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Deoxynivalenol (DON) is considered to be the most harmful mycotoxin that affects the intestinal health of animals and humans. Phenethyl isothiocyanate (PEITC) in feedstuff is an anti-nutritional factor and impairs nutrient digestion and absorption in the animal intestinal. In the current study, we aimed to explore the effects of PEITC on DON-induced apoptosis, intestinal tight junction disorder, and its potential molecular mechanism in the porcine jejunum epithelial cell line (IPEC-J2). Our results indicated that PEITC treatment markedly alleviated DON-induced cytotoxicity, decreasing the apoptotic cell percentage and pro-apoptotic mRNA/protein levels, and increasing zonula occludens-1 (ZO-1), occludin and claudin-1 mRNA/protein expression. Meanwhile, PEITC treatment ameliorated DON-induced an increase of the inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) mRNA levels and intracellular reactive oxygen species (ROS) level, and a decrease of glutathione peroxidase 1 (GPx1), superoxide dismutase 2 (SOD2), catalase (CAT) and heme oxygenase 1 (HO-1) mRNA levels. Additionally, PEITC treatment significantly down-regulated autophagy-related protein 5 (ATG5), beclin-1 and microtubule-associated protein 1 light chain 3B (LC3-Ⅱ) mRNA/protein levels, decreased the number of green fluorescent protein-microtubule-associated protein 1 light-chain 3 (GFP-LC3) puncta and phosphatidylinositol 3 kinase (PI3K) protein expression, and up-regulated phospho-protein kinase B (p-Akt) and phospho-mammalian target of rapamycin (p-mTOR) protein expression against DON. However, the activation of autophagy by rapamycin, an autophagy agonist, abolished the protective effects of PEITC against DON-induced cytotoxicity, apoptosis and intestinal tight junction disorder. Collectively, PEITC could confer protection against DON-induced porcine intestinal epithelial cell injury by suppressing ROS-mediated autophagy.

Obesity is defined as excess adipose mass that causes serious health problems. Phenethyl isothiocyanate (PEITC) is a major and relatively nontoxic compound of the isothiocyanates. Although many stu...

Accumulation of cholesterol‐laden macrophage foam cells characteristic of early stage atherosclerotic lesions. Phenethyl isothiocyanate (PEITC) is a naturally occurring isothiocyanate found in cruciferous vegetables that has reported a variety of activities including antioxidant and anti‐inflammatory properties. However, the protective effect of PEITC on foam cell formation and its precise mechanism is not yet clear. Therefore, we investigated whether PEITC suppresses foam cell formation and regulates the expression of genes related to lipid accumulation, cholesterol efflux, and inflammation in THP‐1 derived‐macrophages. We exposed THP‐1 derived‐macrophages to oxidized low‐density lipoprotein (ox‐LDL) (20 μg/mL) and lipopolysaccharide (LPS) (500 ng/ml) to mimic foam cell formation. Here, PEITC downregulated the expression of lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1), cluster of differentiation 36 (CD36), scavenger receptor A1 (SR‐A1), and nuclear factor‐κB (NF‐κB), while upregulated ATP binding cassette subfamily A member 1 (ABCA1)/liver‐X‐receptor α (LXR‐α)/peroxisome proliferator‐activated receptor gamma (PPARγ) and sirtuin 1 (SIRT1) expression compared to co‐treated with ox‐LDL and LPS. Taken together, PEITC, at least in part, inhibits foam cell formation and reduces lipid accumulation in foam cells. Therefore, we suggest that PEITC may be a potential candidate for the treatment and prevention of vascular inflammation and atherosclerosis., PEITC control foam cell formation by promoting cholesterol efflux, reducing lipid accumulation, and modulating the SIRT1‐NF‐κB signaling pathway.

Cancer is a complex disease and cancer development takes 10–50 years involving epigenetics. Evidence suggests that approximately 80% of human cancers are linked to environmental factors impinging upon genetics/epigenetics. Because advanced metastasized cancers are resistant to radiotherapy/chemotherapeutic drugs, cancer prevention by relatively nontoxic chemopreventive “epigenetic modifiers” involving epigenetics/epigenomics is logical. Isothiocyanates are relatively nontoxic at low nutritional and even higher pharmacologic doses, with good oral bioavailability, potent antioxidative stress/antiinflammatory activities, possess epigenetic-modifying properties, great anticancer efficacy in many in vitro cell culture and in vivo animal models. This review summarizes the latest advances on the role of epigenetics/epigenomics by isothiocyanates in prevention of skin, colon, lung, breast, and prostate cancers. The exact molecular mechanism how isothiocyanates modify the epigenetic/epigenomic machinery is unclear. We postulate “redox” processes would play important roles. In addition, isothiocyanates sulforaphane and phenethyl isothiocyanate, possess multifaceted molecular mechanisms would be considered as “general” cancer preventive agents not unlike chemotherapeutic agents like platinum-based or taxane-based drugs. Analogous to chemotherapeutic agents, the isothiocyanates would need to be used in combination with other nontoxic chemopreventive phytochemicals or drugs such as NSAIDs, 5-α-reductase/aromatase inhibitors targeting different signaling pathways would be logical for the prevention of progression of tumors to late advanced metastatic states.

