The role of the redox protein thioredoxin in cell growth and cancer

Powis, Garth; Mustacich, Debbie J.; Coon, Amy

doi:10.1016/s0891-5849(00)00313-0

Cited by 396 publications

(282 citation statements)

References 99 publications

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“…The increased cancer development due to Trx1 overexpression is not a surprising observation because Trx1 is overexpressed in various cancers [39], and Trx1 plays important roles in cancer development [39]. Although most studies that involve investigations of tumors suggest a possible role of Trx1 in carcinogenesis, our study is the first to demonstrate that Trx1 overexpression plays important roles to promote spontaneous tumor development with age in vivo .…”

Section: Discussionmentioning

confidence: 62%

Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice

Flores

Roman

Cunningham

et al. 2018

Pathobiology of Aging & Age-related Diseases

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We examined the effects of continuous overexpression of thioredoxin (Trx) 1 on aging in Trx1 transgenic mice [Tg(TXN)+/0]. This study was conducted to test whether increased thioredoxin expression over the lifespan in mice would alter aging and age-related pathology because our previous study demonstrated that Tg(act-TXN)+/0 mice had no significant maximum life extension, possibly due to the use of actin as a promoter, which may have resulted in loss of Trx1 overexpression during aging. To test this hypothesis, we generated new Trx1 transgenic mice using a fragment of the human genome containing the TXN gene with an endogenous promoter to ensure continuous overexpression of Trx1 throughout the lifespan. Universal overexpression of Trx1 was observed, and Trx1 overexpression was maintained during aging (up to 22–24 months old) in the Tg(TXN)+/0 mice. The levels of Trx1 are significantly higher (approximately 4 to 31 fold) in all of the tissues examined in the Tg(TXN)+/0 mice compared to the wild-type (WT) littermates. The overexpression of Trx1 did not cause any changes in the levels of Trx2, glutaredoxin, glutathione, or other major antioxidant enzymes. The survival study demonstrated that male Tg(TXN)+/0 mice slightly extended the earlier part of the lifespan compared to WT littermates, but no significant life extension was observed over the lifespan. The cross-sectional pathological analysis (22–25 months old) showed that Tg(TXN)+/0 mice had a significantly higher severity of lymphoma and more tumor burden than WT mice, which was associated with the suppression of the apoptosis signal-regulating kinase 1 (ASK1) pathway. Our findings suggest that the increased levels of Trx1 over the lifespan in Tg(TXN)+/0 mice showed some beneficial effects (slight extension of lifespan) in the earlier part of life but had no significant effects on median or maximum lifespans, and increased Trx1 levels enhanced tumor development in old mice.

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Section: Discussionmentioning

confidence: 62%

Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice

Flores

Roman

Cunningham

et al. 2018

Pathobiology of Aging & Age-related Diseases

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“…The basis of resistance to HDACi is not well understood. High levels of Bcl-2 (Pommier et al, 2004), Trx (Powis et al, 2000) and peroxiredoxins (Chung et al, 2001) have been associated with resistance of transformed cells to chemotherapy, and may play a role in the resistance to HDACi. Upregulation of Trx protects normal cells against HDACi-induced cell death (Ungerstedt et al, 2005).…”

Section: The Resistance To Hdacimentioning

confidence: 99%

Histone deacetylase inhibitors: molecular mechanisms of action

2007

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“…Previous studies have demonstrated that many tumor processes are closely related to TrxR, including growth, metastasis and inhibition of apoptosis [1][2][3][4][5]17] . Ethaselen is a small molecule that is specifically combined with TrxR and reduces the TrxR activity levels, exerting good inhibitory effects on several human carcinoma cell lines [11][12][13][14][15]26] .…”

Section: Discussionmentioning

confidence: 99%

“…Mammalian thioredoxin reductase (TrxR) is a component of several redox-sensitive signaling cascades that mediate some physiological processes, especially cell survival, maturation, growth, migration and inhibition of apoptosis [1][2][3][4][5][6] . The TrxR1 expression levels in some human carcinoma cell lines are approximately 10 times higher than those in normal cells [7] , indicating their close relationships with cell proliferation and progression.…”

Section: Introductionmentioning

confidence: 99%

“…It has been reported that TrxR is involved in many aspects of tumor physiology, such as proliferation, apoptosis and metastasis [1][2][3][4][5] . In recent years, an increasing number of TrxR inhibitors have received attention and have eventually been demonstrated as effective [7,[27][28][29] ; Ethaselen is one promising, potent candidate [26] .…”

Section: Introductionmentioning

confidence: 99%

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Dose-biomarker-response modeling of the anticancer effect of ethaselen in a human non-small cell lung cancer xenograft mouse model

et al. 2016

Acta Pharmacol Sin

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Thioredoxin reductase (TrxR) is a component of several redox-sensitive signaling cascades that mediate important biological processes such as cell survival, maturation, growth, migration and inhibition of apoptosis. The expression levels of TrxR1 in some human carcinoma cell lines are nearly 10 times higher than those in normal cells. Ethaselen is a novel antitumor candidate that exerts potent inhibition on non-small cell lung cancer (NSCLC) by targeting TrxR. In this study we explored the relationship between the ethaselen dose and TrxR activity level and the relationship between TrxR degradation and tumor apoptosis in a human lung carcinoma A549 xenograft model. BALB/c nude mice implanted with human NSCLC cell line A54 were administered ethaselen (36, 72, 108 mg·kg -1 ·d -1 , ig) or vehicle for 10 d. The tumor size and TrxR activity levels in tumor tissues were daily recorded and detected. Based on the experimental data, NONMEM 7.2 was used to develop an integrated dose-biomarker-response model for describing the quantitative relationship between ethaselen dose and tumor eradication effects. The time course of TrxR activity levels was modeled using an indirect response model (IDR model), in which the influence of the tumor growth rates on K in with the linear correction factor γ1 (0.021 d/mm). The drug binding-inhibition effects on K out was described using a sigmoidal E max model with S max (5.95), SC 50 (136 mg/kg) and Hill's coefficient γ2 (2.29). The influence of TrxR activity inhibition on tumor eradication was characterized by an E max model with an E max (130 mm 3 /d) and EC 50 (0.0676). This model was further validated using a visual predictive check (VPC) and was used to predict the efficacy of different doses. In conclusion, the properties and characteristics of ethaselen acting on TrxR degradation and subsequently resulting in tumor apoptosis are characterized by the IDR model and integrated dose-biomarker-response model with high goodness-offit and great predicative ability. This approach shed new light on the detailed processes and mechanism of ethaselen action and may offer a valuable reference for an appropriate dosing regimen for use in further clinical applications.

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The role of the redox protein thioredoxin in cell growth and cancer

Cited by 396 publications

References 99 publications

Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice

Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice

Histone deacetylase inhibitors: molecular mechanisms of action

Dose-biomarker-response modeling of the anticancer effect of ethaselen in a human non-small cell lung cancer xenograft mouse model

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