Cellular redox pathways as a therapeutic target in the treatment of cancer.
TL;DR: This article reviews anticancer drugs currently in development that target cellular redox activity to treat cancer and indicates that drugs targeting S-glutathionylation have direct anticancer effects via cell signalling pathways and inhibition of DNA repair, and have an impact on a wide range of signalling pathways.
Abstract: The vulnerability of some cancer cells to oxidative signals is a therapeutic target for the rational design of new anticancer agents. In addition to their well characterized effects on cell division, many cytotoxic anticancer agents can induce oxidative stress by modulating levels of reactive oxygen species (ROS) such as the superoxide anion radical, hydrogen peroxide and hydroxyl radicals. Tumour cells are particularly sensitive to oxidative stress as they typically have persistently higher levels of ROS than normal cells due to the dysregulation of redox balance that develops in cancer cells in response to increased intracellular production of ROS or depletion of antioxidant proteins. In addition, excess ROS levels potentially contribute to oncogenesis by the mediation of oxidative DNA damage. There are several anticancer agents in development that target cellular redox regulation. The overall cellular redox state is regulated by three systems that modulate cellular redox status by counteracting free radicals and ROS, or by reversing the formation of disulfides; two of these are dependent on glutathione and the third on thioredoxin. Drugs targeting S-glutathionylation have direct anticancer effects via cell signalling pathways and inhibition of DNA repair, and have an impact on a wide range of signalling pathways. Of these agents, NOV-002 and canfosfamide have been assessed in phase III trials, while a number of others are undergoing evaluation in early phase clinical trials. Alternatively, agents including PX-12, dimesna and motexafin gadolinium are being developed to target thioredoxin, which is overexpressed in many human tumours, and this overexpression is associated with aggressive tumour growth and poorer clinical outcomes. Finally, arsenic derivatives have demonstrated antitumour activity including antiproliferative and apoptogenic effects on cancer cells by pro-oxidant mechanisms, and the induction of high levels of oxidative stress and apoptosis by an as yet undefined mechanism. In this article we review anticancer drugs currently in development that target cellular redox activity to treat cancer.
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TL;DR: The present review highlights the role of GSH and related cytoprotective effects in the susceptibility to carcinogenesis and in the sensitivity of tumors to the cytotoxic effects of anticancer agents.
Abstract: Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and disturbances in GSH homeostasis are involved in the etiology and progression of many human diseases including cancer. While GSH deficiency, or a decrease in the GSH/glutathione disulphide (GSSG) ratio, leads to an increased susceptibility to oxidative stress implicated in the progression of cancer, elevated GSH levels increase the antioxidant capacity and the resistance to oxidative stress as observed in many cancer cells. The present review highlights the role of GSH and related cytoprotective effects in the susceptibility to carcinogenesis and in the sensitivity of tumors to the cytotoxic effects of anticancer agents.
895 citations
TL;DR: In these interactions, the addition of SOs to reactive cysteine residues in specific molecular targets triggers biological activity, Ultimately, SOs are multifunctional drugs that regulate the activity of entire networks.
Abstract: We review the rationale for the use of synthetic oleanane triterpenoids (SOs) for prevention and treatment of disease, as well as extensive biological data on this topic resulting from both cell culture and in vivo studies. Emphasis is placed on understanding mechanisms of action. SOs are noncytotoxic drugs with an excellent safety profile. Several hundred SOs have now been synthesized and in vitro have been shown to: 1) suppress inflammation and oxidative stress and therefore be cytoprotective, especially at low nanomolar doses, 2) induce differentiation, and 3) block cell proliferation and induce apoptosis at higher micromolar doses. Animal data on the use of SOs in neurodegenerative diseases and in diseases of the eye, lung, cardiovascular system, liver, gastrointestinal tract, and kidney, as well as in cancer and in metabolic and inflammatory/autoimmune disorders, are reviewed. The importance of the cytoprotective Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1/nuclear factor (erythroid-derived 2)-like 2/antioxidant response element (Keap1/Nrf2/ARE) pathway as a mechanism of action is explained, but interactions with peroxisome proliferator-activated receptor γ (PARPγ), inhibitor of nuclear factor-κB kinase complex (IKK), janus tyrosine kinase/signal transducer and activator of transcription (JAK/STAT), human epidermal growth factor receptor 2 (HER2)/ErbB2/neu, phosphatase and tensin homolog (PTEN), the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway, mammalian target of rapamycin (mTOR), and the thiol proteome are also described. In these interactions, Michael addition of SOs to reactive cysteine residues in specific molecular targets triggers biological activity. Ultimately, SOs are multifunctional drugs that regulate the activity of entire networks. Recent progress in the earliest clinical trials with 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) methyl ester (bardoxolone methyl) is also summarized.