Breast cancer is the most frequently diagnosed malignancy and leading cause of cancer-related deaths among women worldwide. Tumor recurrence, or metastasis, is caused by cancer stem cells and has a dismal prognosis for breast cancer patients. Thus, targeting breast cancer stem cells (BCSCs) for eradication is a potential method to improve clinical outcomes. Phenethyl isothiocyanate (PEITC) is a novel epigenetic regulator derived from cruciferous vegetables that has marked antitumor effects. However, the exact mechanism of these antitumor effects by PEITC is unknown. As breast cancer progresses, a tumor suppressor in the breast, cadherin 1 (CDH1), is silenced by hypermethylation of the promoter region, further promoting the stem cell-like properties of cancer. Herein, the ability of PEITC to reduce BCSC-like properties by epigenetic reactivation of CDH1 was investigated by multiple analyses such as MTT, colony formation and sphere formation assays, methylation-specific PCR, western blot analysis, Co-IP and qPCR. It was revealed that PEITC inhibited colony and mammosphere formation and decreased the expression of protein markers associated with BCSC-like properties via epigenetic reactivation of CDH1. Further exploration of this mechanism revealed inhibitory effects of PEITC on DNMTs and HDACs, which play a pivotal role in demethylating the hypermethylated CDH1 promoter region. Reactivated CDH1 suppressed the Wnt/β-catenin pathway which confers BCSC-properties in breast cancer cells. These findings suggest a novel method to eradicate BCSCs from breast cancer patients.

Combination of drugs is extensively used to treat chronic inflammatory disease. Naringin (NAR), sulforaphane (SFN), and phenethyl isothiocyanate (PEITC) are nutraceuticals with promising anti-inflammatory properties. However, their clinical effectiveness gets hindered because of low aqueous solubility and poor bioavailability. In the current study, two combinations of liposome (NAR + SFN and NAR + PEITC) were prepared and studied thoroughly in different in vivo models of acute and chronic models of inflammation. The encapsulation efficiency of NAR, SFN, and PEITC in the combination liposomal formulations (CLFs) prepared with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine/cholesterol/1,2-distearoyl-sn-glycero-3-phosphoethanolamine -020CN (15:4:1 M ratio) was determined to be 79.8 ± 4.2, 46.5 ± 3.6, and 78.5 ± 3.2%, respectively. The CLFs were characterized by differential scanning calorimetry, X-ray diffraction, dynamic light scattering, and Fourier transform infrared spectroscopy. The physicochemical results showed that the preparations were monodisperse (PDI 0.062–0.248) in water with an average size from 140.5 to 165.6 nm and a zeta potential of −47.3 to −53.3 mV. Dissolution studies in vitro showed a slower release of PEITC (>90%, 6 h) in comparison to that of SFN (3 h). Here, we are the first to report the antiarthritic activity of CLF of NAR + SFN and NAR + PEITC in the Freund’s complete adjuvant (FCA)-induced arthritic model. At an intraperitoneal dose (375 + 375 μg/mL) for 3 weeks, the NAR + PEITC liposome significantly improves both % paw edema and arthritic score compared to their free drug combinations in FCA rats. Most importantly, hematological and biochemical results showed improved anemic conditions with significant changes in the SGOT, SGPT, and ALP levels. The ELISA results showed similar trends of increased cytokine (IL-10) and decreased inflammation markers (TNF-α, IL-6, IFN-γ). Histological evaluations showing reduction in cell infiltration, pannus formation, and bone and cartilage destruction further confirm and validate the antiarthritic activity of the CLF. This comprehensive study reveals the effectiveness of combination liposomes of poorly soluble anti-inflammatory molecules (NAR, SFN, PEITC) in the treatment of arthritis.

Osteosarcoma is the most common primary malignancy of the skeleton in children and adults. The outcomes of people with osteosarcomas are unsatisfied. β-Phenethyl isothiocyanate (PEITC) exhibits chemoprevention and chemotherapeutic activities against many human cancers. The molecular mechanism underlying its action on osteosarcoma is still unknown. This study was aimed at investigating the effect of PEITC on human osteosarcoma both in vitro and in vivo. The results showed that PEITC reduced cell viability, inhibited proliferation, and caused G2/M cell cycle arrest in four human osteosarcoma cell lines (MNNG/HOS, U-2 OS, MG-63, and 143B). Then, we found that PEITC altered iron metabolism related to the processes of iron import, storage, and export, which resulted in increased labile iron. Expectedly, PEITC caused oxidative stress as a consequence of GSH depletion-inducing ROS generation and lipid peroxidation. Multiple cell death modalities, including ferroptosis, apoptosis, and autophagy, were triggered in human osteosarcoma cells. Three MAPKs (ERK, p38, and JNK) were all activated after PEITC treatment; however, they presented different responses among the four human osteosarcoma cell lines. ROS generation was proved to be the major cause of PEITC-induced decreased proliferative potential, altered iron metabolism, cell death, and activated MAPKs in human osteosarcoma cells. In addition, PEITC also significantly delayed tumor growth in a xenograft osteosarcoma mouse model with a 30 mg/kg administration dose. In conclusion, this study reveals that PEITC simultaneously triggers ferroptosis, apoptosis, and autophagy in human osteosarcoma cells by inducing oxidative stress.

