Mitochondrial Superoxide Increases Age-Associated Susceptibility of Human Dermal Fibroblasts to Radiation and Chemotherapy

Elderly cancer patients treated with ionizing radiation (IR) or chemotherapy experience more frequent and greater normal tissue toxicity relative to younger patients. The current study demonstrates that exponentially growing fibroblasts from elderly (old) male donor subjects (70, 72, and 78 years) a...

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Vydané v:	Cancer research (Chicago, Ill.) Ročník 77; číslo 18; s. 5054
Hlavní autori:	Mapuskar, Kranti A, Flippo, Kyle H, Schoenfeld, Joshua D, Riley, Dennis P, Strack, Stefan, Hejleh, Taher Abu, Furqan, Muhammad, Monga, Varun, Domann, Frederick E, Buatti, John M, Goswami, Prabhat C, Spitz, Douglas R, Allen, Bryan G
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 15.09.2017
Predmet:	Adult Age Factors Aged Animals Antineoplastic Agents - adverse effects Apoptosis - drug effects Apoptosis - radiation effects Cell Proliferation - drug effects Cell Proliferation - radiation effects Cells, Cultured Cisplatin - adverse effects Fibroblasts - drug effects Fibroblasts - pathology Fibroblasts - radiation effects Humans Male Membrane Potential, Mitochondrial - drug effects Membrane Potential, Mitochondrial - radiation effects Mice Mice, Inbred C57BL Mitochondria - drug effects Mitochondria - pathology Mitochondria - radiation effects Oxidative Stress Radiation, Ionizing Skin - drug effects Skin - pathology Skin - radiation effects Superoxide Dismutase - metabolism Superoxides - metabolism Young Adult
ISSN:	1538-7445, 1538-7445
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Abstract	Elderly cancer patients treated with ionizing radiation (IR) or chemotherapy experience more frequent and greater normal tissue toxicity relative to younger patients. The current study demonstrates that exponentially growing fibroblasts from elderly (old) male donor subjects (70, 72, and 78 years) are significantly more sensitive to clonogenic killing mediated by platinum-based chemotherapy and IR (∼70%-80% killing) relative to young fibroblasts (5 months and 1 year; ∼10%-20% killing) and adult fibroblasts (20 years old; ∼10%-30% killing). Old fibroblasts also displayed significantly increased (2-4-fold) steady-state levels of O , O consumption, and mitochondrial membrane potential as well as significantly decreased (40%-50%) electron transport chain (ETC) complex I, II, IV, V, and aconitase (70%) activities, decreased ATP levels, and significantly altered mitochondrial structure. Following adenoviral-mediated overexpression of SOD2 activity (5-7-fold), mitochondrial ETC activity and aconitase activity were restored, demonstrating a role for mitochondrial O in these effects. Old fibroblasts also demonstrated elevated levels of endogenous DNA damage that were increased following treatment with IR and chemotherapy. Most importantly, treatment with the small-molecule, superoxide dismutase mimetic (GC4419; 0.25 μmol/L) significantly mitigated the increased sensitivity of old fibroblasts to IR and chemotherapy and partially restored mitochondrial function without affecting IR or chemotherapy-induced cancer cell killing. These results support the hypothesis that age-associated increased O and resulting DNA damage mediate the increased susceptibility of old fibroblasts to IR and chemotherapy that can be mitigated by GC4419. .
AbstractList	Elderly cancer patients treated with ionizing radiation (IR) or chemotherapy experience more frequent and greater normal tissue toxicity relative to younger patients. The current study demonstrates that exponentially growing fibroblasts from elderly (old) male donor subjects (70, 72, and 78 years) are significantly more sensitive to clonogenic killing mediated by platinum-based chemotherapy and IR (∼70%-80% killing) relative to young fibroblasts (5 months and 1 year; ∼10%-20% killing) and adult fibroblasts (20 years old; ∼10%-30% killing). Old fibroblasts also displayed significantly increased (2-4-fold) steady-state levels of O , O consumption, and mitochondrial membrane potential as well as significantly decreased (40%-50%) electron transport chain (ETC) complex I, II, IV, V, and aconitase (70%) activities, decreased ATP levels, and significantly altered mitochondrial structure. Following adenoviral-mediated overexpression of SOD2 activity (5-7-fold), mitochondrial ETC activity and aconitase activity were restored, demonstrating a role for mitochondrial O in these effects. Old fibroblasts also demonstrated elevated levels of endogenous DNA damage that were increased following treatment with IR and chemotherapy. Most importantly, treatment with the small-molecule, superoxide dismutase mimetic (GC4419; 0.25 μmol/L) significantly mitigated the increased sensitivity of old fibroblasts to IR and chemotherapy and partially restored mitochondrial function without affecting IR or chemotherapy-induced cancer cell killing. These results support the hypothesis that age-associated increased O and resulting DNA damage mediate the increased susceptibility of old fibroblasts to IR and chemotherapy that can be mitigated by GC4419. . Elderly cancer patients treated with ionizing radiation (IR) or chemotherapy experience more frequent and greater normal tissue toxicity relative to younger patients. The current study demonstrates that exponentially growing fibroblasts from elderly (old) male donor subjects (70, 72, and 78 years) are significantly more sensitive to clonogenic killing mediated by platinum-based chemotherapy and IR (∼70%-80% killing) relative to young fibroblasts (5 months and 1 year; ∼10%-20% killing) and adult fibroblasts (20 years old; ∼10%-30% killing). Old fibroblasts also displayed significantly increased (2-4-fold) steady-state levels of O2•-, O2 consumption, and mitochondrial membrane potential as well as significantly decreased (40%-50%) electron transport chain (ETC) complex I, II, IV, V, and aconitase (70%) activities, decreased ATP levels, and significantly altered mitochondrial structure. Following adenoviral-mediated overexpression of SOD2 activity (5-7-fold), mitochondrial ETC activity and aconitase activity were restored, demonstrating a role for mitochondrial O2•- in these effects. Old fibroblasts also demonstrated elevated levels of endogenous DNA damage that were increased following treatment with IR and chemotherapy. Most importantly, treatment with the small-molecule, superoxide dismutase mimetic (GC4419; 0.25 μmol/L) significantly mitigated the increased sensitivity of old fibroblasts to IR and chemotherapy and partially restored mitochondrial function without affecting IR or chemotherapy-induced cancer cell killing. These results support the hypothesis that age-associated increased O2•- and resulting DNA damage mediate the increased susceptibility of old fibroblasts to IR and chemotherapy that can be mitigated by GC4419. Cancer Res; 77(18); 5054-67. ©2017 AACR.Elderly cancer patients treated with ionizing radiation (IR) or chemotherapy experience more frequent and greater normal tissue toxicity relative to younger patients. The current study demonstrates that exponentially growing fibroblasts from elderly (old) male donor subjects (70, 72, and 78 years) are significantly more sensitive to clonogenic killing mediated by platinum-based chemotherapy and IR (∼70%-80% killing) relative to young fibroblasts (5 months and 1 year; ∼10%-20% killing) and adult fibroblasts (20 years old; ∼10%-30% killing). Old fibroblasts also displayed significantly increased (2-4-fold) steady-state levels of O2•-, O2 consumption, and mitochondrial membrane potential as well as significantly decreased (40%-50%) electron transport chain (ETC) complex I, II, IV, V, and aconitase (70%) activities, decreased ATP levels, and significantly altered mitochondrial structure. Following adenoviral-mediated overexpression of SOD2 activity (5-7-fold), mitochondrial ETC activity and aconitase activity were restored, demonstrating a role for mitochondrial O2•- in these effects. Old fibroblasts also demonstrated elevated levels of endogenous DNA damage that were increased following treatment with IR and chemotherapy. Most importantly, treatment with the small-molecule, superoxide dismutase mimetic (GC4419; 0.25 μmol/L) significantly mitigated the increased sensitivity of old fibroblasts to IR and chemotherapy and partially restored mitochondrial function without affecting IR or chemotherapy-induced cancer cell killing. These results support the hypothesis that age-associated increased O2•- and resulting DNA damage mediate the increased susceptibility of old fibroblasts to IR and chemotherapy that can be mitigated by GC4419. Cancer Res; 77(18); 5054-67. ©2017 AACR.
Author	Strack, Stefan Goswami, Prabhat C Riley, Dennis P Furqan, Muhammad Allen, Bryan G Schoenfeld, Joshua D Buatti, John M Hejleh, Taher Abu Mapuskar, Kranti A Flippo, Kyle H Domann, Frederick E Spitz, Douglas R Monga, Varun
Author_xml	– sequence: 1 givenname: Kranti A surname: Mapuskar fullname: Mapuskar, Kranti A organization: Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa – sequence: 2 givenname: Kyle H surname: Flippo fullname: Flippo, Kyle H organization: Department of Pharmacology, The University of Iowa, Iowa City, Iowa – sequence: 3 givenname: Joshua D surname: Schoenfeld fullname: Schoenfeld, Joshua D organization: Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa – sequence: 4 givenname: Dennis P surname: Riley fullname: Riley, Dennis P organization: Galera Therapeutics, Inc., Malvern, Pennsylvania – sequence: 5 givenname: Stefan surname: Strack fullname: Strack, Stefan organization: Department of Pharmacology, The University of Iowa, Iowa City, Iowa – sequence: 6 givenname: Taher Abu surname: Hejleh fullname: Hejleh, Taher Abu organization: Department of Internal Medicine, The University of Iowa, Iowa City, Iowa – sequence: 7 givenname: Muhammad surname: Furqan fullname: Furqan, Muhammad organization: Department of Internal Medicine, The University of Iowa, Iowa City, Iowa – sequence: 8 givenname: Varun surname: Monga fullname: Monga, Varun organization: Department of Internal Medicine, The University of Iowa, Iowa City, Iowa – sequence: 9 givenname: Frederick E surname: Domann fullname: Domann, Frederick E organization: Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa – sequence: 10 givenname: John M surname: Buatti fullname: Buatti, John M organization: Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa – sequence: 11 givenname: Prabhat C surname: Goswami fullname: Goswami, Prabhat C organization: Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa – sequence: 12 givenname: Douglas R surname: Spitz fullname: Spitz, Douglas R organization: Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa – sequence: 13 givenname: Bryan G surname: Allen fullname: Allen, Bryan G email: bryan-allen@uiowa.edu organization: Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa. bryan-allen@uiowa.edu
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SubjectTerms	Adult Age Factors Aged Animals Antineoplastic Agents - adverse effects Apoptosis - drug effects Apoptosis - radiation effects Cell Proliferation - drug effects Cell Proliferation - radiation effects Cells, Cultured Cisplatin - adverse effects Fibroblasts - drug effects Fibroblasts - pathology Fibroblasts - radiation effects Humans Male Membrane Potential, Mitochondrial - drug effects Membrane Potential, Mitochondrial - radiation effects Mice Mice, Inbred C57BL Mitochondria - drug effects Mitochondria - pathology Mitochondria - radiation effects Oxidative Stress Radiation, Ionizing Skin - drug effects Skin - pathology Skin - radiation effects Superoxide Dismutase - metabolism Superoxides - metabolism Young Adult
Title	Mitochondrial Superoxide Increases Age-Associated Susceptibility of Human Dermal Fibroblasts to Radiation and Chemotherapy
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