Enhanced cytotoxic effect of radiation and temozolomide in malignant glioma cells: Targeting PI3K-AKT-mTOR signaling, HSP90 and histone deacetylases

Eun J. Choi, Bong J. Cho, David J. Lee, Yeo H. Hwang, Sun H. Chun, Hans H. Kim, In A. Kim

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Background: Despite aggressive treatment with radiation therapy and concurrent adjuvant temozolomide (TMZ), glioblastoma multiform (GBM) still has a dismal prognosis. We aimed to identify strategies to improve the therapeutic outcome of combined radiotherapy and TMZ in GBM by targeting pro-survival signaling from the epidermal growth factor receptor (EGFR).Methods: Glioma cell lines U251, T98G were used. Colony formation, DNA damage repair, mode of cell death, invasion, migration and vasculogenic mimicry as well as protein expression were determined.Results: U251 cells showing a low level of methyl guanine transferase (MGMT) were highly responsive to the radiosensitizing effect of TMZ compared to T98G cells having a high level of MGMT. Treatment with a dual inhibitor of Class I PI3K/mTOR, PI103; a HSP90 inhibitor, 17-DMAG; or a HDAC inhibitor, LBH589, further increased the cytotoxic effect of radiation therapy plus TMZ in U251 cells than in T98G cells. However, treatment with a mTOR inhibitor, rapamycin, did not discernibly potentiate the radiosensitizing effect of TMZ in either cell line. The mechanism of enhanced radiosensitizing effects of TMZ was multifactorial, involving impaired DNA damage repair, induction of autophagy or apoptosis, and reversion of EMT (epithelial-mesenchymal transition).Conclusions: Our results suggest possible strategies for counteracting the pro-survival signaling from EGFR to improve the therapeutic outcome of combined radiotherapy and TMZ for high-grade gliomas.

Original languageEnglish
Article number17
JournalBMC Cancer
Volume14
Issue number1
DOIs
StatePublished - 13 Jan 2014

Fingerprint

temozolomide
Histone Deacetylases
Radiation Effects
Phosphatidylinositol 3-Kinases
Glioma
Radiation-Sensitizing Agents
Radiotherapy
17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
Glioblastoma
Epidermal Growth Factor Receptor
DNA Repair
DNA Damage
Therapeutics
Cell Line
Histone Deacetylase Inhibitors
Epithelial-Mesenchymal Transition
Autophagy
Guanine
Sirolimus
Transferases

Keywords

  • Glioblastoma
  • Pro-survival signaling
  • Radiosensitization
  • Temozolomide

Cite this

Choi, Eun J. ; Cho, Bong J. ; Lee, David J. ; Hwang, Yeo H. ; Chun, Sun H. ; Kim, Hans H. ; Kim, In A. / Enhanced cytotoxic effect of radiation and temozolomide in malignant glioma cells : Targeting PI3K-AKT-mTOR signaling, HSP90 and histone deacetylases. In: BMC Cancer. 2014 ; Vol. 14, No. 1.
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abstract = "Background: Despite aggressive treatment with radiation therapy and concurrent adjuvant temozolomide (TMZ), glioblastoma multiform (GBM) still has a dismal prognosis. We aimed to identify strategies to improve the therapeutic outcome of combined radiotherapy and TMZ in GBM by targeting pro-survival signaling from the epidermal growth factor receptor (EGFR).Methods: Glioma cell lines U251, T98G were used. Colony formation, DNA damage repair, mode of cell death, invasion, migration and vasculogenic mimicry as well as protein expression were determined.Results: U251 cells showing a low level of methyl guanine transferase (MGMT) were highly responsive to the radiosensitizing effect of TMZ compared to T98G cells having a high level of MGMT. Treatment with a dual inhibitor of Class I PI3K/mTOR, PI103; a HSP90 inhibitor, 17-DMAG; or a HDAC inhibitor, LBH589, further increased the cytotoxic effect of radiation therapy plus TMZ in U251 cells than in T98G cells. However, treatment with a mTOR inhibitor, rapamycin, did not discernibly potentiate the radiosensitizing effect of TMZ in either cell line. The mechanism of enhanced radiosensitizing effects of TMZ was multifactorial, involving impaired DNA damage repair, induction of autophagy or apoptosis, and reversion of EMT (epithelial-mesenchymal transition).Conclusions: Our results suggest possible strategies for counteracting the pro-survival signaling from EGFR to improve the therapeutic outcome of combined radiotherapy and TMZ for high-grade gliomas.",
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Enhanced cytotoxic effect of radiation and temozolomide in malignant glioma cells : Targeting PI3K-AKT-mTOR signaling, HSP90 and histone deacetylases. / Choi, Eun J.; Cho, Bong J.; Lee, David J.; Hwang, Yeo H.; Chun, Sun H.; Kim, Hans H.; Kim, In A.

