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; Erin P. Shanahan Kauffman; Mary E. Schall; Ray J. 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

doi: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

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 BrownErin P. Shanahan Kauffman, Mary E. Schall, Ray J. 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

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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 language	English (US)
Pages (from-to)	487-500.e8
Journal	Cancer Cell
Volume	31
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2017.02.018
State	Published - Apr 10 2017

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

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Schoenfeld, J. D., Sibenaller, Z. A., Mapuskar, K. A., Wagner, B. A., Cramer-Morales, K. L., Furqan, M., Sandhu, S., Carlisle, T. L., Smith, M. C., Abu Hejleh, T., Berg, D. J., Zhang, J., Keech, J., Parekh, K. R., Bhatia, S., Monga, V., Bodeker, K. L., Ahmann, L., Vollstedt, S., ... 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

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = apr,

day = "10",

doi = "10.1016/j.ccell.2017.02.018",

language = "English (US)",

volume = "31",

pages = "487--500.e8",

journal = "Cancer Cell",

issn = "1535-6108",

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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, RJ, 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

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, Ray J.

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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AN - SCOPUS:85016453133

SN - 1535-6108

VL - 31

SP - 487-500.e8

JO - Cancer Cell

JF - Cancer Cell

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ER -

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

Abstract

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