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.
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Box 8057, St. Louis, MO 63110, USA.
authors.forename: Liya
authors.initials: L
authors.lastname: Yuan
authors.forename: Tracy C
authors.initials: TC
authors.lastname: Holmes
authors.forename: R Edward
authors.initials: RE
authors.lastname: Watts
authors.forename: Chaitan
authors.initials: C
authors.lastname: Khosla
authors.forename: Tom J
authors.initials: TJ
authors.lastname: Broekelmann
authors.forename: Robert
authors.initials: R
authors.lastname: Mecham
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.forename: Enrique W
authors.initials: EW
authors.lastname: Izaguirre
authors.forename: Keith M
authors.initials: KM
authors.lastname: Rich
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D011838:Radiation-Sensitizing Agents / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; C561342:ERW1227B; D007555:Isoxazoles; C510621:KCC 009; D011838:Radiation-Sensitizing Agents
references.citation: Curr Biol. 1998 Oct 22;8(21):1195-8
references.pmid: 9799739
references.citation: Nature. 2004 Mar 18;428(6980):267-9
references.pmid: 15029179
references.citation: J Cell Physiol. 2004 Feb;198(2):209-22
references.pmid: 14603523
references.citation: J Microsc. 2002 Jun;206(Pt 3):209-17
references.pmid: 12067365
references.citation: Cancer Res. 2001 Sep 15;61(18):6674-8
references.pmid: 11559533
references.citation: Nature. 1999 Feb 11;397(6719):534-9
references.pmid: 10028971
references.citation: Med Phys. 2008 Oct;35(10):4735-43
references.pmid: 18975718
references.citation: J Cell Physiol. 2006 Apr;207(1):87-96
references.pmid: 16261592
references.citation: Gastroenterology. 2002 Dec;123(6):1980-91
references.pmid: 12454855
references.citation: J Neurochem. 2003 Jan;84(2):273-81
references.pmid: 12558990
references.citation: Mol Cancer Ther. 2005 Sep;4(9):1293-302
references.pmid: 16170020
references.citation: J Neurooncol. 2004 Jul;68(3):233-41
references.pmid: 15332326
references.citation: Med Phys. 2007 Dec;34(12):4706-16
references.pmid: 18196798
references.citation: Cancer Res. 1998 Dec 1;58(23):5285-90
references.pmid: 9850049
references.citation: J Pharmacol Exp Ther. 2007 Feb;320(2):853-64
references.pmid: 17099073
references.citation: Development. 2004 Jun;131(12):2887-97
references.pmid: 15151986
references.citation: N Engl J Med. 2005 Mar 10;352(10):997-1003
references.pmid: 15758010
references.citation: Cancer Res. 2003 Jul 15;63(14):4044-7
references.pmid: 12874004
references.citation: Annu Rev Cell Biol. 1988;4:487-525
references.pmid: 3058164
references.citation: J Cell Biol. 1994 Feb;124(4):619-26
references.pmid: 8106557
references.citation: Pharmacol Ther. 2003 Apr;98(1):71-108
references.pmid: 12667889
references.citation: Cancer Res. 1999 Jun 1;59(11):2724-30
references.pmid: 10363998
references.citation: J Neurooncol. 2001 Jun;53(2):161-76
references.pmid: 11716068
references.citation: J Neurochem. 2004 Apr;89(1):168-78
references.pmid: 15030401
references.citation: J Cell Physiol. 2002 Sep;192(3):259-67
references.pmid: 12124771
references.citation: Chem Biol. 2005 Apr;12(4):469-75
references.pmid: 15850984
references.citation: Int J Cancer. 2002 Apr 10;98(5):690-7
references.pmid: 11920637
references.citation: Oncogene. 2007 Apr 19;26(18):2563-73
references.pmid: 17099729
references.citation: J Med Chem. 2006 Dec 14;49(25):7493-501
references.pmid: 17149878
references.citation: J Cell Sci. 2003 Aug 15;116(Pt 16):3269-76
references.pmid: 12857786
references.citation: Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8856-60
references.pmid: 7522323
references.citation: Trends Cell Biol. 2006 Sep;16(9):453-60
references.pmid: 16893648
references.citation: J Cell Sci. 2003 Nov 1;116(Pt 21):4409-17
references.pmid: 13130092
references.citation: J Cell Physiol. 2001 Oct;189(1):1-13
references.pmid: 11573199
references.citation: Cancer Res. 2003 Nov 1;63(21):7443-50
references.pmid: 14612544