359 citations
Cites background from "Cellular redox pathways as a therap..."
...This approach could exploit the altered levels of oxidative stress in tumor cells versus normal cells for therapeutic benefit (Trachootham et al., 2006, 2009; Acharya et al., 2010; Montero and Jassem, 2011)....
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...Because of the importance of redox-sensing thiols in signaling and disease (Jones, 2010), the proteins that compose or regulate this signaling network are currently being targeted for drug development (Montero and Jassem, 2011)....
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TL;DR: The interaction between mitochondrial reactive oxygen and nitrogen species, and the involvement of these oxidants in mitochondrial diseases, cancer, neurological, and cardiovascular disorders are discussed.
Abstract: Mitochondrially generated reactive oxygen species are involved in a myriad of signaling and damaging pathways in different tissues. In addition, mitochondria are an important target of reactive oxygen and nitrogen species. Here, we discuss basic mechanisms of mitochondrial oxidant generation and removal and the main factors affecting mitochondrial redox balance. We also discuss the interaction between mitochondrial reactive oxygen and nitrogen species, and the involvement of these oxidants in mitochondrial diseases, cancer, neurological, and cardiovascular disorders. Antioxid. Redox Signal. 18, 2029–2074.
351 citations
Cites background or methods from "Cellular redox pathways as a therap..."
...Indeed, compounds that either enhance ROS generation or abrogate key antioxidant mechanisms in tumor cells have been used in combination with radio- and chemotherapy to improve therapeutic response and to circumvent chemotherapy resistance, with a significant clinical impact [(357, 463), Fig....
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..., 2-methoxyestradiol), are currently being used in clinical trials for different types of cancer (357)....
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TL;DR: This review aims in summarizing and providing the recent developments of the understanding of the molecular mechanisms that underlie the potential anticancer effects of selenium compounds, as well as designing and optimizing compounds with more specific antitumor properties for possible future application in the treatment of cancer.
321 citations
TL;DR: New knowledge about recent tools that provide powerful antioxidant strategies, and designing methods to deliver to target cells, in the prevention and treatment of cancer are discussed.
Abstract: The oxygen paradox tells us that oxygen is both necessary for aerobic life and toxic to all life forms. Reactive oxygen species (ROS) touch every biological and medical discipline, especially those involving proliferative status, supporting the idea that active oxygen may be increased in tumor cells. In fact, metabolism of oxygen and the resulting toxic byproducts can cause cancer and death. Efforts to counteract the damage caused by ROS are gaining acceptance as a basis for novel therapeutic approaches, and the field of prevention of cancer is experiencing an upsurge of interest in medically useful antioxidants. Apoptosis is an important means of regulating cell numbers in the developing cell system, but it is so important that it must be controlled. Normal cell death in homeostasis of multicellular organisms is mediated through tightly regulated apoptotic pathways that involve oxidative stress regulation. Defective signaling through these pathways can contribute to both unbalance in apoptosis and development of cancer. Finally, in this review, we discuss new knowledge about recent tools that provide powerful antioxidant strategies, and designing methods to deliver to target cells, in the prevention and treatment of cancer.
289 citations
Cites background from "Cellular redox pathways as a therap..."
...If apoptosis and ROS regulation were fully understood, new treatments for cancer might be developed (Montero and Jassem 2011)....
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References
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TL;DR: The current understanding of how disturbance in redox homeostasis may affect cell death and contribute to the development of diseases such as cancer and degenerative disorders is reviewed and the basic knowledge on redox regulation of cell survival can be used to develop strategies for the treatment or prevention of those diseases.
Abstract: Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play important roles in regulation of cell survival. In general, moderate levels of ROS/RNS may function as signals to promote cell proliferation and survival, whereas severe increase of ROS/RNS can induce cell death. Under physiologic conditions, the balance between generation and elimination of ROS/RNS maintains the proper function of redox-sensitive signaling proteins. Normally, the redox homeostasis ensures that the cells respond properly to endogenous and exogenous stimuli. However, when the redox homeostasis is disturbed, oxidative stress may lead to aberrant cell death and contribute to disease development. This review focuses on the roles of key transcription factors, signal-transduction pathways, and cell-death regulators in affecting cell survival, and how the redox systems regulate the functions of these molecules. The current understanding of how disturbance in redox homeostasis may affect cell death and contribute to the development of diseases such as cancer and degenerative disorders is reviewed. We also discuss how the basic knowledge on redox regulation of cell survival can be used to develop strategies for the treatment or prevention of those diseases. Antioxid. Redox Signal. 10, 1343–1374.
