Sulforaphane suppresses the growth of glioblastoma cells, glioblastoma stem cell-like spheroids, and tumor xenografts through multiple cell signaling pathways

Khadijeh Bijangi-Vishehsaraei, M. Reza Saadatzadeh, Haiyan Wang, Angie Nguyen, Malgorzata M. Kamocka, Wenjing Cai, Aaron A. Cohen-Gadol, Stacey L. Halum, Jann N Sarkaria, Karen E. Pollok, Ahmad R. Safa

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

OBJECTIVE Defects in the apoptotic machinery and augmented survival signals contribute to drug resistance in glioblastoma (GBM). Moreover, another complexity related to GBM treatment is the concept that GBM development and recurrence may arise from the expression of GBM stem cells (GSCs). Therefore, the use of a multifaceted approach or multitargeted agents that affect specific tumor cell characteristics will likely be necessary to successfully eradicate GBM. The objective of this study was to investigate the usefulness of sulforaphane (SFN)-a constituent of cruciferous vegetables with a multitargeted effect-as a therapeutic agent for GBM. METHODS The inhibitory effects of SFN on established cell lines, early primary cultures, CD133-positive GSCs, GSCderived spheroids, and GBM xenografts were evaluated using various methods, including GSC isolation and the sphereforming assay, analysis of reactive oxygen species (ROS) and apoptosis, cell growth inhibition assay, comet assays for assessing SFN-triggered DNA damage, confocal microscopy, Western blot analysis, and the determination of in vivo efficacy as assessed in human GBM xenograft models. RESULTS SFN triggered the significant inhibition of cell survival and induced apoptotic cell death, which was associated with caspase 3 and caspase 7 activation. Moreover, SFN triggered the formation of mitochondrial ROS, and SFNtriggered cell death was ROS dependent. Comet assays revealed that SFN increased single-and double-strand DNA breaks in GBM. Compared with the vehicle control cells, a significantly higher amount of g-H2AX foci correlated with an increase in DNA double-strand breaks in the SFN-treated samples. Furthermore, SFN robustly inhibited the growth of GBM cell-induced cell death in established cell cultures and early-passage primary cultures and, most importantly, was effective in eliminating GSCs, which play a major role in drug resistance and disease recurrence. In vivo studies revealed that SFN administration at 100 mg/kg for 5-day cycles repeated for 3 weeks significantly decreased the growth of ectopic xenografts that were established from the early passage of primary cultures of GBM10. CONCLUSIONS These results suggest that SFN is a potent anti-GBM agent that targets several apoptosis and cell survival pathways and further preclinical and clinical studies may prove that SFN alone or in combination with other therapies may be potentially useful for GBM therapy.

Original languageEnglish (US)
Pages (from-to)1219-1230
Number of pages12
JournalJournal of Neurosurgery
Volume127
Issue number6
DOIs
StatePublished - Dec 1 2017

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Glioblastoma
Heterografts
Stem Cells
Growth
Neoplasms
Reactive Oxygen Species
Cell Death
Comet Assay
Double-Stranded DNA Breaks
Drug Resistance
sulforafan
Cell Survival
Apoptosis
Caspase 7
Single-Stranded DNA Breaks
Recurrence
Cell Separation
Confocal Microscopy
Caspase 3
Vegetables

Keywords

  • Apoptosis
  • Cancer stem cells
  • Glioblastoma
  • Oncology
  • Sulforaphane

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

Cite this

Sulforaphane suppresses the growth of glioblastoma cells, glioblastoma stem cell-like spheroids, and tumor xenografts through multiple cell signaling pathways. / Bijangi-Vishehsaraei, Khadijeh; Saadatzadeh, M. Reza; Wang, Haiyan; Nguyen, Angie; Kamocka, Malgorzata M.; Cai, Wenjing; Cohen-Gadol, Aaron A.; Halum, Stacey L.; Sarkaria, Jann N; Pollok, Karen E.; Safa, Ahmad R.

In: Journal of Neurosurgery, Vol. 127, No. 6, 01.12.2017, p. 1219-1230.

