Sulforaphane induces phase II detoxication enzymes in mouse skin and prevents mutagenesis induced by a mustard gas analog

Abel, Erika L.; Boulware, Stephen; Fields, Tammy Y.; McIvor, Elizabeth; Powell, Katherine; DiGiovanni, John; Vásquez, Karen M.; MacLeod, Michael C.

doi:10.1016/j.taap.2012.11.020

Cited by 17 publications

(9 citation statements)

References 29 publications

(56 reference statements)

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“…SFN is particularly appealing as a cancer prevention and treatment agent, as it is highly bioavailable in blood and tissues and has no known side effects (27)(28)(29)(30)(31). SFN suppresses skin cancer development and is regarded as an important potential skin cancer prevention/treatment agent (32)(33)(34)(35)(36)(37). SFN is known to suppress activity of several epigenetic regulators leading to reduced cell survival, but its impact on PRMT5/MEP50 has not been explored.…”

Section: Introductionmentioning

confidence: 99%

Sulforaphane suppresses PRMT5/MEP50 function in epidermal squamous cell carcinoma leading to reduced tumor formation

Saha¹,

Fisher²,

Adhikary³

et al. 2017

Carcinogenesis

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Protein arginine methyltransferase 5 (PRMT5) cooperates with methylosome protein 50 (MEP50) to arginine methylate histone H3 and H4 to silence gene expression, and increased PRMT5 activity is associated with enhanced cancer cell survival. We have studied the role of PRMT5 and MEP50 in epidermal squamous cell carcinoma. We show that knockdown of PRMT5 or MEP50 results in reduced H4R3me2s formation, and reduced cell proliferation, invasion, migration and tumor formation. We further show that treatment with sulforaphane (SFN), a cancer preventive agent derived from cruciferous vegetables, reduces PRMT5 and MEP50 level and H4R3me2s formation, and this is associated with reduced cell proliferation, invasion and migration. The SFN-dependent reduction in PRMT5 and MEP50 level requires proteasome activity. Moreover, SFN-mediated responses are partially reversed by forced PRMT5 or MEP50 expression. SFN treatment of tumors results in reduced MEP50 level and H4R3me2s formation, confirming that that SFN impacts this complex in vivo. These studies suggest that the PRMT5/MEP50 is required for tumor growth and that reduced expression of this complex is a part of the mechanism of SFN suppression of tumor formation.

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Section: Introductionmentioning

confidence: 99%

Sulforaphane suppresses PRMT5/MEP50 function in epidermal squamous cell carcinoma leading to reduced tumor formation

Saha¹,

Fisher²,

Adhikary³

et al. 2017

Carcinogenesis

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“…SFN can also suppress skin tumorigenesis caused by 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) in C57BL/6 mice, an effect that is potentially mediated through the regulation of Nrf2 (25). SFN also protects mouse skin from mustard gas analog 2-(chloroethyl) ethyl sulfide-induced mutagenesis through the induction of phase II detoxification enzymes (26). Moreover, these results suggest that epigenetic modification, including the inhibition of HDAC activity, may contribute to the multitargeted chemopreventive activity of SFN (27).…”

Section: Introductionmentioning

confidence: 99%

Requirement and Epigenetics Reprogramming of Nrf2 in Suppression of Tumor Promoter TPA-Induced Mouse Skin Cell Transformation by Sulforaphane