Phenethyl isothiocyanate (PEITC) is an isothiocyanate that largely exists in cruciferous vegetables and exhibits chemopreventive and chemotherapeutic potential against various cancers. However, it is little known about the molecular mechanisms of its antitumor action against osteosarcoma, which is the second highest cause of cancer-related death in children and adolescents. In this study, we investigated the effects of PEITC on K7M2 murine osteosarcoma both in vitro and in vivo. We found that treatment with PEITC dose-dependently inhibited the viability of K7M2 murine osteosarcoma cells with an IC50 value of 33.49 μM at 24 h. PEITC (1, 15, 30 μM) dose-dependently inhibited the cell proliferation, caused G2/M cell cycle arrest, depleted glutathione (GSH), generated reactive oxygen species (ROS), altered iron metabolism, and triggered multiple forms of cell death, namely ferroptosis, apoptosis, and autophagy in K7M2 cells. We further revealed that PEITC treatment activated MAPK signaling pathway, and ROS generation was a major cause of PEITC-induced cell death. In a syngeneic orthotopic osteosarcoma mouse model, administration of PEITC (30, 60 mg/kg every day, ig, for 24 days) significantly inhibited the tumor growth, but higher dose of PEITC (90 mg/kg every day) compromised its anti-osteosarcoma effect. Histological examination showed that multiple cell death processes were initiated, iron metabolism was altered and MAPK signaling pathway was activated in the tumor tissues. In conclusion, we demonstrate that PEITC induces ferroptosis, autophagy, and apoptosis in K7M2 osteosarcoma cells by activating the ROS-related MAPK signaling pathway. PEITC has promising anti-osteosarcoma activity. This study sheds light on the redox signaling-based chemotherapeutics for cancers.

2-Phenethyl isothiocyanate (PEITC) is a natural product found as a conjugate in cruciferous vegetables. It has been reported to have preventative properties against lung cancer and to inhibit metabolic activation of tobacco carcinogens. In this study, we evaluated the ability of PEITC to influence the metabolism of the human carcinogen 1,3-butadiene in current smokers in a phase II clinical trial with a crossover design. Urinary mercapturic acids of 1,3-butadiene were quantified at baseline and during PEITC treatment. Seventy-nine smokers were randomly assigned to one of two arms: PEITC followed by placebo or placebo followed by PEITC. During the 1-week treatment period, each subject took PEITC (10 mg in 1 mL of olive oil, 4 times per day). There was a 1-week washout period between the PEITC and placebo periods. Oral ingestion of PEITC increased urinary levels of BD-mercapturic acids (MHBMA and DHBMA) by 11.1% and 3.7%, respectively, but these increases were not statistically significant (P = 0.17 and 0.64, respectively). A much stronger effect was observed among subjects with the null genotype of both GSTM1 and GSTT1: in these individuals, PEITC increased urinary levels of MHBMA by 58.7% (P = 0.004) and 90.0% (P = 0.001), respectively, but did not have a significant effect on urinary DHBMA. These results reveal a potentially protective effect of PEITC treatment with respect to the detoxification of 1,3-butadiene in cigarette smokers, specifically in those null for GSTT1, and provide further evidence in support of stronger chemopreventive effects from consumption of dietary isothiocyanates in these individuals.

Phenethyl isothiocyanate isolated from Armoracia rusticana root oil and its derivatives were tested at different doses in a bioassay designed to evaluate repellency against individual Haemaphysalis longicornis nymphs. Among the tested compounds, benzyl isothiocyanate exhibited repellency against H. longicornis nymphs at the lowest dose of 0.00625 mg/cm2, followed by phenethyl isothiocyanate (0.0125 mg/cm2) and phenyl isothiocyanate (0.025 mg/cm2). The behavioral responses of H. longicornis nymphs exposed to benzyl isothiocyanate and phenethyl isothiocyanate indicated that the mode of action of these compounds can be mainly attributed to the vapor phase. Encapsulated benzyl isothiocyanate showed repellency up to 120 min post-application at 0.1 mg/cm2, whereas pure benzyl isothiocyanate showed repellency up to 60 min post-application at 0.1 mg/cm2. The present study suggests that benzyl isothiocyanate is a potential repellent for protection against H. longicornis nymphs, and encapsulation in yeast cells may enhance the repellency effect.

Acrylonitrile (AN) is a known animal carcinogen and suspected human carcinogen. Recently, occupational exposure to AN has considerably increased. Previously, we demonstrated that streptozotocin-induced diabetes potentiates AN-induced acute toxicity in rats and that the induced cytochrome P450 2E1 (CYP2E1) is responsible for this effect. In the present study, we examined whether induction of CYP2E1 is also the underlying mechanism for the potentiation of AN-induced acute toxicity in type 2 diabetes in db/db mice. The effect of phenethyl isothiocyanate (PEITC) in reducing potentiation was also investigated. The mice were randomly divided into the normal control, diabetic control, AN, diabetes + AN, PEITC + AN, and diabetes + PEITC + AN groups. PEITC (40 mg/kg) was orally administered to rats for 3 days, and 1 h after the last PEITC gavage, 45 mg/kg AN was intraperitoneally injected. Time to death was observed. The CYP2E1 level and enzymatic activity, cytochrome c oxidase (CCO) activity, and reactive oxygen species (ROS) levels were measured. The survival rate was decreased in AN-treated db/db mice compared with that in AN-treated wild-type mice. The hepatic CYP2E1 level and enzymatic activity remained unaltered in db/db mice. Phenethyl isothiocyanate alleviated AN-induced acute toxicity in db/db mice as evident in the increased survival rate, restored CCO activity, and decreased ROS level in both the liver and brain. The study results suggested that CYP2E1 may not be responsible for the sensitivity to AN-induced acute toxicity in db/db mice and that PEITC reduced the potentiation of AN-induced acute toxicity in db/db mice.

