Abstract
Glioblastoma multiforme (GBM) is associated with high mortality due to infiltrative growth and recurrence. Median survival of the patients is less than 15 months, increasing requirements for new therapies. We found that both arsenic trioxide and 10058F4, an inhibitor of Myc, induced differentiation of cancer stem-like cells (CSC) of GBM and that arsenic trioxide drastically enhanced the anti-proliferative effect of 10058F4 but not apoptotic effects. EGFR-driven genetically engineered GBM mouse model showed that this cooperative effect is higher in EGFRvIII-expressing INK4a/Arf-/- neural stem cells (NSCs) than in control wild type NSCs. In addition, treatment of GBM CSC xenografts with arsenic trioxide and 10058F4 resulted in significant decrease in tumor growth and increased differentiation with concomitant decrease of proneural and mesenchymal GBM CSCs in vivo. Our study was the first to evaluate arsenic trioxide and 10058F4 interaction in GBM CSC differentiation and to assess new opportunities for arsenic trioxide and 10058F4 combination as a promising approach for future differentiation therapy of GBM.
Highlights
Glioblastoma multiforme (GBM) is one of the most common malignant primary brain tumors in adult and highly resistant to conventional chemotherapy[1,2]
Our results demonstrated that a low concentration of arsenic trioxide (2μM) enhanced the sensitivity of GBM cancer stem-like cells (CSC) to 10058F4 and that arsenic trioxide and 10058F4 combination treatment enhanced differentiation of GBM CSCs
This preclinical efficacy of arsenic trioxide and 10058F4 combination therapy were confirmed across multiple GBM models: human GBM CSCs, geneticallyengineered mice GBM model, and human-derived GBM CSC xenografts in vivo
Summary
Glioblastoma multiforme (GBM) is one of the most common malignant primary brain tumors in adult and highly resistant to conventional chemotherapy[1,2]. Constitutive-active mutation of EGFR (EGFRvIII) and loss of CDKN2a (INK4a/Arf) are often observed in GBM[3,4,5,6,7]. Constitutive EGFR activation is sufficient to transform INK4a/Arf-deficient neural stem cells (NSCs) and astrocytes into cancer stem-like cells (CSCs), which has high tumorigenicity in vivo[8]. GBM CSCs are considered to be an origin of tumor and recurrence [9] and are an important therapeutic target. CSCs can be cultured in serum-free medium supplemented with.
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