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Novel chemo-sensitizing agent, ERW1227B, impairs cellular motility and enhances cell death in glioblastomas
Liya Yuan1, Tracy C Holmes, R Edward Watts
1Department of Neurological Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Box 8057, St. Louis, MO 63110, USA.
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.
Insights
A new compound, ERW1227B, effectively kills glioblastoma cells and reduces their movement. It also enhances the effectiveness of chemotherapy and radiation, offering a promising new treatment strategy for glioblastoma.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Glioblastomas are aggressive brain tumors characterized by drug resistance, high motility, and resistance to cell death, leading to treatment failure.
- Novel therapeutic strategies are needed to overcome glioblastoma's resistance mechanisms and improve patient outcomes.
- Targeting cellular pathways that regulate cell death and motility is a promising approach.
Purpose of the Study:
- To synthesize and evaluate novel compounds targeting glioblastoma.
- To investigate the effects of compound ERW1227B on glioblastoma cell death and motility.
- To assess the potential of ERW1227B as a therapeutic agent for glioblastoma, alone and in combination with standard treatments.
Main Methods:
- Synthesis of novel small molecules with a 3-bromo-4,5-dihydroisoxazole component.
- In vitro studies using glioblastoma cell lines to assess cell death and motility.
- Analysis of the PI-3 kinase/Akt pathway and focal adhesion complexes.
- In vivo studies using murine glioblastoma models to evaluate therapeutic efficacy.
Main Results:
- Compound ERW1227B demonstrated significant glioblastoma cell death and impaired cellular motility.
- ERW1227B treatment led to down-regulation of the PI-3 kinase/Akt pathway and disruption of focal adhesion complexes.
- In vivo studies showed ERW1227B sensitized glioblastoma cells to chemotherapy and radiation, enhancing tumor cell death.
- The compound's activity was observed irrespective of its ability to inhibit tissue transglutaminase (TG2).
Conclusions:
- ERW1227B is a novel compound with potent anti-glioblastoma activity, inducing cell death and reducing motility.
- ERW1227B modulates key signaling pathways (PI-3K/Akt) and cellular structures (focal adhesions, actin) involved in glioblastoma progression.
- ERW1227B shows potential as a sensitizing agent, enhancing the efficacy of chemotherapy and radiation in glioblastoma treatment.
- ERW1227B represents a promising therapeutic candidate for glioblastoma treatment strategies.