Diabetic nephropathy (DN) is a diabetic complication characterized by disruption of renal microvasculature, reactive oxygen species accumulation and increased inflammation, all of which contribute to renal injury. Phenethyl isothiocyanate (PEITC) is a naturally occurring isothiocyanate well known for its antioxidant and anti-inflammatory effects, yet its reno-preventive effects against DN has not been investigated. The current study looked into the in vivo reno-protective effects of PEITC in STZ-induced DN in rats. PEITC (3, 10 and 30 mg/kg) was administered orally for 8 weeks post DM establishment. PEITC treatment significantly improved kidney and liver functions, renal histopathological features, tissue fibrosis, macrophage infiltration and blood glucose levels compared to DN control. Mechanistically, PEITC treatment alleviated DN-induced renal damage via modulating glycation and oxidative stresses and inflammatory response. As such, PEITC activated glyoxalase 1 (GLO1) that induced a retraction in renal tissue expression of advanced glycation end products (AGEs) and its receptor (RAGE). PEITC activated nuclear erythroid 2-related factor 2 (Nrf2) and increased expression of its downstream targets, hemeoxygenase-1 (HO-1) and gamma glutamate–cysteine (γ-GCS). Additionally, PEITC treatment decreased the expression of Nrf2 repressor protein, keap1. The anti-inflammatory effect of PEITC was driven, at least in part, via reducing the NLRP3 inflammasome activation as indicated by down regulation of NLRP3, TXNIP, capsase-1 and IL-1β, TNF-alpha and IL-6. In conclusion; PEITC attenuated DN progression in a dose dependent manner mainly via interruption of AGE/RAGE and NLPR3/TXNIP/NrF2 crosstalk.

Background: Increasing evidence suggests that combinations of phytochemicals are more efficient than single components in the modulation of signaling pathways involved in cancer development. In this study, the impact of phenethyl isothiocyanate (PEITC), indole-3-carbinol (I3C), xanthohumol, (X), and resveratrol (RES) and their combinations on the activation and expression of Nrf2 and NF-κB in human hepatocytes and HCC cells were evaluated. Methods: THLE-2 and HepG2 cells were exposed to single phytochemicals and their combinations for 24 h. The activation of Nrf2 and NF-κB, expression of their target genes, and effect on cells survival were assessed. The tumor burden was evaluated in mice carrying xenografts. Results: All phytochemicals enhanced the activation and expression of Nrf2 and its target genes SOD and NQO1 in HepG2 cells. The increased expression of NQO1 (~90%) was associated with increased ROS generation. X + PEITC downregulated NF-κB activation reducing binding of its active subunits to DNA resulting in diminished COX-2 expression. In contrast to single phytochemicals, X + PEITC induced apoptosis. Moderate reduction of tumor burden in mice carrying xenografts following X and PEITC or their combination was observed. Conclusions: Since Nrf2 is overexpressed in HCC its reduced activation together with diminished level of NF-κB by X + PEITC may be considered as a strategy to support conventional HCC therapy.

Cancer prevention particularly related to aging can be improved by the use of phytochemicals combinations. In this study, we evaluated the effect of phenethyl isothiocyanate (PEITC), xanthohumol (XAN), indole-3-carbinol (I3C), and resveratrol (RES) and their combinations on the Nrf2 signaling pathway. Human pancreatic cancer cells MIA-Pa-Ca-2 were treated with the phytochemicals alone or their equimolar mixture for 24 h and activation of Nrf2 and expression of its target genes were evaluated. Phytochemicals alone enhanced Nrf2 activation and expression, but their combinations were more efficient. The mixture of XAN and PEITC was found to be the most potent modulator of the Nrf2 pathway. Moreover, increased levels of P-Nrf2 and P-JNK and decreased level of P-GSK-3β suggested possible activation of Nrf2 through modulation of these kinases. The combinations of XAN with PEITC and RES with PEITC increased mostly the expression of

