Mild oxidative stress induces S-glutathionylation of STAT3 and enhances chemosensitivity of tumoural cells to chemotherapeutic drugs

Butturini, Elena; Prati, Alessandra Carcereri de; Chiavegato, Giulia; Rigo, Antonella; Cavalieri, Elisabetta; Darra, Elena; Mariotto, Sofia

doi:10.1016/j.freeradbiomed.2013.09.015

Cited by 67 publications

(70 citation statements)

References 33 publications

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“…Cynaropicrin suppressed IL-6-inducible and constitutive Signal Transducer and Activator of Transcription 3 (STAT3) activation (Butturini et al, 2013). STAT3 is a cytoplasmic transcription protein factor that is activated in various cancers.…”

Section: Anti-tumor and Cytotoxic Activitymentioning

confidence: 99%

“…Cynaropicrin induces a rapid drop in intracellular GSH concentration in a dose-dependent manner through Michael addition reaction, thereby triggering S-glutathionylation of STAT3, interfering with its phosphorylation. Cynaropicrin was found to regulate STAT3 function through induction of redox-dependent post-translational modification of STAT3 cysteine residues (Butturini et al, 2013). …”

Section: Anti-tumor and Cytotoxic Activitymentioning

confidence: 99%

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Cynaropicrin: A Comprehensive Research Review and Therapeutic Potential As an Anti-Hepatitis C Virus Agent

2016

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The different pharmacologic properties of plants-containing cynaropicrin, especially artichokes, have been known for many centuries. More recently, cynaropicrin exhibited a potential activity against all genotypes of hepatitis C virus (HCV). Cynaropicrin has also shown a wide range of other pharmacologic properties such as anti-hyperlipidemic, anti-trypanosomal, anti-malarial, antifeedant, antispasmodic, anti-photoaging, and anti-tumor action, as well as activation of bitter sensory receptors, and anti-inflammatory properties (e.g., associated with the suppression of the key pro-inflammatory NF-κB pathway). These pharmacological effects are very supportive factors to its outstanding activity against HCV. Structurally, cynaropicrin might be considered as a potential drug candidate, since it has no violations for the rule of five and its water-solubility could allow formulation as therapeutic injections. Moreover, cynaropicrin is a small molecule that can be easily synthesized and as the major constituent of the edible plant artichoke, which has a history of safe dietary use. In summary, cynaropicrin is a promising bioactive natural product that, with minor hit-to-lead optimization, might be developed as a drug for HCV.

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Section: Anti-tumor and Cytotoxic Activitymentioning

confidence: 99%

Section: Anti-tumor and Cytotoxic Activitymentioning

confidence: 99%

Cynaropicrin: A Comprehensive Research Review and Therapeutic Potential As an Anti-Hepatitis C Virus Agent

2016

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“…As the MPTP is activated in response to a number of cellular stressors including ROS and elevated intra-mitochondrial Ca 2+ concentrations (the latter likely due to the tight connection between Ca 2+ homeostasis and ROS production), it is possible that oxidative modification of STAT3 in the mitochondria regulates its association and control of the MPTP. STAT3 has been shown to be S-glutathionylated [56–58] and S-nitrosylated [59] in the cytosol, and it is capable of forming multimers following an oxidative insult that impinges on its ability to bind DNA [60]. Whether similar events are modifying STAT3 in the mitochondria and if this has a functional significance remains to be determined [61].…”

Section: Signal Transducer and Activator Of Transcription 3 (Stat3)mentioning

confidence: 99%

Toward a new STATe: The role of STATs in mitochondrial function

Meier¹,

Larner²

2014

Seminars in Immunology

146

139

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Signal Transducers and Activators of Transcription (STATs) have been studied extensively and have been associated with virtually every biochemical pathway. Until recently, however, they were thought to exert these effects solely as a nuclear transcription factor. The finding that STAT3 localizes to the mitochondria and modulates respiration has opened up a new avenue through which STATs may regulate the cell. Recently, other members of the STAT family (STAT1, STAT2, STAT5, and STAT6) have also been shown to be present in the mitochondria. Coordinate regulation at the nucleus and mitochondria by these proteins places them in a unique position to drive cellular processes to achieve a specific response. This review summarizes recent findings that have led to our current understanding of how STATs influence mitochondrial function in health and disease.

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“…However, it remains unclear how BSO actually suppresses the expression of antiapoptotic proteins. Previous work has revealed that mild oxidative stress may induce S-glutathionylation of signal transducer and activator of transcription 3 (STAT3), leading to the suppression of the STAT3 pathway, downregulation of STAT3-dependent gene expression and chemosensitization of tumor cells to chemotherapy (42). It has also been established that Mcl-1 and Bcl-2 are regulated by STAT3 (43,44).…”

Section: Discussionmentioning

confidence: 99%

The effects of buthionine sulfoximine on the proliferation and apoptosis of biliary tract cancer cells induced by cisplatin and gemcitabine

Yin

Wang

et al. 2015

Oncology Letters

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Abstract.Patients with biliary tract cancer (BTC) have a poor prognosis. Advanced BTC patients have been treated with cisplatin in combination with gemcitabine, however, the treatment has had little impact on survival rates, and more effective treatments are urgently required for this disease. Previous studies discovered that buthionine sulfoximine (BSO), a potent inhibitor of glutathione (GSH) synthesis, was able to enhance the cytotoxic effect of various drugs in cancer cells. Phase I studies demonstrated that continuous-infusion of BSO was relatively non-toxic and resulted in the depletion of tumor GSH. However, the synergistic effect of BSO and cisplatin in BTC cells remains unknown, and no reports are available regarding sensitization to gemcitabine by BSO. In the present study, the effect of BSO in combination with cisplatin or gemcitabine in the treatment of BTC cells was examined in vitro. Cytotoxic effects were measured using an MTT assay, Annexin V assay and fluorescence-activated cell sorting analysis. Antiapoptotic protein expression levels were examined using western blot analysis. The results revealed that a sub-toxic concentration of BSO was capable of significantly enhancing cisplatin-induced apoptosis in BTC cells. The mechanisms of BSO's effect on BTC cells may be attributable to the reduction of GSH levels and downregulation of the expression of antiapoptotic proteins (Bcl-2, Bcl-xL and Mcl-1). Furthermore, BSO enhanced the antiproliferative effect of gemcitabine. In conclusion, the present data are the first results to indicate that BSO may sensitize BTC cells to standard first-line chemotherapeutic agents (cisplatin and gemcitabine). Combining BSO with cisplatin and gemcitabine is a promising therapeutic strategy for the treatment of BTC.

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Mild oxidative stress induces S-glutathionylation of STAT3 and enhances chemosensitivity of tumoural cells to chemotherapeutic drugs

Cited by 67 publications

References 33 publications

Cynaropicrin: A Comprehensive Research Review and Therapeutic Potential As an Anti-Hepatitis C Virus Agent

Cynaropicrin: A Comprehensive Research Review and Therapeutic Potential As an Anti-Hepatitis C Virus Agent

Toward a new STATe: The role of STATs in mitochondrial function

The effects of buthionine sulfoximine on the proliferation and apoptosis of biliary tract cancer cells induced by cisplatin and gemcitabine

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