1,536 citations
"Cellular redox pathways as a therap..." refers background in this paper
...Because of this heightened basal level of oxidative stress, cancer cells may be more susceptible to further oxidative stress than normal cells because their endogenous antioxidant systems can be overwhelmed.([27]) This important biological difference between normal and neoplastic cells may potentially be exploited therapeutically by agents that further augment ROS levels or weaken antioxidant defenses in cancer cells....
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TL;DR: This review will address some of the current paradigms for oxidative stress and apoptosis, and discuss the potential mechanisms by which oxidants can modulate the apoptotic pathway.
1,278 citations
"Cellular redox pathways as a therap..." refers background in this paper
...However, GSSG, through S-glutathiolynation and induction of mild oxidative stress, regulates important cellular functions such as the elimination of reactive thiol-containing proteins.([29])...
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TL;DR: Evidence suggests that transformed cells use ROS signals to drive proliferation and other events required for tumor progression, making them vulnerable to chemotherapeutic agents that further augment ROS generation or that weaken antioxidant defenses of the cell.
1,125 citations
"Cellular redox pathways as a therap..." refers background in this paper
...This important biological difference between normal and neoplastic cells may potentially be exploited therapeutically by agents that further augment ROS levels or weaken antioxidant defenses in cancer cells.([28]) The vulnerabilities of cancer cells to oxidative signals are now recognized as a potential target for the rational design of new anticancer agents....
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TL;DR: The addition of four cycles of preoperative docetaxel after four cyclesof preoperative AC significantly increased clinical and pathologic response rates for operable breast cancer.
Abstract: Purpose: The National Surgical Adjuvant Breast and Bowel Project Protocol B-27 was designed to determine the effect of adding docetaxel after four cycles of preoperative doxorubicin and cyclophosphamide (AC) on clinical and pathological response rates and on disease-free and overall survival of women with operable breast cancer. Patients and Methods: Women (N = 2,411) with operable primary breast cancer were randomly assigned to receive either four cycles of preoperative AC followed by surgery (group I), or four cycles of AC followed by four cycles of docetaxel, followed by surgery (group II), or four cycles of AC followed by surgery and then four cycles of docetaxel (group III). Clinical and pathologic tumor responses to preoperative therapy were assessed. Results: Mean tumor size (4.5 cm) and other key characteristics were evenly balanced among the three treatment arms. Grade 4 toxicity was observed in 10.3% of 2,400 patients during AC treatment, and in 23.4% of 1584 patients during docetaxel treatment....
1,049 citations
"Cellular redox pathways as a therap..." refers result in this paper
...These data compare favourably to results reported in the large, phase III NSABP (National Surgical Adjuvant Breast and Bowel Project) B-27 trial,([55]) which also assessed AC/T in...
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TL;DR: The present report highlights and integrates the growing connections between imbalances in GSH homeostasis and a multitude of human diseases and suggests the high GSH content makes cancer cells chemoresistant, which is a major factor that limits drug treatment.
Abstract: Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and as a result, disturbances in GSH homeostasis are implicated in the etiology and/or progression of a number of human diseases, including cancer, diseases of aging, cystic fibrosis, and cardiovascular, inflammatory, immune, metabolic, and neurodegenerative diseases. Owing to the pleiotropic effects of GSH on cell functions, it has been quite difficult to define the role of GSH in the onset and/or the expression of human diseases, although significant progress is being made. GSH levels, turnover rates, and/or oxidation state can be compromised by inherited or acquired defects in the enzymes, transporters, signaling molecules, or transcription factors that are involved in its homeostasis, or from exposure to reactive chemicals or metabolic intermediates. GSH deficiency or a decrease in the GSH/glutathione disulfide ratio manifests itself largely through an increased susceptibility to oxidative stress, and the resulting damage is thought to be involved in diseases, such as cancer, Parkinson's disease, and Alzheimer's disease. In addition, imbalances in GSH levels affect immune system function, and are thought to play a role in the aging process. Just as low intracellular GSH levels decrease cellular antioxidant capacity, elevated GSH levels generally increase antioxidant capacity and resistance to oxidative stress, and this is observed in many cancer cells. The higher GSH levels in some tumor cells are also typically associated with higher levels of GSH-related enzymes and transporters. Although neither the mechanism nor the implications of these changes are well defined, the high GSH content makes cancer cells chemoresistant, which is a major factor that limits drug treatment. The present report highlights and integrates the growing connections between imbalances in GSH homeostasis and a multitude of human diseases.
909 citations
"Cellular redox pathways as a therap..." refers background in this paper
...Differences in ROS levels between normal and neoplastic cells are due to the dysregulation of redox balance in cancer cells that develops when, for instance, intracellular production of ROS increases, or when levels of antioxidant agents become depleted.([14]) Of the classic cytotoxic agents known to modulate cellular redox balance, the anthracyclines doxorubicin and epirubicin are among the most widely used....
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