Environmental toxicants such as heavy metals from contaminated water or soil and isothiocyanates (ITC) from dietary sources act as pro-oxidants by directly generating reactive oxygen species (ROS) or through depleting cellular antioxidants such as glutathione. Toxicants can alter drug metabolism, and it was reported that CYP2B10 and UGT1A1 are induced by phenethyl isothiocyanate (PEITC) through the constitutive androstane receptor (CAR). The possibility that nuclear factor erythroid 2-related factor 2 (NRF2), the master regulator of the antioxidant response, could coactivate CAR was investigated in neonatal hUGT1/Nrf2(−/−) mice. Neonatal mice were treated with PEITC or cadmium (Cd(2+)) by oral gavage for 2 days. Both PEITC and Cd(2+) induced UGT1A1 RNA and protein in intestinal tissues in both hUGT1/Nrf2(+/−) and hUGT1/Nrf2(−/−) neonates, indicating NRF2-independent regulation of UGT1A1. Increases in CYP2B10 RNA in intestinal tissues were observed following PEITC or Cd(2+) exposure. Activation of intestinal CAR by Cd(2+) exposure was directly assessed by nuclear fractionation and Western blot analyses at 0.5, 1, 2, and 4 hours after treatment in hUGT1 neonates and after 48 hours in hUGT1/Nrf2(+/−) and hUGT1/Nrf2(−/−) neonates. CAR localized to the nucleus independently of NRF2 48 hours after exposure. Substantial CAR localization to the nucleus occurred at the 2- and 4-hour time points, coinciding with a decrease in phosphorylation of cytoplasmic extracellular signal-regulated kinases 1 and 2 and a nuclear increase in P38/p-P38 content. This suggests that a novel oxidative stress-MAPK-CAR axis exists with phenotypic consequences. SIGNIFICANCE STATEMENT: Pro-oxidant toxicants can alter drug metabolism through activation of CAR, independent of the NRF2-KEAP1 signaling pathway. Changes in proteins associated with drug metabolism and linked to increases in intestinal maturation are mediated through an oxidative stress-MAPK-CAR axis.

Isothiocyanates (ITCs) derived from cruciferous plants reveal antibacterial activity, although detailed mechanism is not fully elucidated. Recently it has been reported that ITCs induce the stringent response in Escherichia coli strains. The aim of this work was to determine whether two isothiocyanates, sulforaphane (SFN) and phenethyl isothiocyanate (PEITC), similarly as in E. coli induce stringent response in Bacillus subtilis, model Gram(+) bacterium, and test their potency against a panel of clinical isolates belonging to Gram(+) or Gram(−) groups. Minimal inhibitory concentrations were determined as well as effect of ITCs on membranes integrity, synthesis of DNA, RNA and stringent response alarmones was assessed. SFN and PEITC are effective against B. subtilis and bacterial isolates, namely E. coli, K. pneumonia, S. aureus, S. epidermidis and E. faecalis. Interestingly, in B. subtilis and E. faecalis the inhibition of growth and nucleic acids synthesis is independent of ppGpp accumulation. In bacteria, which do not induce the stringent response in the presence of ITCs, membrane integrity disruption is observed. Thus, ITCs are effective against different pathogenic bacteria and act by at least two mechanisms depending on bacteria species.

© 2019, International Society for Cellular Oncology. Purpose: Isothiocyanates elicit anticancer effects by targeting cancer stem cells (CSCs). Here, we tested the antitumor activity of phenethyl-isothiocyanate (PEITC), either alone or in combination with trastuzumab, in HER2-positive tumor models. Methods: We assessed the in vitro anticancer activity of PEITC, alone or combined with trastuzumab, in HER2-positive BT474, SKBR3, HCC1954 and SKOV3 cancer cells by measuring their sphere forming efficiency (SFE). The expression of the human/rodent CSC biomarkers aldehyde-dehydrogenase (ALDH) and CD29High/CD24+/Sca1Low was evaluated by cytofluorimetric analysis. The expression of wild type HER2 (WTHER2), its splice variant d16HER2 and NOTCH was analysed by quantitative RT-PCR and Western blotting. The in vivo activity of PEITC and trastuzumab was evaluated in mice orthotopically implanted with MI6 tumor cells transgenic for the human d16HER2 splice isoform. Magnetic resonance imaging/spectroscopy and immunohistochemistry were used to assess morpho-functional and metabolic profiles of treated versus untreated mice. Results: We found that PEITC significantly impaired the SFE of HER2-positive human cancer cells by decreasing their ALDH-positive compartments. The anti-CSC activity of PEITC was demonstrated by a reduced expression/activation of established cancer-stemness biomarkers. Similar results were obtained with MI6 cells, where PEITC, alone or in combination with trastuzumab, significantly inhibited their SFE. We also found that PEITC hampered the in vivo growth of MI6 nodules by inducing hemorrhagic and necrotic intra-tumor areas and, in combination with trastuzumab, by significantly reducing spontaneous tumor development in d16HER2 transgenic mice. Conclusions: Our results indicate that PEITC targets HER2-positive CSCs and that its combination with trastuzumab may pave the way for a novel therapeutic strategy for HER2-positive tumors.

Chemotherapy resistance hinders the successful clinical cancer therapy, because of the low sensitivity of drugs to resistant cancer cells. In resistant cancer cells, the mutant p53 possesses anti-apoptosis capability to tolerate chemotherapeutic drugs such as doxorubicin (DOX). Phenethyl isothiocyanate (PEITC) derived from cruciferous vegetables can deplete intracellular mutant p53. In this work, the black phosphorus nanosheets-based (BPNs-based) drug delivery system integrated with PEITC can effectively decrease mutant p53 level in resistant cancer cells and realize multiple drug resistance (MDR) reversal. The intrinsic properties of BPNs could achieve synergistic photothermal/photodynamic/chemo-therapy of resistant cancer. Magnetic resonance imaging (MRI) is used to investigate the biodistribution of nanoparticles which confirmed the efficient accumulations of nanoparticles at tumor sites. In vitro and in vivo anticancer experiments demonstrate the drug resistance tumor is effectively inhibited with minimal side effects by BPNs-based drug delivery system.

