2

M3 - Article

VL - 103

SP - 207

EP - 219

JO - Journal of Neuro-Oncology

JF - Journal of Neuro-Oncology

SN - 0167-594X

IS - 2

ER -