O2⋅− and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate

Joshua D. Schoenfeld, Zita A. Sibenaller, Kranti A. Mapuskar, Brett A. Wagner, Kimberly L. Cramer-Morales, Muhammad Furqan, Sonia Sandhu, Thomas L. Carlisle, Mark C. Smith, Taher Abu Hejleh, Daniel J. Berg, Jun Zhang, John Keech, Kalpaj R. Parekh, Sudershan Bhatia, Varun Monga, Kellie L. Bodeker, Logan Ahmann, Sandy Vollstedt, Heather Brown & 15 others Erin P. Shanahan Kauffman, Mary E. Schall, Raymond Hohl, Gerald H. Clamon, Jeremy D. Greenlee, Matthew A. Howard, Michael K. Shultz, Brian J. Smith, Dennis P. Riley, Frederick E. Domann, Joseph J. Cullen, Garry R. Buettner, John M. Buatti, Douglas R. Spitz, Bryan G. Allen

Research output: Contribution to journalArticle

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Abstract

Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2⋅− and H2O2 are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.

Original languageEnglish (US)
Pages (from-to)487-500.e8
JournalCancer Cell
Volume31
Issue number4
DOIs
StatePublished - Apr 10 2017

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Glioblastoma
Non-Small Cell Lung Carcinoma
Pharmacology
Neoplasms
Iron
Oxidation-Reduction
Reactive Oxygen Species
Clinical Trials
Radiation
Drug Therapy
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Schoenfeld, J. D., Sibenaller, Z. A., Mapuskar, K. A., Wagner, B. A., Cramer-Morales, K. L., Furqan, M., ... Allen, B. G. (2017). O2⋅− and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. Cancer Cell, 31(4), 487-500.e8. https://doi.org/10.1016/j.ccell.2017.02.018
Schoenfeld, Joshua D. ; Sibenaller, Zita A. ; Mapuskar, Kranti A. ; Wagner, Brett A. ; Cramer-Morales, Kimberly L. ; Furqan, Muhammad ; Sandhu, Sonia ; Carlisle, Thomas L. ; Smith, Mark C. ; Abu Hejleh, Taher ; Berg, Daniel J. ; Zhang, Jun ; Keech, John ; Parekh, Kalpaj R. ; Bhatia, Sudershan ; Monga, Varun ; Bodeker, Kellie L. ; Ahmann, Logan ; Vollstedt, Sandy ; Brown, Heather ; Shanahan Kauffman, Erin P. ; Schall, Mary E. ; Hohl, Raymond ; Clamon, Gerald H. ; Greenlee, Jeremy D. ; Howard, Matthew A. ; Shultz, Michael K. ; Smith, Brian J. ; Riley, Dennis P. ; Domann, Frederick E. ; Cullen, Joseph J. ; Buettner, Garry R. ; Buatti, John M. ; Spitz, Douglas R. ; Allen, Bryan G. / O2⋅− and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. In: Cancer Cell. 2017 ; Vol. 31, No. 4. pp. 487-500.e8.
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abstract = "Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2⋅− and H2O2 are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.",
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Schoenfeld, JD, Sibenaller, ZA, Mapuskar, KA, Wagner, BA, Cramer-Morales, KL, Furqan, M, Sandhu, S, Carlisle, TL, Smith, MC, Abu Hejleh, T, Berg, DJ, Zhang, J, Keech, J, Parekh, KR, Bhatia, S, Monga, V, Bodeker, KL, Ahmann, L, Vollstedt, S, Brown, H, Shanahan Kauffman, EP, Schall, ME, Hohl, R, Clamon, GH, Greenlee, JD, Howard, MA, Shultz, MK, Smith, BJ, Riley, DP, Domann, FE, Cullen, JJ, Buettner, GR, Buatti, JM, Spitz, DR & Allen, BG 2017, 'O2⋅− and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate', Cancer Cell, vol. 31, no. 4, pp. 487-500.e8. https://doi.org/10.1016/j.ccell.2017.02.018

O2⋅− and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. / Schoenfeld, Joshua D.; Sibenaller, Zita A.; Mapuskar, Kranti A.; Wagner, Brett A.; Cramer-Morales, Kimberly L.; Furqan, Muhammad; Sandhu, Sonia; Carlisle, Thomas L.; Smith, Mark C.; Abu Hejleh, Taher; Berg, Daniel J.; Zhang, Jun; Keech, John; Parekh, Kalpaj R.; Bhatia, Sudershan; Monga, Varun; Bodeker, Kellie L.; Ahmann, Logan; Vollstedt, Sandy; Brown, Heather; Shanahan Kauffman, Erin P.; Schall, Mary E.; Hohl, Raymond; Clamon, Gerald H.; Greenlee, Jeremy D.; Howard, Matthew A.; Shultz, Michael K.; Smith, Brian J.; Riley, Dennis P.; Domann, Frederick E.; Cullen, Joseph J.; Buettner, Garry R.; Buatti, John M.; Spitz, Douglas R.; Allen, Bryan G.

In: Cancer Cell, Vol. 31, No. 4, 10.04.2017, p. 487-500.e8.

Research output: Contribution to journalArticle

TY - JOUR

T1 - O2⋅− and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate

AU - Schoenfeld, Joshua D.

AU - Sibenaller, Zita A.

AU - Mapuskar, Kranti A.

AU - Wagner, Brett A.

AU - Cramer-Morales, Kimberly L.

AU - Furqan, Muhammad

AU - Sandhu, Sonia

AU - Carlisle, Thomas L.

AU - Smith, Mark C.

AU - Abu Hejleh, Taher

AU - Berg, Daniel J.

AU - Zhang, Jun

AU - Keech, John

AU - Parekh, Kalpaj R.

AU - Bhatia, Sudershan

AU - Monga, Varun

AU - Bodeker, Kellie L.

AU - Ahmann, Logan

AU - Vollstedt, Sandy

AU - Brown, Heather

AU - Shanahan Kauffman, Erin P.

AU - Schall, Mary E.

AU - Hohl, Raymond

AU - Clamon, Gerald H.

AU - Greenlee, Jeremy D.

AU - Howard, Matthew A.

AU - Shultz, Michael K.

AU - Smith, Brian J.

AU - Riley, Dennis P.

AU - Domann, Frederick E.

AU - Cullen, Joseph J.

AU - Buettner, Garry R.

AU - Buatti, John M.

AU - Spitz, Douglas R.

AU - Allen, Bryan G.

PY - 2017/4/10

Y1 - 2017/4/10

N2 - Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2⋅− and H2O2 are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.

AB - Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2⋅− and H2O2 are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.

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U2 - 10.1016/j.ccell.2017.02.018

DO - 10.1016/j.ccell.2017.02.018

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JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

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