Inhibition of Mitochondrial Respiration and Rapid Depletion of Mitochondrial Glutathione by β-Phenethyl Isothiocyanate: Mechanisms for Anti-Leukemia Activity

Chen, Gang; Chen, Zhao; Hu, Yumin; Huang, Peng

doi:10.1089/ars.2011.4170

Cited by 71 publications

(61 citation statements)

References 47 publications

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“…Given the role of GSH in the reduction of H 2 O 2 and the oxidation of sulfhydryl group, it is believed that GSH depletion will cause toxicity via accumulation of H 2 O 2 and oxidized proteins (6). It has been previously suggested that electrophilic small molecules such as buthionine sulfoximine (BSO), piperlongumine (PL), and phenethyl isothiocyanate (PEITC) convey at least part of their toxicity via this mechanism (9,16,39,49,51,56), and all of these drugs have been shown to be selectively toxic to certain in vitro and in vivo tumor models (1,5,13,39). Incubation of tumor cells with piperlongumine and PEITC results in depletion of GSH and elevation of fluorescence from dichloro-dihydro-fluorescein diacetate (DCFH-DA), a cell permeable dye that exhibits increasing fluorescence intensity upon oxidation (9,39,49,56).…”

Section: Innovationmentioning

confidence: 99%

“…One of the mechanisms of piperlongumine and PEITC toxicity suggested by previous studies is the depletion of the total GSH level and the subsequent increase in oxidative stress (5,9,39,49,56). We used a specific, small-molecule inhibitor of GSH synthesis, BSO, as a control for determining whether the level of depletion in the two compounds is an important contributor to tumor inhibition (57).…”

Section: Differential Response Of Hela and A549 Cells To Piperlongumimentioning

confidence: 99%

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Using Sensors and Generators of H₂O₂to Elucidate the Toxicity Mechanism of Piperlongumine and Phenethyl Isothiocyanate

Huang

Langford

Sikes

2016

Antioxidants & Redox Signaling

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Aims: Chemotherapeutics target vital functions that ensure survival of cancer cells, including their increased reliance on defense mechanisms against oxidative stress compared to normal cells. Many chemotherapeutics exploit this vulnerability to oxidative stress by elevating the levels of intracellular reactive oxygen species (ROS). A quantitative understanding of the oxidants generated and how they induce toxicity will be important for effective implementation and design of future chemotherapeutics. Molecular tools that facilitate measurement and manipulation of individual chemical species within the context of the larger intracellular redox network present a means to develop this understanding. In this work, we demonstrate the use of such tools to elucidate the roles of H 2 O 2 and glutathione (GSH) in the toxicity mechanism of two ROS-based chemotherapeutics, piperlongumine and phenethyl isothiocyanate. Results: Depletion of GSH as a result of treatment with these compounds is not an important part of the toxicity mechanisms of these drugs and does not lead to an increase in the intracellular H 2 O 2 level. Measuring peroxiredoxin-2 (Prx-2) oxidation as evidence of increased H 2 O 2 , only piperlongumine treatment shows elevation and it is GSH independent. Using a combination of a sensor (HyPer) along with a generator (D-amino acid oxidase) to monitor and mimic the drug-induced H 2 O 2 production, it is determined that H 2 O 2 produced during piperlongumine treatment acts synergistically with the compound to cause enhanced cysteine oxidation and subsequent toxicity. The importance of H 2 O 2 elevation in the mechanism of piperlongumine promotes a hypothesis of why certain cells, such as A549, are more resistant to the drug than others. Innovation and Conclusion: The approach described herein sheds new light on the previously proposed mechanism of these two ROS-based chemotherapeutics and advocates for the use of both sensors and generators of specific oxidants to isolate their effects. Antioxid. Redox Signal. 24, 924-938.

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Section: Innovationmentioning

confidence: 99%

Section: Differential Response Of Hela and A549 Cells To Piperlongumimentioning

confidence: 99%

Using Sensors and Generators of H₂O₂to Elucidate the Toxicity Mechanism of Piperlongumine and Phenethyl Isothiocyanate

Huang

Langford

Sikes

2016

Antioxidants & Redox Signaling

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“…b-Phenylethyl isothiocyanate (PEITC), a natural compound found in cruciferous vegetables, depletes GSH and selectively kills cancer cells while sparing healthy cells (14)(15)(16)(17). Given the fact that stimulation of ROS is generated by gemcitabine in PDAC cells, we hypothesized that the cells increase cellular GSH to prevent oxidative damage and that PEITC enhances the effect of gemcitabine-induced ROS through the redox modulation.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation

