Phenethyl isothiocyanate induces DNA damage-associated G2/M arrest and subsequent apoptosis in oral cancer cells with varying p53 mutations

Yeh, Yao‐Tsung; Yeh, Hua; Su, Shih Bin; Lin, Jie; Lee, Kuo-Jui; Shyu, Huey-Wen; Chen, Zifeng; Huang, Shengyun; Su, Shu-Jem

doi:10.1016/j.freeradbiomed.2014.06.008

Cited by 57 publications

(53 citation statements)

References 53 publications

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“…Curiously, no significant difference was attained for SFN treatment at the same dose. Taken together, although results from cyclin A2 analysis (Figure 4B) did not confirm the G 2 /M cell cycle arrest results (Figure 4A), they could be related with the DNA-damaging abilities of both ITCs [56,57,58,59] and with DNA double-strand-breaks repair by homologous recombination [60,61]. In agreement, increased Cyclin A expression levels have previously been shown in HT29 monolayers treated with SFN [50].…”

Section: Resultsmentioning

confidence: 74%

Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

Pereira

Silva²,

Duarte³

et al. 2017

Nutrients

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Colorectal cancer (CRC) recurrence is often attributable to circulating tumor cells and/or cancer stem cells (CSCs) that resist to conventional therapies and foster tumor progression. Isothiocyanates (ITCs) derived from Brassicaceae vegetables have demonstrated anticancer effects in CRC, however little is known about their effect in CSCs and tumor initiation properties. Here we examined the effect of ITCs-enriched Brassicaceae extracts derived from watercress and broccoli in cell proliferation, CSC phenotype and metastasis using a previously developed three-dimensional HT29 cell model with CSC-like traits. Both extracts were phytochemically characterized and their antiproliferative effect in HT29 monolayers was explored. Next, we performed cell proliferation assays and flow cytometry analysis in HT29 spheroids treated with watercress and broccoli extracts and respective main ITCs, phenethyl isothiocyanate (PEITC) and sulforaphane (SFN). Soft agar assays and relative quantitative expression analysis of stemness markers and Wnt/β-catenin signaling players were performed to evaluate the effect of these phytochemicals in stemness and metastasis. Our results showed that both Brassicaceae extracts and ITCs exert antiproliferative effects in HT29 spheroids, arresting cell cycle at G2/M, possibly due to ITC-induced DNA damage. Colony formation and expression of LGR5 and CD133 cancer stemness markers were significantly reduced. Only watercress extract and PEITC decreased ALDH1 activity in a dose-dependent manner, as well as β-catenin expression. Our research provides new insights on CRC therapy using ITC-enriched Brassicaceae extracts, specially watercress extract, to target CSCs and circulating tumor cells by impairing cell proliferation, ALDH1-mediated chemo-resistance, anoikis evasion, self-renewal and metastatic potential.

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Section: Resultsmentioning

confidence: 74%

Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

Pereira

Silva²,

Duarte³

et al. 2017

Nutrients

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“…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). However, recent comprehensive studies involving a broader class of small molecules suggest that the depletion of GSH is often insufficient to induce death of tumor cells.…”

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%

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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“…11 Previous studies have demonstrated that PEITC killed malignant cancer cells by disabling glutathione (GSH) antioxidant system and disrupting redox-sensitive survival pathways. 10, 12 Moreover, PEITC has been registered in clinical trials for cancer prevention and treatment (ClinicalTrials.gov Identifiers: NCT00005883, NCT00691132 and NCT01790204), indicating that PEITC could hold a therapeutic promise to treat cancer patients. In our recent work, using PEITC as the lead compound, a series of small molecular analogs of PEITC were designed and synthesized in order to discover more potent ROS modulator with better anticancer capacity (data not shown).…”

mentioning

confidence: 99%

Inhibition of cancer growth in vitro and in vivo by a novel ROS-modulating agent with ability to eliminate stem-like cancer cells

Wang

Luo²,

et al. 2017

Cell Death Dis

110

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Reactive oxygen species (ROS) have a crucial role in cell signaling and cellular functions. Mounting evidences suggest that abnormal increase of ROS is often observed in cancer cells and that this biochemical feature can be exploited for selective killing of the malignant cells. A naturally occurring compound phenethyl isothiocyanate (PEITC) has been shown to have promising anticancer activity by modulating intracellular ROS. Here we report a novel synthetic analog of PEITC with superior in vitro and in vivo antitumor effects. Mechanistic study showed that LBL21 induced a rapid depletion of intracellular glutathione (GSH), leading to abnormal ROS accumulation and mitochondrial dysfunction, evident by a decrease in mitochondrial respiration and transmembrane potential. Importantly, LBL21 exhibited the ability to abrogate stem cell-like cancer side population (SP) cells in non-small cell lung cancer A549 cells associated with a downregulation of stem cell markers including OCT4, ABCG2, SOX2 and CD133. Functionally, LBL21 inhibited the ability of cancer cells to form colonies in vitro and develop tumor in vivo. The therapeutic efficacy of LBL21 was further demonstrated in mice bearing A549 lung cancer xenografts. Our study suggests that the novel ROS-modulating agent LBL21 has promising anticancer activity with an advantage of elimination of stem-like cancer cells. This compound merits further study to evaluate its potential for use in cancer treatment.

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Phenethyl isothiocyanate induces DNA damage-associated G2/M arrest and subsequent apoptosis in oral cancer cells with varying p53 mutations

Cited by 57 publications

References 53 publications

Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

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

Inhibition of cancer growth in vitro and in vivo by a novel ROS-modulating agent with ability to eliminate stem-like cancer cells

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Phenethyl isothiocyanate induces DNA damage-associated G2/M arrest and subsequent apoptosis in oral cancer cells with varying p53 mutations

Cited by 57 publications

References 53 publications

Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

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

Inhibition of cancer growth in vitro and in vivo by a novel ROS-modulating agent with ability to eliminate stem-like cancer cells

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