Zhang

Lee

et al. 2014

Cancer Prevention Research

126

116

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Nrf2 is a transcription factor that plays critical roles in regulating the expression of cellular defensive antioxidants and detoxification enzymes. However, the role of Nrf2 and Nrf2's epigenetics reprogramming in skin tumor transformation is unknown. In this study, we investigated the inhibitory role and epigenetics of Nrf2 on tumor transformation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse skin epidermal JB6 (JB6 Pþ) cells and the anticancer effect of sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables. After five days of treatment, SFN significantly inhibited TPA-induced JB6 cellular transformation and SFN enhanced the nuclear translocation of Nrf2 and increased the mRNA and protein levels of the Nrf2 target genes HO-1, NQO1 and UGT1A1. Knockdown of Nrf2 attenuated the induction of Nrf2, HO-1 and NQO1 by SFN, enhanced TPA-induced colony formation and dampened the inhibitory effect of SFN on TPA-induced JB6 transformation. Epigenetics investigation using bisulfite genomic sequencing showed that SFN decreased the methylation ratio of the first 15 CpGs of the Nrf2 gene promoter, which was corroborated by increased Nrf2 mRNA expression. Furthermore, SFN strongly reduced the protein expression of DNA methyltransferases (DNMT1, DNMT3a and DNMT3b). SFN also inhibited the total histone deacetylase (HDAC) activity and decreased the protein expression of HDAC1, HDAC2, HDAC3 and HDAC4. Collectively, these results suggest that the anti-cancer effect of SFN against TPAinduced neoplastic transformation of mouse skin could involve the epigenetic reprogramming of anticancer genes such as Nrf2, leading to the epigenetic reactivation of Nrf2 and the subsequent induction of downstream target genes involved in cellular protection. Cancer Prev Res; 7(3); 319-29. Ó2014 AACR.

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“…Owing to reported adverse health effects and their unsuitability for use in HVTs, 17 simulants were deemed too toxic and were excluded from further assessment (Supporting information, Table SB). These discounted simulants included sulphur‐containing compounds [2‐(chloroethyl)phenyl sulphide, tetrahydrothiophene] and phosphorous containing compounds (paraoxon, O , S ‐diethyl methylphosphonothioate), which can be highly toxic and potentially mutagenic (Abel, Boulware, Fields, et al, ; Boulware, Fields, McIvor, et al, ; Powell, Boulware, Thames, Vasquez, & MacLeod, ).…”

Section: Resultsmentioning

confidence: 99%

Chemical warfare agent simulants for human volunteer trials of emergency decontamination: A systematic review

James

Wyke

Marczylo

et al. 2017

J of Applied Toxicology

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Incidents involving the release of chemical agents can pose significant risks to public health. In such an event, emergency decontamination of affected casualties may need to be undertaken to reduce injury and possible loss of life. To ensure these methods are effective, human volunteer trials (HVTs) of decontamination protocols, using simulant contaminants, have been conducted. Simulants must be used to mimic the physicochemical properties of more harmful chemicals, while remaining non‐toxic at the dose applied. This review focuses on studies that employed chemical warfare agent simulants in decontamination contexts, to identify those simulants most suitable for use in HVTs of emergency decontamination. Twenty‐two simulants were identified, of which 17 were determined unsuitable for use in HVTs. The remaining simulants (n = 5) were further scrutinized for potential suitability according to toxicity, physicochemical properties and similarities to their equivalent toxic counterparts. Three suitable simulants, for use in HVTs were identified; methyl salicylate (simulant for sulphur mustard), diethyl malonate (simulant for soman) and malathion (simulant for VX or toxic industrial chemicals). All have been safely used in previous HVTs, and have a range of physicochemical properties that would allow useful inference to more toxic chemicals when employed in future studies of emergency decontamination systems.

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Sulforaphane induces phase II detoxication enzymes in mouse skin and prevents mutagenesis induced by a mustard gas analog

Cited by 17 publications

References 29 publications

Sulforaphane suppresses PRMT5/MEP50 function in epidermal squamous cell carcinoma leading to reduced tumor formation

Sulforaphane suppresses PRMT5/MEP50 function in epidermal squamous cell carcinoma leading to reduced tumor formation

Requirement and Epigenetics Reprogramming of Nrf2 in Suppression of Tumor Promoter TPA-Induced Mouse Skin Cell Transformation by Sulforaphane

Chemical warfare agent simulants for human volunteer trials of emergency decontamination: A systematic review

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