Targeting the Thioredoxin System for Cancer Therapy

Zhang, Junmin; Li, Xinming; Han, Xiao; Liu, Ruijuan; Fang, Jianguo

doi:10.1016/j.tips.2017.06.001

Cited by 356 publications

(330 citation statements)

References 115 publications

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“…Since TrxR is the only enzyme known to catalyze the reduction of Trx-1, it is reasonable that alterations in TrxR activity is likely to regulate some of the activities of Trx-1 [43]. Importantly, high expression of TrxR is associated with a poor cancer prognosis in clinic [16,44]. Our data demonstrated that the enzyme activity of TrxR was dropped though no obvious change in expression was observed following the treatment of DATS.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 63%

“…Activation of redox signaling pathways facilitates breast cancer progression and is closely linked to poor prognosis in breast cancer patients [15]. Thioredoxin (Trx) system, mainly consisted of Trx, thioredoxin reductase (TrxR) and nicotinamide adenine dinucleotide phosphate (NAPDH), plays a pivotal role in modulating cellular thiol/disulfide redox status [16,17]. Thioredoxin-1 (Trx-1) as the predominant isoform of Trx is a 12kD ubiquitous protein containing a redox-active disulfide/ dithiol and its cysteine residues are converted to the oxidized intramolecular disulfide bond state (Trx-1-S2) in a reaction [18].…”

Section: Introductionmentioning

confidence: 99%

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Targeting Thioredoxin System with an Organosulfur Compound, Diallyl Trisulfide (DATS), Attenuates Progression and Metastasis of Triple-Negative Breast Cancer (TNBC)

Liu¹,

Zhao²,

Wei³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Metastasis is the leading cause resulting in high mortality in triple negative breast cancer (TNBC) patients. Cancer cells are skilled at utilizing thioredoxin (Trx) system as an efficient antioxidant system to counteract oxidative damage, facilitating the occurrence of metastasis. Here, we identified an organosulfur compound named DATS isolated from garlic, that inhibits the expression of Trx-1 and the enzyme activity of Trx reductase in breast cancer cells. Methods: Tissue microarray of breast cancer patients and immunohistochemical method were used to analyze the role of Trx-1 in breast cancer metastasis. Spotaneous metastasis model and experimental metastasis model combined with HE staining, immunohistochemistry were used to verify in vivo anti-metastatic effect of DATS as well as its regulation on thioredoxin. Western blot, immunofluorescence, redox state assessment and detection of enzyme activity were employed to determine the effect of DATS on thioredoxin system. Trx-1 siRNA interference was used to investigate the conclusive evidence that Trx-1 was the target of DATS. Results: In agreement with reduced Trx-1 nuclear translocation from cytoplasm by DATS, the production of reduced form of Trx-1 was dramatically decreased. Furthermore, in vivo, DATS administration was observed to significantly suppress spontaneous and experimental metastasis in nude mice. Delivery of DATS also resulted in decreased expression of Trx-1 as the direct target, as well as expression of NF-κB and MMP2/9 in primary tumor and lung tissue. Notably, the effects of DATS on the expression of downstream metastasis-associated genes were mediated by Trx-1, as demonstrated by the combination use of DATS and Trx-1 siRNA. Conclusion: Collectively, this present study indicates that targeting Trx system with DATS may provide a promising strategy for treating metastasis of TNBC.

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Section: Cellular Physiology and Biochemistrymentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Targeting Thioredoxin System with an Organosulfur Compound, Diallyl Trisulfide (DATS), Attenuates Progression and Metastasis of Triple-Negative Breast Cancer (TNBC)

Liu¹,

Zhao²,

Wei³

et al. 2018

Cell Physiol Biochem

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“…Tr xR systems play an important role in regulating diverse cellular redox events, [13] and defects in Tr xR2 were reported to induce ac ollapse in mitochondrial cristae and respiration. [34] We thus evaluated the effects of TTP on the mitochondrial and cellular Tr xR activities.T he activity of purified Tr xR for 5,5'-dithiobis(2-nitrobenzoic acid) was dramatically inhibited by TTP (IC 50 = 74 nm), which is more potent than CDDP (IC 50 > 1000 nm ;F igure 7A;s ee also Figure S13).…”

