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Arsenic trioxide sensitizes glioblastoma to a myc inhibitor
Yayoi Yoshimura1, Akihiko Shiino2, Kazue Muraki3
1Research Institute, Shiga Medical Center, Moriyama 5-4-30, Shiga 524-8524, Japan; Department of Neurosurgery, Shiga University of Medical Science, Shiga 520-2192, Japan.
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.
Insights
Arsenic trioxide and 10058F4 (Myc inhibitor) promote glioblastoma cancer stem-cell differentiation. This combination therapy significantly reduces tumor growth and offers a promising new approach for glioblastoma treatment.
Area of Science:
- Neuro-oncology
- Cancer Stem Cell Biology
- Drug Discovery
Background:
- Glioblastoma multiforme (GBM) has a poor prognosis with median survival under 15 months.
- Infiltrative growth and recurrence necessitate novel therapeutic strategies.
- Cancer stem-like cells (CSCs) are implicated in GBM progression and treatment resistance.
Purpose of the Study:
- To investigate the combined effect of arsenic trioxide and 10058F4 on GBM CSC differentiation.
- To evaluate the therapeutic potential of this combination in preclinical GBM models.
- To explore the interaction between arsenic trioxide and 10058F4 in targeting GBM CSCs.
Main Methods:
- Assessed the differentiation-inducing effects of arsenic trioxide and 10058F4 on GBM CSCs.
- Utilized an EGFR-driven genetically engineered GBM mouse model.
- Evaluated tumor growth, CSC differentiation, and CSC subtype populations in xenograft models.
Main Results:
- Both arsenic trioxide and 10058F4 induced GBM CSC differentiation.
- Arsenic trioxide significantly enhanced the anti-proliferative effects of 10058F4.
- Combination therapy reduced tumor growth and CSC populations in vivo, particularly proneural and mesenchymal subtypes.
Conclusions:
- The combination of arsenic trioxide and 10058F4 demonstrates synergistic effects in inducing GBM CSC differentiation.
- This combination therapy shows significant anti-tumor activity and CSC reduction in vivo.
- Arsenic trioxide and 10058F4 represent a promising therapeutic strategy for differentiation-based GBM treatment.
