دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Mitochondrial Superoxide Increases Age-Associated Susceptibility of Human Dermal Fibroblasts to Radiation and Chemotherapy.
المؤلفون: Mapuskar KA; Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa., Flippo KH; Department of Pharmacology, The University of Iowa, Iowa City, Iowa., Schoenfeld JD; Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa., Riley DP; Galera Therapeutics, Inc., Malvern, Pennsylvania., Strack S; Department of Pharmacology, The University of Iowa, Iowa City, Iowa., Hejleh TA; Department of Internal Medicine, The University of Iowa, Iowa City, Iowa., Furqan M; Department of Internal Medicine, The University of Iowa, Iowa City, Iowa., Monga V; Department of Internal Medicine, The University of Iowa, Iowa City, Iowa., Domann FE; Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa., Buatti JM; Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa., Goswami PC; Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa., Spitz DR; Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa., Allen BG; Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa. bryan-allen@uiowa.edu.
المصدر: Cancer research [Cancer Res] 2017 Sep 15; Vol. 77 (18), pp. 5054-5067. Date of Electronic Publication: 2017 Aug 01.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE
أسماء مطبوعة: Publication: Baltimore, Md. : American Association for Cancer Research
Original Publication: Chicago [etc.]
مواضيع طبية MeSH: Radiation, Ionizing*, Cisplatin/*adverse effects , Fibroblasts/*pathology , Mitochondria/*pathology , Skin/*pathology , Superoxides/*metabolism, 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 ; Fibroblasts/drug effects ; Fibroblasts/radiation effects ; Humans ; Male ; Membrane Potential, Mitochondrial/drug effects ; Membrane Potential, Mitochondrial/radiation effects ; Mice ; Mice, Inbred C57BL ; Mitochondria/drug effects ; Mitochondria/radiation effects ; Oxidative Stress ; Skin/drug effects ; Skin/radiation effects ; Superoxide Dismutase/metabolism ; Young Adult
مستخلص: 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 2 •- , O 2 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 2 •- 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 2 •- 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 .
(©2017 American Association for Cancer Research.)
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معلومات مُعتمدة: R01 CA111365 United States CA NCI NIH HHS; P30 ES005605 United States ES NIEHS NIH HHS; P30 CA086862 United States CA NCI NIH HHS; R01 NS056244 United States NS NINDS NIH HHS; T32 CA078586 United States CA NCI NIH HHS; R01 CA182804 United States CA NCI NIH HHS; T32 GM007337 United States GM NIGMS NIH HHS
المشرفين على المادة: 0 (Antineoplastic Agents)
11062-77-4 (Superoxides)
EC 1.15.1.1 (Superoxide Dismutase)
Q20Q21Q62J (Cisplatin)
تواريخ الأحداث: Date Created: 20170803 Date Completed: 20171030 Latest Revision: 20181113
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC5600863
DOI: 10.1158/0008-5472.CAN-17-0106
PMID: 28765155
قاعدة البيانات: MEDLINE
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