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Antioxidants
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Mitochondrial Superoxide Dismutase in Cancer Biology and Therapy
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Mitochondrial Superoxide Dismutase in Cancer Biology and Therapy

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Antioxidant Enzyme Systems".

Deadline for manuscript submissions: closed (15 February 2022) | Viewed by 14953

Special Issue Editors

Prof. Dr. David R Gius

E-Mail Website
Guest Editor
Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA
Interests: sirtuins (ISIRT3); mitochondrial metabolism; acetylation; MnSOD; ACSS1
Prof. Dr. Douglas R. Spitz

E-Mail Website
Co-Guest Editor
Carver College of Medicine, University of Iowa Healthcare, Iowa City, IA, USA
Interests: cancer; oxidative metabolism; redox regulation; mitochondria; degenerative diseases

Special Issue Information

Dear Colleagues,

Since the original proposal that disruptions in superoxide metabolism were fundamental to malignant transformation and cancer progression (PMID: 217531; PMID: 6254638; PMID: 6253771; PMID: 6259499), many studies have shown that the mitochondrial superoxide dismutase enzyme can act both as a suppressor of the malignant phenotype as well as a promoter of progression to a more malignant state depending on the stage of carcinogenesis. Furthermore, manipulations of mitochondrial superoxide/hydrogen peroxide metabolism, including post-translational acetylation modifications by sirtuins, can be targeted to improve cancer therapy, and several are currently in clinical trials. In this special issue of Antioxidants, specific mechanistic aspects of the role that mitochondrial superoxide dismutase plays, as well as the detoxification enzymes that regulate its cellular levels, in malignant transformation and cancer progression will be explored with a focus on exploiting fundamental differences in superoxide metabolism in cancer versus normal cells for the purpose of improving cancer therapy outcomes.

Prof. Dr. David Gius
Prof. Dr. Douglas R. Spitz
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (5 papers)

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Research

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18 pages, 5114 KiB  
Article
Venetoclax-Resistant MV4-11 Leukemic Cells Activate PI3K/AKT Pathway for Metabolic Reprogramming and Redox Adaptation for Survival
by Hind A. Alkhatabi, Samir F. Zohny, Mohammed Razeeth Shait Mohammed, Hani Choudhry, Mohd Rehan, Aamir Ahmad, Farid Ahmed and Mohammad Imran Khan
Antioxidants 2022, 11(3), 461; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11030461 - 25 Feb 2022
Cited by 9 | Viewed by 3649
Abstract
Venetoclax (ABT199) is a selective B-cell lymphoma 2 (BCL-2) inhibitor. The US FDA recently approved it to be used in combination with low-dose cytarabine or hypomethylating agents in acute myeloid leukemia (AML) or elderly patients non-eligible for chemotherapy. However, acquiring resistance to venetoclax [...] Read more.
Venetoclax (ABT199) is a selective B-cell lymphoma 2 (BCL-2) inhibitor. The US FDA recently approved it to be used in combination with low-dose cytarabine or hypomethylating agents in acute myeloid leukemia (AML) or elderly patients non-eligible for chemotherapy. However, acquiring resistance to venetoclax in AML patients is the primary cause of treatment failure. To understand the molecular mechanisms inherent in the resistance to BCL-2 inhibitors, we generated a venetoclax-resistant cell line model and assessed the consequences of this resistance on its metabolic pathways. Untargeted metabolomics data displayed a notable impact of resistance on the PI3K/AKT pathway, the Warburg effect, glycolysis, the TCA cycle, and redox metabolism. The resistant cells showed increased NADPH and reduced glutathione levels, switching their energy metabolism towards glycolysis. PI3K/AKT pathway inhibition shifted resistant cells towards oxidative phosphorylation (OXPHOS). Our results provide a metabolic map of resistant cells that can be used to design novel metabolic targets to challenge venetoclax resistance in AML. Full article
(This article belongs to the Special Issue Mitochondrial Superoxide Dismutase in Cancer Biology and Therapy)
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Review