Gocho

Aguilar

et al. 2015

Molecular Cancer Therapeutics

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118

111

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Pancreatic ductal adenocarcinoma (PDAC) frequently develops therapeutic resistances, which can be divided into extrinsic and intrinsic resistance. The extrinsic resistance that arises from the surrounding dense tumor stroma is much better understood. However, the mechanisms of intrinsic resistance are not well understood. Here, we report that reactive oxygen species (ROS) induced by gemcitabine treatment, a newly discovered cytotoxic activity, served as a probe in our study to reveal the mechanisms of the intrinsic therapeutic resistance. Our results showed that gemcitabine-induced ROS is generated by NOX and through the increase of p22 -phox expression via NF-kB activation. As a feedback mechanism, nuclear translocation of Nrf2 stimulated the transcription of cytoprotective antioxidant genes, especially genes encoding enzymes that catalyze glutathione (GSH) production to reduce elevated ROS as an intrinsic resistance countermeasure. RNAi-mediated depletion of Nrf2 or addition of b-phenylethyl isothiocyanate inhibited the ROS detoxification process by reducing GSH levels, which, in turn, increased the efficacy of gemcitabine in vitro and in vivo. Thus, our study suggests that a redoxmediated pathway contributes to the intrinsic resistance of PDAC to gemcitabine and provides a basis for developing strategies to preferentially kill PDAC cells through ROS-mediated mechanism. The combination of gemcitabine and PEITC has a selective cytotoxic effect against pancreatic cancer cells in vivo and could thus prove valuable as a cancer treatment. Mol Cancer Ther; 14(3); 788-98.Ó2014 AACR.

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“…Indeed, there are data supporting the beneficial effects of targeting selected TME parameters, including tumor hypoxia (22,52,54,71), acidosis (4,35,36,60,61,68) (see Fig. 4), redox (10,57), and GSH content (11,44,56). A combination therapy aimed to normalize several of these interrelated TME parameters may provide further therapeutic advantages.…”

Section: Resultsmentioning

confidence: 98%

Janus-Faced Tumor Microenvironment and Redox

Khramtsov

Gillies

2014

Antioxidants & Redox Signaling

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Significance: Tumor microenvironment (TME) is a complex term that includes extracellular matrix, blood vessels, endothelial, stromal, and inflammatory cells, and other supporting structures of the particular organ; and physiological components such as oxygen, pH, nutrients, waste products, signaling molecules, reducing/oxidizing species, growth factors, protumorigenic factors, etc. TME is now widely recognized as a major contributor to cancer aggression and treatment resistance and as a potential target for therapeutic intervention. Recent Advances: Among important physiological parameters of the TME, tissue hypoxia is considered to be a consequence of imbalanced angiogenesis and is associated with changes in metabolic pathways, including a higher dependence on glycolysis resulting in tissue acidosis. Both hypoxia and acidosis affect the tissue redox status and its key intracellular component, glutathione (GSH). Numerous publications support that these local TME conditions select for outgrowth of cells with appropriate phenotypes, which can reflect underlying genetics. Critical Issues: Here, we hypothesize that specific patterns of local TME, namely, tumor oxygenation, extracellular pH, redox, and GSH homeostasis, acting in orchestrated mechanism, can promote cancer cell survival, while at the same time being highly toxic and mutagenic for normal cells, thus contributing to the growth of cancers at the expense of the normal tissues they are invading. This review summarizes the experimental observations that support the hypothesized Janus-faced character of the redox axis. Future Directions: Normalizing the TME redox parameters may decrease the selection pressure for malignant phenotypes, therefore providing a tool for TME-targeted anticancer therapy. Antioxid. Redox Signal. 21, 723-729.

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Inhibition of Mitochondrial Respiration and Rapid Depletion of Mitochondrial Glutathione by β-Phenethyl Isothiocyanate: Mechanisms for Anti-Leukemia Activity

Cited by 71 publications

References 47 publications

Using Sensors and Generators of H₂O₂to Elucidate the Toxicity Mechanism of Piperlongumine and Phenethyl Isothiocyanate

Using Sensors and Generators of H₂O₂to Elucidate the Toxicity Mechanism of Piperlongumine and Phenethyl Isothiocyanate

Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation

Janus-Faced Tumor Microenvironment and Redox

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Inhibition of Mitochondrial Respiration and Rapid Depletion of Mitochondrial Glutathione by β-Phenethyl Isothiocyanate: Mechanisms for Anti-Leukemia Activity

Cited by 71 publications

References 47 publications

Using Sensors and Generators of H2O2to Elucidate the Toxicity Mechanism of Piperlongumine and Phenethyl Isothiocyanate

Using Sensors and Generators of H2O2to Elucidate the Toxicity Mechanism of Piperlongumine and Phenethyl Isothiocyanate

Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation

Janus-Faced Tumor Microenvironment and Redox

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Product

Resources

About

Using Sensors and Generators of H₂O₂to Elucidate the Toxicity Mechanism of Piperlongumine and Phenethyl Isothiocyanate

Using Sensors and Generators of H₂O₂to Elucidate the Toxicity Mechanism of Piperlongumine and Phenethyl Isothiocyanate