All statistical analyses were performed using the Stata All data generated or analyzed during this study are included in this published article and its supplementary information files. Hesse, G. Inner Ear Hearing Loss. Laryngorhinootologie 95 , — Olusanya, B. PLoS Med 4 , e84 Carvill, S.
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JCI - Dual targeting of the thioredoxin and glutathione systems in cancer and HIV
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In toto, these data set the stage for important contributions of redox- and NO-based signaling in immune responses against cancer and HIV, as discussed below. In recent years, there has been a growing appreciation that a cellular nitroso-redox imbalance can promote tumor growth and resistance to therapy. This imbalance involves not only the cancer cells themselves but also other cells that populate the tumor and its microenvironment including cancer stem cells, vascular cells, and immune cells 43 — However, mounting evidence has shown that antioxidant supplementation fails to provide cancer protection and might even increase cancer risk 54 — These observations are supported and rationalized by recent mechanistic, interdisciplinary studies demonstrating that oxidative stress can inhibit cancer progression and metastasis and that the GSH and Trx systems may promote tumorigenesis and resistance to therapy 51 — 53 , 57 — Increased levels of Trx or TrxR have been detected in multiple tumors e.
A recent study showed that mitochondrial TrxR contributes to tumor growth through the HIF-1 pathway 64 , supporting the idea that mitochondrial redox signaling is important for tumorigenesis. Conversely, the TrxR inhibitor auranofin partially inhibits the growth of leukemia and relapsed Hodgkin lymphoma cells in vitro 65 , TrxR inhibitors may generally promote apoptosis or differentiation.
Indeed, auranofin was shown to induce apoptosis of acute promyelocytic leukemia cells in vitro and promote the differentiation of these cells when used in combination with retinoic acid 67 — effects reminiscent of arsenicals, which, apart from their main target, the promyelocytic leukemia protein, also inhibit TrxR Inhibition of the Trx system may also sensitize cancer cells to ionizing radiation and chemotherapeutic drugs, which have pro-oxidant effects 69 , 70 , and to the antitumor effects of NO donor compounds, likely via S-nitrosylation 71 , Additionally, auranofin administered as a single agent to patients with chronic lymphocytic leukemia had a significant, albeit transient, cidal effect A larger clinical trial has been completed, and its results await publication ClinicalTrials.
Auranofin is also being administered along with several other chemotherapeutics as a salvage therapy for recurrent glioblastoma A clinical trial of auranofin-based combination therapy is expected to start in Ulm, Germany, in European Clinical Trials Database [EudraCT] number Collectively, these studies support the viability of Trx and TrxR inhibition as an anticancer strategy.
Blockade of the GSH system represents another potentially important anticancer strategy Like Trx, GSH content increases during malignant transformation of lymphocytes and other cell types 76 , This change to a more reducing intracellular environment often involves the transcription factor nuclear factor, erythroid-derived 2, like 2 NRF2 , which positively regulates antioxidant and detoxification enzymes 79 , including enzymes needed for synthesis and handling of GSH.
This mechanism of detoxification can lead to the development of resistance against chemotherapeutic agents Tumorigenic effects of GSTs may also be mediated by inhibition of phosphorylation of the transcription factor c-Jun, resulting in antiapoptotic effects The important role of GSH and GSH-associated enzymes in tumor development and progression and drug resistance has been recently demonstrated in mouse models. Specifically, Harris and colleagues demonstrated that blocking GSH synthesis with BSO or through genetic approaches inhibits the spontaneous development of lymphomas, sarcomas, and breast tumors in mice BSO was, however, ineffective when malignant transformation had already occurred.
Further analyses supported the conclusion that the upregulation of Trx may have compensated for the inhibition of GSH. More generally, despite the lack of activity of BSO when used alone, inhibition of GSH synthesis may find a place in rationally designed combination therapy. For example, melphalan, which is detoxified by GST, showed synergistic effects with BSO in a number of tumor lines Moreover, BSO and melphalan proved generally well tolerated in phase I clinical trials involving advanced cancers 85 , 86 , the one exception being in children with recurrent neuroblastoma Of note, melphalan was shown to inhibit TrxR in vitro, although this is probably not the mechanism of action at physiological plasma concentrations, as melphalan is principally an alkylating agent Several studies, including the study by Harris and colleagues 83 , indicate that dual targeting of the GSH and Trx redox systems can result in powerful and synergistic antitumor effects.