Diabetes mellitus is a significant global public health issue. The diabetic state not only precipitates chronic disease but also has the potential to change the toxicity of drugs and chemicals. Acrylonitrile (AN) is a potent neurotoxin widely used in industrial products. This study used a streptozotocin (STZ)-induced diabetic rat model to examine the role of cytochrome P450 2E1 (CYP2E1) in acute AN toxicity. The protective effect of phenethyl isothiocyanate (PEITC), a phytochemical inhibitor of CYP2E1, was also investigated. A higher incidence of convulsions and loss of the righting reflex, and decreased rates of survival, as well as elevated CYP2E1 activity, were observed in diabetic rats treated with AN when compared to those in non-diabetic rats, suggesting that diabetes confers susceptibility to the acute toxicity of AN. Pretreatment with PEITC (20-80 mg/kg) followed by AN injection alleviated the acute toxicity of AN in diabetic rats as evidenced by the decreased incidence of convulsions and loss of righting reflex, and increased rates of survival. PEITC pretreatment at 40 and 80 mg/kg decreased hepatic CYP2E1 activity in AN-exposed diabetic rats. PEITC pretreatment (20 mg/kg) increased the glutathione (GSH) content and glutathione S-transferase (GST) activity and further decreased ROS levels in AN-exposed diabetic rats. Collectively, STZ-induced diabetic rats were more sensitive to AN-induced acute toxicity mainly due to CYP2E1 induction, and PEITC pretreatment significantly alleviated the acute toxicity of AN in STZ-induced diabetic rats. PEITC might be considered as a potential effective chemo-preventive agent against AN-induced acute toxicity in individuals with an underlying diabetic condition.

Benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC) are organosulfur phytochemicals rich in cruciferous vegetables. We investigated the antiobesity and antihepatosteatosis activities of BITC and PEITC and the working mechanisms involved. C57BL/6J mice were fed a low-fat diet (LFD), a high-fat diet (HFD), or a HFD supplemented with 0.5 (L) or 1 g/kg (H) BITC or PEITC for 18 weeks. Compared with the HFD group, BITC or PEITC decreased the final body weight of mice in a dose-dependent manner [39.0 ± 3.1 (HFD), 34.4 ± 3.2 (BITC-L), 32.4 ± 2.8 (BITC-H), 36.2 ± 4.4 (PEITC-L), and 32.8 ± 2.9 (PEITC-H) g, p < 0.05], relative weight of epididymal fat [5.7 ± 0.4 (HFD), 4.7 ± 0.7 (BITC-L), 3.7 ± 0.3 (BITC-H), 4.4 ± 1.0 (PEITC-L), and 3.2 ± 0.6 (PEITC-H) %, p < 0.05], hepatic triglycerides [98.4 ± 6.0 (HFD), 81.0 ± 8.9 (BITC-L), 63.5 ± 5.6 (BITC-H), 69.3 ± 5.6 (PEITC-L), and 49.4 ± 2.9 (PEITC-H) mg/g, p < 0.05], and plasma total cholesterol [140 ± 21.3 (HFD), 109 ± 5.6 (BITC-L), 101 ± 11.3 (BITC-H), 126 ± 8.3 (PEITC-L), and 91.8 ± 12.7 (PEITC-H) mg/dL, p < 0.05]. Q-PCR and immunoblotting assays revealed that BITC and PEITC suppressed the expression of liver X receptor α, sterol regulatory element-binding protein 1c, stearoyl-CoA desaturase 1, fatty acid synthase, and acetyl-CoA carboxylase in both epididymal adipose and liver tissues. After a single oral administration of 85 mg/kg BITC or PEITC, the maximum plasma concentrations ( Cmax) of BITC and PEITC were 5.8 ± 2.0 μg/mL and 4.3 ± 1.9 μg/mL, respectively. In 3T3-L1 adipocytes, BITC and PEITC dose-dependently reduced adipocyte differentiation and cell cycle was arrested in G0/G1 phase. These findings indicate that BITC and PEITC ameliorate HFD-induced obesity and fatty liver by down-regulating adipocyte differentiation and the expression of lipogenic transcription factors and enzymes.

Purpose Isothiocyanates (ITCs) are compounds derived from Brassica plants with documented anticancer activity. Molecular mechanisms of their selective activity against cancer cells are still underexplored. In this work, the impact of ITC on DNA replication and damage was compared between PC-3 prostate cancer cells and HDFa normal fibroblasts as well as PNT2 prostate epithelial cells. Methods Cells were treated with sulforaphane or phenethyl isothiocyanate. [3H]thymidine incorporation and the level of histone γH2A.X were estimated as indicators of DNA replication and double-strand breaks (DSB), respectively. Levels of HDAC3, CtIP, and p-RPA were investigated by immunoblotting. Comet assay was performed to visualize DNA damage. Results ITCs inhibited DNA replication in all tested cell lines, and this activity was independent of reactive oxygen species of mitochondrial origin. It was followed by DSB which were more pronounced in cancer than noncancerous cells. This difference was independent of HDAC activity which was decreased in both cell lines when treated with ITCs. On the other hand, it correlated with faster removal of DSB, and thus, transient activation of repair proteins in normal cells, while in PC-3 prostate cancer, cell DNA repair was significantly less effective. Conclusion DNA damage induced by ITCs is a consequence of the block in DNA replication which is observed in both, cancer and normal cells. Selective antiproliferative activity of ITCs towards cancer cells results from less efficient DNA repair in cancer cells relative to normal cells.

