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.