Selenadiazole derivatives as potent thioredoxin reductase inhibitors that enhance the radiosensitivity of cancer cells

Liang, Yuanwei; Zheng, Jun; Li, Xiaoling; Zheng, Wenjie; Chen, Tianfeng

doi:10.1016/j.ejmech.2014.07.032

Cited by 50 publications

(26 citation statements)

References 24 publications

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“…Along with improved radiation responses, AF sensitized breast cancer stem cells, and in combination with BSO decreased cell migration and invasion [20]. Of note, inhibition of TrxR by curcumin and 1, 2, 5-selenadiazole showed a comparable array of antitumor effects including radiosensitization [32, 45–47], while the disruption of GSH pathways by genistein and gadolinium (III) texaphyrin resulted in ROS-mediated radiosensitization [48, 49]. Compelling evidence also suggests that the abundant GSH pool is an important backup to keep Trx reduced, and therefore a dual targeting of the GSH/Trx antioxidant systems is required [43, 50].…”

Section: Discussionmentioning

confidence: 99%

Auranofin radiosensitizes tumor cells through targeting thioredoxin reductase and resulting overproduction of reactive oxygen species

et al. 2017

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Auranofin (AF) is an anti-arthritic drug considered for combined chemotherapy due to its ability to impair the redox homeostasis in tumor cells. In this study, we asked whether AF may in addition radiosensitize tumor cells by targeting thioredoxin reductase (TrxR), a critical enzyme in the antioxidant defense system operating through the reductive protein thioredoxin. Our principal findings in murine 4T1 and EMT6 tumor cells are that AF at 3–10 μM is a potent radiosensitizer in vitro, and that at least two mechanisms are involved in TrxR-mediated radiosensitization. The first one is linked to an oxidative stress, as scavenging of reactive oxygen species (ROS) by N-acetyl cysteine counteracted radiosensitization. We also observed a decrease in mitochondrial oxygen consumption with spared oxygen acting as a radiosensitizer under hypoxic conditions. Overall, radiosensitization was accompanied by ROS overproduction, mitochondrial dysfunction, DNA damage and apoptosis, a common mechanism underlying both cytotoxic and antitumor effects of AF. In tumor-bearing mice, a simultaneous disruption of the thioredoxin and glutathione systems by the combination of AF and buthionine sulfoximine was shown to significantly improve tumor radioresponse. In conclusion, our findings illuminate TrxR in cancer cells as an exploitable radiobiological target and warrant further validation of AF in combination with radiotherapy.

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Section: Discussionmentioning

confidence: 99%

Auranofin radiosensitizes tumor cells through targeting thioredoxin reductase and resulting overproduction of reactive oxygen species

et al. 2017

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“…(ROS)-mediated DNA damage, the extracellular signal-regulated kinase (ERK) and protein kinase B( AKT) pathways, [18] inhibiting thioredoxin reductase (TrxR) to disruptc ellular redox balance, ando vercoming hyperglycemia-induced drug resistance. [19,20] These reports demonstrate their potentiali nc ancer therapy. [21] Although selenadiazole and benzimidazole are structurally similar,d rug developers seldom introduce the two groups into one compound, so we were interested to fulfill such at ask.…”

Section: Introductionmentioning

confidence: 90%

Microwave‐Assisted Syntheses of Benzimidazole‐Containing Selenadiazole Derivatives That Induce Cell‐Cycle Arrest and Apoptosis in Human Breast Cancer Cells by Activation of the ROS/AKT Pathway

et al. 2016

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The use of selenium-containing heterocyclic compounds as potent cancer chemopreventive and chemotherapeutic agents has been well documented by a large number of clinical studies. In this study we developed a new approach to synthesize four benzimidazole-containing selenadiazole derivatives (BSeDs). The method uses a combination of peptide coupling reagents and microwave irradiation. This strategy features milder reaction conditions, higher yields, and shorter reaction times. The synthetic BSeDs were identified as potent antiproliferative agents against the human MCF-7 and MDA-MB-231 breast cancer cell lines. Compounds 1 b (5-(6-methyl-1H-benzo[d]imidazol-2-yl)benzo[c][1,2,5]selenadiazole), 1 c (5-(6-chloro-1H-benzo[d]imidazol-2-yl)benzo[c][1,2,5]selenadiazole), and 1 d (5-(6-bromo-1H-benzo[d]imidazol-2-yl)benzo[c][1,2,5]selenadiazole) were found to show greater cytotoxicity against the triple-negative breast cancer cell line MDA-MB-231 than MCF-7, and to exhibit dose-dependent inhibition of cell migration, in which a significant decrease in the zone of cell monolayer wound closure was observed relative to untreated controls. Our results demonstrate that BSeDs can cause cell-cycle arrest and apoptosis in MDA-MB-231 cells by inducing DNA damage, inhibiting protein kinase B (AKT), and activating mitogen-activated protein kinase (MAPK) family members through the overproduction of reactive oxygen species (ROS). Taken together, the results of this study provide a facile microwave-assisted strategy for the synthesis of selenium-containing organic compounds that exhibit a high level of anticancer efficacy.

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“…In addition, the binding site of the enzyme with 1, 2, 5‐selenadiazole ( 284 , Figure ) was studied by MALDI‐TOF MS using a model peptide of TrxR. Treatment of cells with 284 also significantly decreased the TrxR activity, and 284 in combination with 8 Gy caused comparatively high decrease in TrxR activity . They also demonstrated SeD‐3, a selenadiazole derivative ( 285 , Figure ) significantly enhanced the sensitivity of HeLa cervical cells to X‐ray‐induced apoptosis by targeting the inhibition of TrxR with an IC 50 value of 18.70 μM .…”

Section: Thioredoxin Reductase Inhibitorsmentioning

confidence: 99%

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

Zhang

et al. 2018

Medicinal Research Reviews

127

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Mammalian thioredoxin reductase (TrxR) enzymes are homodimeric flavin proteins sharing a unique yet essential selenocysteine residue at their C-terminus. TrxRs, together with their endogenous substrate thioredoxins, play a crucial role in regulating diverse cellular redox events. A wealth of evidence from both clinic observations and bench studies supports that overactivation/dysfunction of TrxRs has a close link to the onset and development of various diseases, such as cancer and neurodegeneration. Thus, an increasing interest has been attracted to find small molecule modulators of TrxRs during the past years. Herein, we briefly discussed the relevance of targeting TrxRs inhibition for cancer treatment, and presented the small molecule inhibitors of mammalian TrxRs published in the nonpatent literatures from 2011 to 2016. The mechanisms of inhibition by different classes of molecules were summarized, and some inhibitors with promising anticancer activity were further discussed. We expect this work would be a comprehensive reference in the medicinal chemistry, and have a broad audience across multiple disciplines.

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Selenadiazole derivatives as potent thioredoxin reductase inhibitors that enhance the radiosensitivity of cancer cells

Cited by 50 publications

References 24 publications

Auranofin radiosensitizes tumor cells through targeting thioredoxin reductase and resulting overproduction of reactive oxygen species

Auranofin radiosensitizes tumor cells through targeting thioredoxin reductase and resulting overproduction of reactive oxygen species

Microwave‐Assisted Syntheses of Benzimidazole‐Containing Selenadiazole Derivatives That Induce Cell‐Cycle Arrest and Apoptosis in Human Breast Cancer Cells by Activation of the ROS/AKT Pathway

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

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