This conclusion is in line with studies showing that BSO markedly increased the effects of auranofin in leukemias and lymphomas, including chronic lymphocytic leukemia 65 , large B cell lymphoma an HIV-associated malignancy , mantle cell lymphoma, and in multiple myeloma Potential redox-sensitive targets implicated in the antitumor effects of GSH and Trx silencing include ribonucleotide reductase inhibition and ASK1 activation refs.
Recent evidence shows that glucose metabolism e. Involvement of additional oxidized or nitrosylated proteins is likely. The interrelation between the glycolytic pathway and Trx and GSH inhibition is also suggested by in vitro and in vivo data: the glycolysis inhibitor 2-deoxy-D-glucose 2DG enhanced the antitumor effect of the combination of auranofin and BSO in a mouse xenograft model Taken together, these and other studies support the idea that dual inhibition of the GSH and Trx pathways may represent an effective anticancer approach against tumors of multiple origins refs.
Notably, the combination of auranofin and BSO has been well tolerated in macaques and mice 70 , 96 , indicating that it may also be tolerated in patients. Cell death is in part mediated by inhibition of ribonucleotide reductase RNR and through activation of the proapoptotic kinase ASK1. ART blocks HIV replication and partially counteracts the effects of oxidative stress, but is unable to target the latently infected cells.
Inhibition of TrxR by auranofin increases oxidative and potentially nitrosative stress and apoptosis. TrxR inhibition also leads to a prodifferentiation effect on the latently HIV-infected cells, driving them toward short-lived phenotypes i. Arrows beside the names of the molecules indicate the variation over time.
SH, thiol. Preclinical susceptibility of various tumors to combined Trx and GSH inhibition. HIV and AIDS exhibit interesting similarities with cancer in terms of redox regulation and the history of its therapeutic exploitation, starting from the failure of antioxidant-based therapies and culminating in novel therapeutic strategies based on dual inhibition of the Trx and GSH systems. The net result was oxidative stress that is linked to increased viral replication 98 , These findings paved the way for several clinical trials aimed at boosting antioxidant defenses.
Numerous compounds were tested, including N -acetylcysteine a thiol antioxidant, denitrosylating agent and a precursor of GSH ; vitamins A, C, and E; and zinc, selenium, and several carotenoids. This trend paralleled the wave of studies of antioxidant therapies for cancer, with similarly disappointing effects on disease progression in this case measured by viral load and CD4 counts — The subsequent success of combined antiretroviral therapy ART led to a decline in interest in alternative or complementary therapeutic approaches using agents such as antioxidants.
However, while ART transformed a deadly disease into a manageable chronic condition, antiretroviral drugs proved unable to cure HIV infection, and the incidence of AIDS-related conditions, including cancer and heart disease, remains high in ART-treated individuals In its dormant form, the virus, integrated within the host genome, is sheltered from both the immune system and antiretroviral drugs Latent virus can survive for years in central and transitional memory T cells, and mathematical estimates suggest that viral reservoirs persist for more than 70 years Latent proviral DNA may also spread through low-level antigenic activation and homeostatic proliferation of memory T cells, thus increasing the number of proviral DNA copies within the organism Although not directly harmful, the HIV reservoir cell population does represent a danger for the host, as the virus can become reactivated following suspension of therapy The population of latently infected cells living and proliferating within the organism may share an interesting similarity with cancer.
This paradigm of viral persistence has had important implications for the reevaluation of the role of oxidative and nitrosative stress in HIV infection Figure 2. While increases in oxidative stress favor productive viral replication, antioxidant defenses favor the development and maintenance of latency — Antioxidants may therefore silence transcriptional activity , , while pro-oxidants, such as arsenic trioxide, may reactivate the viral reservoir