Bacterial conjugation is the main mechanism for the transfer of multiple antimicrobial resistance genes among pathogenic micro-organisms. This process may be controlled by compounds that inhibit bacterial conjugation. In this study, the effects of allyl isothiocyanate, l-sulforaphane, benzyl isothiocyanate, phenylethyl isothiocyanate and 4-methoxyphenyl isothiocyanate on the conjugation of broad-host-range plasmids harbouring various antimicrobial resistance genes in Escherichia coli were investigated, namely plasmids pKM101 (IncN), TP114 (IncI2), pUB307 (IncP) and the low-copy-number plasmid R7K (IncW). Benzyl isothiocyanate (32 mg/L) significantly reduced conjugal transfer of pKM101, TP114 and pUB307 to 0.3 ± 0.6%, 10.7 ± 3.3% and 6.5 ± 1.0%, respectively. l-sulforaphane (16 mg/L; transfer frequency 21.5 ± 5.1%) and 4-methoxyphenyl isothiocyanate (100 mg/L; transfer frequency 5.2 ± 2.8%) were the only compounds showing anti-conjugal specificity by actively reducing the transfer of R7K and pUB307, respectively.

Phenylethyl isothiocyanate (PEITC), a chemopreventive compound, is highly reactive due to its considerably electrophilic nature. Furthermore, it is hydrophobic and has low stability, bioavailability and bioaccessibility, restricting its use in biomedical and nutraceutical or food applications. Thus, the encapsulation of this agent has the function of overcoming these limitations, promoting its solubility in water, and stabilizing it, preserving its bioactivity. So, polymeric microparticles were developed using chitosan-olive oil-PEITC systems. For this, an optimisation process (factors: olive oil: chitosan ratio and PEITC: chitosan ratio) were implemented through a central composite design. The responses were: the particle size, zeta-potential, polydisperse index, and entrapment efficiency. The optimal formulation was further characterized by FTIR and biocompatibility in Caco-2 cells. Optimal conditions were olive oil: chitosan and PEITC: chitosan ratios of 1.46 and 0.25, respectively. These microparticles had a size of 629 nm, a zeta-potential of 32.3 mV, a polydispersity index of 0.329, and an entrapment efficiency of 98.49%. We found that the inclusion process affected the optical behaviour of the PEITC, as well as the microparticles themselves and their interaction with the medium. Furthermore, the microparticles did not show cytotoxicity within the therapeutic values of PEITC. Thus, PEITC was microencapsulated with characteristics suitable for potential biomedical, nutraceutical and food applications.

Natural isothiocyanates (ITCs) are phytochemicals abundant in cruciferous vegetables with the general structure, R–N C S. They are bioactive organosulfur compounds derived from the hydrolysis of glucosinolates by myrosinase. A significant number of isothiocyanates have been isolated from different plant sources that include broccoli, Brussels sprouts, cabbage, cauliflower, kale, mustard, wasabi, and watercress. Several ITCs have been demonstrated to possess significant pharmacological properties including: antioxidant, anti-inflammatory, anti-cancer and antimicrobial activities. Due to their chemopreventive effects on many types of cancer, ITCs have been regarded as a promising anti-cancer therapeutic agent without major toxicity concerns. However, their clinical application has been hindered by several factors including their low aqueous solubility, low bioavailability, instability as well as their hormetic effect. Moreover, the typical dietary uptake of ITCs consumed for promotion of good health may be far from their bioactive (or cytotoxic) dose necessary for cancer prevention and/or treatment. Nanotechnology is one of best options to attain enhanced efficacy and minimize hormetic effect for ITCs. Nanoformulation of ITCs leads to enhance stability of ITCs in plasma and emphasize on their chemopreventive effects. This review provides a summary of the potential bioactivities of ITCs, their mechanisms of action for the prevention and treatment of cancer, as well as the recent research progress in their nanodelivery strategies to enhance solubility, bioavailability, and anti-cancer efficacy.

Epigenetics/epigenomics has been shown to be involved in carcinogenesis. However, how the epigenome would be altered in the transgenic adenocarcinoma of the mouse prostate (TRAMP) cancer model and the effect of cancer chemopreventive phytochemical phenethyl isothiocyanate (PEITC) on the epigenome in TRAMP mice are not known. PEITC has been reported to reduce the risk of many cancers including prostate cancer (PCa). In this study, male TRAMP mice were fed a control diet or diet containing 0.05% PEITC from 8 weeks to 16 weeks. The tumor incidence was reduced in the PEITC diet (0/6) as compared with the control diet (6/7). RNA-sequencing (RNA-seq) analyses on nontumor and tumor prostatic tissues revealed several pathways like cell cycle/Cdc42 signaling, inflammation, and cancer-related signaling, were activated in prostate tissues of TRAMP mice but were reversed or attenuated in TRAMP mice fed with PEITC diet. DNA CpG methyl-seq analyses showed that global methylation patterns of prostate samples from TRAMP mice were hugely different from those of wild-type mice. Dietary PEITC partially reversed the global methylation changes during prostatic carcinogenesis. Integration of RNA-seq and DNA methyl-seq analyses identified a list of genes, including Adgrb1 and Ebf4, with an inverse regulatory relationship between their RNA expression and CpG methylation. In summary, our current study demonstrates that alteration of the global epigenome in TRAMP prostate tumor and PEITC administration suppresses PCa carcinogenesis, impacts global CpG epigenome and transcriptome, and attenuates carcinogenic pathways like cell cycle arrest and inflammation. These results may provide insights and epigenetic markers/targets for PCa prevention and treatment in human PCa patients.