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14 pages, 1797 KiB  
Review
Manganese Superoxide Dismutase Acetylation and Regulation of Protein Structure in Breast Cancer Biology and Therapy
by Meredith M. Ogle, Rolando Trevino, Jr., Joseph Schell, Mahboubeh Varmazyad, Nobuo Horikoshi and David Gius
Antioxidants 2022, 11(4), 635; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11040635 - 25 Mar 2022
Cited by 2 | Viewed by 2735
Abstract
The loss and/or dysregulation of several cellular and mitochondrial antioxidants’ expression or enzymatic activity, which leads to the aberrant physiological function of these proteins, has been shown to result in oxidative damage to cellular macromolecules. In this regard, it has been surmised that [...] Read more.
The loss and/or dysregulation of several cellular and mitochondrial antioxidants’ expression or enzymatic activity, which leads to the aberrant physiological function of these proteins, has been shown to result in oxidative damage to cellular macromolecules. In this regard, it has been surmised that the disruption of mitochondrial networks responsible for maintaining normal metabolism is an established hallmark of cancer and a novel mechanism of therapy resistance. This altered metabolism leads to aberrant accumulation of reactive oxygen species (ROS), which, under specific physiological conditions, leads to a potential tumor-permissive cellular environment. In this regard, it is becoming increasingly clear that the loss or disruption of mitochondrial oxidant scavenging enzymes may be, in specific tumors, either an early event in transformation or exhibit tumor-promoting properties. One example of such an antioxidant enzyme is manganese superoxide dismutase (MnSOD, also referred to as SOD2), which detoxifies superoxide, a ROS that has been shown, when its normal physiological levels are disrupted, to lead to oncogenicity and therapy resistance. Here, we will also discuss how the acetylation of MnSOD leads to a change in detoxification function that leads to a cellular environment permissive for the development of lineage plasticity-like properties that may be one mechanism leading to tumorigenic and therapy-resistant phenotypes. Full article
(This article belongs to the Special Issue Mitochondrial Superoxide Dismutase in Cancer Biology and Therapy)
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12 pages, 268 KiB  
Review
Radioresistance in Prostate Cancer: Focus on the Interplay between NF-κB and SOD
by Sameera Kumar and Daret St. Clair
Antioxidants 2021, 10(12), 1925; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10121925 - 30 Nov 2021
Cited by 8 | Viewed by 2022
Abstract
Prostate cancer occurs frequently in men and can often lead to death. Many cancers, including prostate cancer, can be initiated by oxidative insult caused by free radicals and reactive oxygen species. The superoxide dismutase family removes the oxygen-derived reactive oxygen species, and increased [...] Read more.
Prostate cancer occurs frequently in men and can often lead to death. Many cancers, including prostate cancer, can be initiated by oxidative insult caused by free radicals and reactive oxygen species. The superoxide dismutase family removes the oxygen-derived reactive oxygen species, and increased superoxide dismutase activity can often be protective against prostate cancer. Prostate cancer can be treated in a variety of ways, including surgery, androgen deprivation therapy, radiation therapy, and chemotherapy. The clinical trajectory of prostate cancer varies from patient to patient, but more aggressive tumors often tend to be radioresistant. This is often due to the free-radical and reactive-oxygen-species-neutralizing effects of the superoxide dismutase family. Superoxide dismutase 2, which is especially important in this regard, can be induced by the NF-κB pathway, which is an important mechanism in radioresistance. This information has enabled the development of interventions that manipulate the NF-κB mechanism to treat prostate cancer. Full article
(This article belongs to the Special Issue Mitochondrial Superoxide Dismutase in Cancer Biology and Therapy)
16 pages, 769 KiB  
Review
Mitochondrial Superoxide Dismutase in Cisplatin-Induced Kidney Injury
by Kranti A. Mapuskar, Emily J. Steinbach, Amira Zaher, Dennis P. Riley, Robert A. Beardsley, Jeffery L. Keene, Jon T. Holmlund, Carryn M. Anderson, Diana Zepeda-Orozco, John M. Buatti, Douglas R. Spitz and Bryan G. Allen
Antioxidants 2021, 10(9), 1329; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10091329 - 24 Aug 2021
Cited by 27 | Viewed by 3841
Abstract
Cisplatin is a chemotherapy agent commonly used to treat a wide variety of cancers. Despite the potential for both severe acute and chronic side effects, it remains a preferred therapeutic option for many malignancies due to its potent anti-tumor activity. Common cisplatin-associated side-effects [...] Read more.
Cisplatin is a chemotherapy agent commonly used to treat a wide variety of cancers. Despite the potential for both severe acute and chronic side effects, it remains a preferred therapeutic option for many malignancies due to its potent anti-tumor activity. Common cisplatin-associated side-effects include acute kidney injury (AKI) and chronic kidney disease (CKD). These renal injuries may cause delays and potentially cessation of cisplatin therapy and have long-term effects on renal function reserve. Thus, developing mechanism-based interventional strategies that minimize cisplatin-associated kidney injury without reducing efficacy would be of great benefit. In addition to its action of cross-linking DNA, cisplatin has been shown to affect mitochondrial metabolism, resulting in mitochondrially derived reactive oxygen species (ROS). Increased ROS formation in renal proximal convoluted tubule cells is associated with cisplatin-induced AKI and CKD. We review the mechanisms by which cisplatin may induce AKI and CKD and discuss the potential of mitochondrial superoxide dismutase mimetics to prevent platinum-associated nephrotoxicity. Full article
(This article belongs to the Special Issue Mitochondrial Superoxide Dismutase in Cancer Biology and Therapy)
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13 pages, 381 KiB  
Review
Gene Therapy for Systemic or Organ Specific Delivery of Manganese Superoxide Dismutase
by Joel S. Greenberger, Amitava Mukherjee and Michael W. Epperly
Antioxidants 2021, 10(7), 1057; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10071057 - 30 Jun 2021
Cited by 5 | Viewed by 2002
Abstract
Manganese superoxide dismutase (MnSOD) is a dominant component of the antioxidant defense system in mammalian cells. Since ionizing irradiation induces profound oxidative stress, it was logical to test the effect of overexpression of MnSOD on radioresistance. This task was accomplished by introduction of [...] Read more.
Manganese superoxide dismutase (MnSOD) is a dominant component of the antioxidant defense system in mammalian cells. Since ionizing irradiation induces profound oxidative stress, it was logical to test the effect of overexpression of MnSOD on radioresistance. This task was accomplished by introduction of a transgene for MnSOD into cells in vitro and into organs in vivo, and both paradigms showed clear radioresistance following overexpression. During the course of development and clinical application of using MnSOD as a radioprotector, several prominent observations were made by Larry Oberley, Joel Greenberger, and Michael Epperly which include (1) mitochondrial localization of either manganese superoxide dismutase or copper/zinc SOD was required to provide optimal radiation protection; (2) the time required for optimal expression was 12–18 h, and while acceptable for radiation protection, the time delay was impractical for radiation mitigation; (3) significant increases in intracellular elevation of MnSOD activity were required for effective radioprotection. Lessons learned during the development of MnSOD gene therapy have provided a strategy for delivery of small molecule SOD mimics, which are faster acting and have shown the potential for both radiation protection and mitigation. The purpose of this review is to summarize the current status of using MnSOD-PL and SOD mimetics as radioprotectors and radiomitigators. Full article
(This article belongs to the Special Issue Mitochondrial Superoxide Dismutase in Cancer Biology and Therapy)
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