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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Published in:Cancer research (Chicago, Ill.) Vol. 77; no. 18; p. 5054
Main Authors: 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
Format: Journal Article
Language:English
Published: United States 15.09.2017
Subjects:
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
Online Access:Get more information
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Summary: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. .
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ISSN:1538-7445
1538-7445
DOI:10.1158/0008-5472.CAN-17-0106