Arsenic trioxide sensitizes glioblastoma to a myc inhibitor

Yayoi Yoshimura; Akihiko Shiino; Kazue Muraki; Tadateru Fukami; Shigeki Yamada; Takeshi Satow; Miyuki Fukuda; Masaaki Saiki; Masato Hojo; Susumu Miyamoto; Nobuyuki Onishi; Hideyuki Saya; Toshiro Inubushi; Kazuhiko Nozaki; Kenji Tanigaki

doi:10.1371/journal.pone.0128288

Arsenic trioxide sensitizes glioblastoma to a myc inhibitor

PLoS One. 2015 Jun 3;10(6):e0128288. doi: 10.1371/journal.pone.0128288. eCollection 2015.

Authors

Affiliations

¹ Research Institute, Shiga Medical Center, Moriyama 5-4-30, Shiga 524-8524, Japan; Department of Neurosurgery, Shiga University of Medical Science, Shiga 520-2192, Japan.
² Biomedical MR Science Center, Shiga University of Medical Science, Shiga 520-2192, Japan; Department of Neurosurgery, Shiga University of Medical Science, Shiga 520-2192, Japan.
³ Research Institute, Shiga Medical Center, Moriyama 5-4-30, Shiga 524-8524, Japan.
⁴ Department of Neurosurgery, Shiga University of Medical Science, Shiga 520-2192, Japan.
⁵ Department of Neurosurgery, Shiga Medical Center, Shiga 524-8524, Japan.
⁶ Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
⁷ Division of Gene Regulation, School of Medicine, Keio University, Tokyo 160-8582, Japan.
⁸ Biomedical MR Science Center, 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects
Arsenic Trioxide
Arsenicals / therapeutic use*
Brain Neoplasms / drug therapy*
Brain Neoplasms / pathology
Cell Differentiation / drug effects
Cell Proliferation / drug effects
Disease Progression
ErbB Receptors / metabolism
Female
Glioblastoma / drug therapy*
Glioblastoma / pathology
Hedgehog Proteins / metabolism
Humans
Magnetic Resonance Imaging
Male
Mice, SCID
Middle Aged
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / pathology
Oxides / therapeutic use*
Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
Proto-Oncogene Proteins c-myc / metabolism
Signal Transduction / drug effects
Thiazoles / pharmacology
Thiazoles / therapeutic use*
Xenograft Model Antitumor Assays

Substances

5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one
Antineoplastic Agents
Arsenicals
Hedgehog Proteins
Oxides
Proto-Oncogene Proteins c-myc
SHH protein, human
Thiazoles
ErbB Receptors
Arsenic Trioxide

Grants and funding

This work was supported by Sagawa Foundation (K.T.) and Yasuda Medical Foundation (K.T.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.