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

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

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

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.

Original language	English
Article number	e0128288
Journal	PloS one
Volume	10
Issue number	6
DOIs	https://doi.org/10.1371/journal.pone.0128288
Publication status	Published - 03-06-2015
Externally published	Yes

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title = "Arsenic trioxide sensitizes glioblastoma to a Myc inhibitor",

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.",

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AU - Yoshimura, Yayoi

AU - Shiino, Akihiko

AU - Muraki, Kazue

AU - Fukami, Tadateru

AU - Yamada, Shigeki

AU - Satow, Takeshi

AU - Fukuda, Miyuki

AU - Saiki, Masaaki

AU - Hojo, Masato

AU - Miyamoto, Susumu

AU - Onishi, Nobuyuki

AU - Saya, Hideyuki

AU - Inubushi, Toshiro

AU - Nozaki, Kazuhiko

AU - Tanigaki, Kenji

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PY - 2015/6/3

Y1 - 2015/6/3

N2 - 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.

AB - 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.

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Arsenic trioxide sensitizes glioblastoma to a Myc inhibitor

Abstract

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