Research output: Contribution to journalArticle

Bijangi-Vishehsaraei, K, Saadatzadeh, MR, Wang, H, Nguyen, A, Kamocka, MM, Cai, W, Cohen-Gadol, AA, Halum, SL, Sarkaria, JN, Pollok, KE & Safa, AR 2017, 'Sulforaphane suppresses the growth of glioblastoma cells, glioblastoma stem cell-like spheroids, and tumor xenografts through multiple cell signaling pathways', Journal of Neurosurgery, vol. 127, no. 6, pp. 1219-1230. https://doi.org/10.3171/2016.8.JNS161197
Bijangi-Vishehsaraei, Khadijeh ; Saadatzadeh, M. Reza ; Wang, Haiyan ; Nguyen, Angie ; Kamocka, Malgorzata M. ; Cai, Wenjing ; Cohen-Gadol, Aaron A. ; Halum, Stacey L. ; Sarkaria, Jann N ; Pollok, Karen E. ; Safa, Ahmad R. / Sulforaphane suppresses the growth of glioblastoma cells, glioblastoma stem cell-like spheroids, and tumor xenografts through multiple cell signaling pathways. In: Journal of Neurosurgery. 2017 ; Vol. 127, No. 6. pp. 1219-1230.
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T1 - Sulforaphane suppresses the growth of glioblastoma cells, glioblastoma stem cell-like spheroids, and tumor xenografts through multiple cell signaling pathways

AU - Bijangi-Vishehsaraei, Khadijeh

AU - Saadatzadeh, M. Reza

AU - Wang, Haiyan

AU - Nguyen, Angie

AU - Kamocka, Malgorzata M.

AU - Cai, Wenjing

AU - Cohen-Gadol, Aaron A.

AU - Halum, Stacey L.

AU - Sarkaria, Jann N

AU - Pollok, Karen E.

AU - Safa, Ahmad R.

PY - 2017/12/1

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N2 - OBJECTIVE Defects in the apoptotic machinery and augmented survival signals contribute to drug resistance in glioblastoma (GBM). Moreover, another complexity related to GBM treatment is the concept that GBM development and recurrence may arise from the expression of GBM stem cells (GSCs). Therefore, the use of a multifaceted approach or multitargeted agents that affect specific tumor cell characteristics will likely be necessary to successfully eradicate GBM. The objective of this study was to investigate the usefulness of sulforaphane (SFN)-a constituent of cruciferous vegetables with a multitargeted effect-as a therapeutic agent for GBM. METHODS The inhibitory effects of SFN on established cell lines, early primary cultures, CD133-positive GSCs, GSCderived spheroids, and GBM xenografts were evaluated using various methods, including GSC isolation and the sphereforming assay, analysis of reactive oxygen species (ROS) and apoptosis, cell growth inhibition assay, comet assays for assessing SFN-triggered DNA damage, confocal microscopy, Western blot analysis, and the determination of in vivo efficacy as assessed in human GBM xenograft models. RESULTS SFN triggered the significant inhibition of cell survival and induced apoptotic cell death, which was associated with caspase 3 and caspase 7 activation. Moreover, SFN triggered the formation of mitochondrial ROS, and SFNtriggered cell death was ROS dependent. Comet assays revealed that SFN increased single-and double-strand DNA breaks in GBM. Compared with the vehicle control cells, a significantly higher amount of g-H2AX foci correlated with an increase in DNA double-strand breaks in the SFN-treated samples. Furthermore, SFN robustly inhibited the growth of GBM cell-induced cell death in established cell cultures and early-passage primary cultures and, most importantly, was effective in eliminating GSCs, which play a major role in drug resistance and disease recurrence. In vivo studies revealed that SFN administration at 100 mg/kg for 5-day cycles repeated for 3 weeks significantly decreased the growth of ectopic xenografts that were established from the early passage of primary cultures of GBM10. CONCLUSIONS These results suggest that SFN is a potent anti-GBM agent that targets several apoptosis and cell survival pathways and further preclinical and clinical studies may prove that SFN alone or in combination with other therapies may be potentially useful for GBM therapy.

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