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Antitumor effect of dehydroxymethylepoxyquinomicin, a small molecule inhibitor of nuclear factor-κB, on glioblastoma
Tsuyoshi Fukushima1, Makiko Kawaguchi, Kenji Yorita
1Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
Abstract:
Glioblastoma is the most malignant type of brain tumor. Despite recent advances in therapeutic modalities, the prognosis of glioblastoma remains very poor. Recent studies have indicated that RelA/nuclear factor (NF)-κB is consistently activated in human glioblastoma. In this study, we searched for a new treatment modality for glioblastoma, by examining the effects of dehydroxymethylepoxyquinomicin (DHMEQ), a unique small molecule inhibitor of NF-κB. Addition of DHMEQ to cultured human glioblastoma cells inhibited the nuclear translocation of RelA. It also reduced the growth rate of human glioblastoma cells significantly in 6 cell lines and modestly in 3 among 10 cell lines examined. Then, we performed further analyses using 3 sensitive cell lines (U87, U251, and YKG-1). The growth retardation was accompanied by G2/M arrest in vitro. Increased apoptosis was observed in U87 and YKG-1, but not U251 cells after DHMEQ treatment. Then, we tested the efficacy of DHMEQ in chemoprevention through the use of a nude mouse model. Subcutaneous tumors formed by U87 or U251 cells were reduced by ∼40% in size by intraperitoneal administration of DHMEQ started immediately after implantation of the cells. DHMEQ treatment achieved statistically significant improvements in survival curves of mice intracranially implanted with U87 or U251 cells. Histological analysis revealed increased areas of necrosis, increased numbers of collapsed microvessels, decreased nuclear immunoreactivity of RelA, and decreased immunoreactivity of urokinase-type plasminogen activator in the DHMEQ-treated U87 tumor tissues. These results suggest that the targeting of NF-κB by DHMEQ may serve as a promising treatment modality in glioblastoma.
Insights
Dehydroxymethylepoxyquinomicin (DHMEQ), an inhibitor of nuclear factor-kappa B (NF-κB), shows promise for treating glioblastoma. DHMEQ reduced glioblastoma cell growth and improved survival in mouse models, suggesting NF-κB targeting as a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Glioblastoma is an aggressive brain tumor with a poor prognosis.
- Nuclear factor-kappa B (NF-κB) signaling is consistently activated in human glioblastoma.
- There is a need for novel therapeutic strategies targeting glioblastoma.
Purpose of the Study:
- To investigate dehydroxymethylepoxyquinomicin (DHMEQ), a small molecule inhibitor of NF-κB, as a potential treatment for glioblastoma.
- To evaluate the effects of DHMEQ on glioblastoma cell growth, proliferation, and apoptosis in vitro.
- To assess the efficacy of DHMEQ in glioblastoma chemoprevention and treatment in vivo using mouse models.
Main Methods:
- In vitro studies involved treating human glioblastoma cell lines with DHMEQ to assess its effects on RelA nuclear translocation, cell growth, cell cycle progression, and apoptosis.
- In vivo studies utilized nude mouse models with subcutaneous and intracranial glioblastoma xenografts to evaluate DHMEQ's chemopreventive and therapeutic efficacy.
- Histological and immunohistochemical analyses were performed on tumor tissues to examine markers of tumor growth, apoptosis, and NF-κB pathway activity.
Main Results:
- DHMEQ inhibited RelA nuclear translocation and significantly reduced the growth rate of multiple glioblastoma cell lines.
- DHMEQ treatment induced G2/M cell cycle arrest and apoptosis in sensitive glioblastoma cell lines.
- In vivo, DHMEQ administration reduced tumor size, improved survival rates in mice with glioblastoma, and decreased tumor markers associated with NF-κB activity.
Conclusions:
- Targeting the NF-κB pathway with DHMEQ demonstrates significant anti-tumor activity against glioblastoma.
- DHMEQ exhibits potential as a novel therapeutic agent for glioblastoma treatment.
- Further investigation into DHMEQ's mechanism of action and clinical application is warranted.