Section: Angewandte Chemiementioning

confidence: 99%

“…[10] Thioredoxin reductase (TrxR) plays ap ivotal role in defending reactive oxygen species (ROS)incellular compartments [11] and exists in three isoforms,T rxR1 in cytosol, Tr xR2 in mitochondria, and Tr xR3 in testicles.O verexpression of Tr xR in cancer cells has been related to drug resistance; [12] and Tr xR has been demonstrated to influence the cancer metabolic state by regulating cellular redox signaling pathways. [13] Moreover,T rxR2 specifically regulates redox status in mitochondria, and its inhibition may lead to ad istinct pharmacodynamic profile. [14] Among Tr xR inhibitors,m etal complexes,s uch as those of Au,A g, Ru, or Ir, have been found to possess anticancer potency.…”

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confidence: 99%

Restraining Cancer Cells by Dual Metabolic Inhibition with a Mitochondrion‐Targeted Platinum(II) Complex

et al. 2019

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Cancer cells usually adapt metabolic phenotypes to chemotherapeutics.Adefensive strategy against this flexibility is to modulate signaling pathwaysr elevant to cancer bioenergetics.Atriphenylphosphonium-modified terpyridine platinum(II) complex (TTP) was designed to inhibit thioredoxin reductase (TrxR) and multiple metabolisms of cancer cells. TTP exhibited enhanced cytotoxicity against cisplatin-insensitive human ovarian cancer cells in ac aspase-3-independent manner and showed preferential inhibition to mitochondrial TrxR. The morphology and function of mitochondria were severely damaged, and the levels of mitochondrial and cellular reactive oxygen species were decreased. As ar esult, TTP exerted strong inhibition to both mitochondrial and glycolytic bioenergetics,t hus inducing cancer cells to enter ah ypometabolic state.

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“…Likewise, ROS production during hypoxia overwhelms the ROS scavenging capability, with the potential to generate a net mitochondrial ROS overload thereby causing oxidative damage. Either way, targeting these enzymes will increase cancer cell death by exceeding the ROS threshold to overload the capacity of cellular antioxidant coping mechanisms …”

Section: Introductionmentioning

confidence: 99%

Repurposing drugs as pro‐oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers

Ralph

Nozuhur

ALHulais

et al. 2019

Medicinal Research Reviews

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Over the last decade, three major advances have contributed in improving the response rates against cancer including, immunotherapy; greater understanding of the molecular, biochemical, and cellular mechanisms in carcinogenesis thereby providing drug targets; and identification of reliable biomarkers for early detection to facilitate the earlier stage treatment of disease. However, no single universal cancer cure has yet been found, although combinations from the above areas have steadily improved survival outcomes. Hence, chemotherapy remains a key component in the oncologist's arsenal for cancer therapy, despite frequent development of drug resistance and more aggressive cancers with onset of advanced stage metastases. The focus here is to explore the repurposing of old drugs that cause pro‐oxidative overload to overcome onset of resistance to chemotherapy and enhance chemotherapeutic responses, particularly against metastatic cancer. Excellent examples of US Food and Drug Administration approved drugs suitable for repurposing are the potent and specific thioreductase inhibitor auranofin and the nonsteroidal anti‐inflammatory drug, celecoxib. Recently, both drugs were shown to selectively target and kill metastatic cancer cells and cancer stem cells (CSCs), predominantly by promoting excessive mitochondrial reactive oxygen species. Thus, targeting intracellular redox systems of advanced stage metastatic cancer cells and CSCs can promote an overload of pro‐oxidative stress to activate the intrinsic pathway for programmed cell death. It is envisaged that more clinical studies will incorporate longer term use of repurposed drugs, such as auranofin or celecoxib, to target redox systems in cancer cells as part of common practice postcancer diagnosis, providing enhanced chemotherapeutic responses and increased cancer survival.

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Targeting the Thioredoxin System for Cancer Therapy

Cited by 356 publications

References 115 publications

Targeting Thioredoxin System with an Organosulfur Compound, Diallyl Trisulfide (DATS), Attenuates Progression and Metastasis of Triple-Negative Breast Cancer (TNBC)

Targeting Thioredoxin System with an Organosulfur Compound, Diallyl Trisulfide (DATS), Attenuates Progression and Metastasis of Triple-Negative Breast Cancer (TNBC)

Restraining Cancer Cells by Dual Metabolic Inhibition with a Mitochondrion‐Targeted Platinum(II) Complex

Repurposing drugs as pro‐oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers

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