In: BMC Cancer, Vol. 14, No. 1, 17, 13.01.2014.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Enhanced cytotoxic effect of radiation and temozolomide in malignant glioma cells

T2 - Targeting PI3K-AKT-mTOR signaling, HSP90 and histone deacetylases

AU - Choi, Eun J.

AU - Cho, Bong J.

AU - Lee, David J.

AU - Hwang, Yeo H.

AU - Chun, Sun H.

AU - Kim, Hans H.

AU - Kim, In A.

PY - 2014/1/13

Y1 - 2014/1/13

N2 - Background: Despite aggressive treatment with radiation therapy and concurrent adjuvant temozolomide (TMZ), glioblastoma multiform (GBM) still has a dismal prognosis. We aimed to identify strategies to improve the therapeutic outcome of combined radiotherapy and TMZ in GBM by targeting pro-survival signaling from the epidermal growth factor receptor (EGFR).Methods: Glioma cell lines U251, T98G were used. Colony formation, DNA damage repair, mode of cell death, invasion, migration and vasculogenic mimicry as well as protein expression were determined.Results: U251 cells showing a low level of methyl guanine transferase (MGMT) were highly responsive to the radiosensitizing effect of TMZ compared to T98G cells having a high level of MGMT. Treatment with a dual inhibitor of Class I PI3K/mTOR, PI103; a HSP90 inhibitor, 17-DMAG; or a HDAC inhibitor, LBH589, further increased the cytotoxic effect of radiation therapy plus TMZ in U251 cells than in T98G cells. However, treatment with a mTOR inhibitor, rapamycin, did not discernibly potentiate the radiosensitizing effect of TMZ in either cell line. The mechanism of enhanced radiosensitizing effects of TMZ was multifactorial, involving impaired DNA damage repair, induction of autophagy or apoptosis, and reversion of EMT (epithelial-mesenchymal transition).Conclusions: Our results suggest possible strategies for counteracting the pro-survival signaling from EGFR to improve the therapeutic outcome of combined radiotherapy and TMZ for high-grade gliomas.

AB - Background: Despite aggressive treatment with radiation therapy and concurrent adjuvant temozolomide (TMZ), glioblastoma multiform (GBM) still has a dismal prognosis. We aimed to identify strategies to improve the therapeutic outcome of combined radiotherapy and TMZ in GBM by targeting pro-survival signaling from the epidermal growth factor receptor (EGFR).Methods: Glioma cell lines U251, T98G were used. Colony formation, DNA damage repair, mode of cell death, invasion, migration and vasculogenic mimicry as well as protein expression were determined.Results: U251 cells showing a low level of methyl guanine transferase (MGMT) were highly responsive to the radiosensitizing effect of TMZ compared to T98G cells having a high level of MGMT. Treatment with a dual inhibitor of Class I PI3K/mTOR, PI103; a HSP90 inhibitor, 17-DMAG; or a HDAC inhibitor, LBH589, further increased the cytotoxic effect of radiation therapy plus TMZ in U251 cells than in T98G cells. However, treatment with a mTOR inhibitor, rapamycin, did not discernibly potentiate the radiosensitizing effect of TMZ in either cell line. The mechanism of enhanced radiosensitizing effects of TMZ was multifactorial, involving impaired DNA damage repair, induction of autophagy or apoptosis, and reversion of EMT (epithelial-mesenchymal transition).Conclusions: Our results suggest possible strategies for counteracting the pro-survival signaling from EGFR to improve the therapeutic outcome of combined radiotherapy and TMZ for high-grade gliomas.

KW - Glioblastoma

KW - Pro-survival signaling

KW - Radiosensitization

KW - Temozolomide

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U2 - 10.1186/1471-2407-14-17

DO - 10.1186/1471-2407-14-17

M3 - Article

C2 - 24418474

AN - SCOPUS:84892380757

VL - 14

JO - BMC cancer

JF - BMC cancer

SN - 1471-2407

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ER -