The incidence of gastrointestinal diseases (cancer in particular) has increased progressively with considerable morbidity, mortality, and a high economic impact on the healthcare system. Dietary intake of natural bioactive phytochemicals showed to have cancer-preventing and therapeutic effects. This includes the cruciferous vegetable derivative phenethyl isothiocyanate (PEITC), a bioactive compound from watercress. PEITC antioxidant, anti-inflammatory and anti-cancer properties are of particular importance. This review summarizes the current knowledge on the role of PEITC as a potential natural nutraceutical or an adjuvant against oxidative/inflammatory-related disorders in the gastrointestinal tract. We also discuss the safe and recommended dose of PEITC. Besides, we establish a framework to guide the research and development of sustainable methodologies for obtaining and stabilizing this natural nutraceutical for industrial use. This is a topic that still needs more scientific development, but with the potential to lead to a viable strategy in the prevention of cancer and other associated diseases of the gastrointestinal tract.

It is currently estimated that one in every five Americans will develop skin cancer during their lifetime. Squamous cell carcinoma (SCC) is a common type of skin cancer that can develop due to the skin&rsquo, s exposure to the sun. Herein, we prepared a topical gel containing 0.5% v/w phenethyl isothiocyanate (PEITC) for the treatment of SCC. PEITC is a naturally occurring isothiocyanate that has been shown to have efficacy against various types of cancer in preclinical studies. We first incorporated PEITC into a carbomer gel. A uniform formulation was prepared, and its viscosity was appropriate for topical application. We then demonstrated the release of PEITC from the gel into and through a Strat-M skin-like membrane. Finally, the effects of the PEITC-containing gel were tested against SCC and normal keratinocytes skin cells in culture, and these results were compared to those obtained for free 5-fluoruracil (5-FU), a commonly used skin-cancer drug. Our results show that a homogeneous PEITC-containing topical gel can be prepared and used to kill SCC cells. Thus, our formulation may be useful for treating SCC in the clinic.

Bacterial resistance to known antibiotics comprises a serious threat to public health. Propagation of multidrug-resistant pathogenic strains is a reason for undertaking a search for new therapeutic strategies, based on newly developed chemical compounds and the agents present in nature. Moreover, antibiotic treatment of infections caused by enterotoxin toxin-bearing strain—enterohemorrhagic Escherichia coli (EHEC) is considered hazardous and controversial due to the possibility of induction of bacteriophage-encoded toxin production by the antibiotic-mediated stress. The important source of potentially beneficial compounds are secondary plant metabolites, isothiocyanates (ITC), and phytoncides from the Brassicaceae family. We reported previously that sulforaphane and phenethyl isothiocyanate, already known for their chemopreventive and anticancer features, exhibit significant antibacterial effects against various pathogenic bacteria. The mechanism of their action is based on the induction of the stringent response and accumulation of its alarmones, the guanosine penta- and tetraphosphate. In this process, the amino acid starvation path is employed via the RelA protein, however, the precise mechanism of amino acid limitation in the presence of ITCs is yet unknown. In this work, we asked whether ITCs could act synergistically with each other to increase the antibacterial effect. A set of aliphatic ITCs, such as iberin, iberverin, alyssin, erucin, sulforaphen, erysolin, and cheirolin was tested in combination with sulforaphane against E. coli. Our experiments show that all tested ITCs exhibit strong antimicrobial effect individually, and this effect involves the stringent response caused by induction of the amino acid starvation. Interestingly, excess of specific amino acids reversed the antimicrobial effects of ITCs, where the common amino acid for all tested compounds was glycine. The synergistic action observed for iberin, iberverin, and alyssin also led to accumulation of (p)ppGpp, and the minimal inhibitory concentration necessary for the antibacterial effect was four- to eightfold lower than for individual ITCs. Moreover, the unique mode of ITC action is responsible for inhibition of prophage induction and toxin production, in addition to growth inhibition of EHEC strains. Thus, the antimicrobial effect of plant secondary metabolites by the stringent response induction could be employed in potential therapeutic strategies.

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths in the United States. It is extremely difficult to treat, and its survival rate is low. Today, the most effective treatments are still those that implement the platinum anticancer drug cisplatin (CDDP) in combination with other drugs. We previously demonstrated that the naturally occurring compound phenethyl isothiocyanate (PEITC) could be used to sensitize NSCLC cells to CDDP. Furthermore, co-encapsulation of PEITC and CDDP in liposomes enhances their toxicity toward NSCLC cells. We have optimized a liposomal-PEITC-CDDP formulation and investigated its cytotoxicity. We determined that liposomal-PEITC-CDDP is much more toxic toward human NSCLC cell lines than it is toward human normal lung cell lines. In this chapter, we describe detailed methods for preparing liposomal-PEITC-CDDP and determining its cytotoxicity.

Naturally occurring isothiocyanates (ITCs) from edible vegetables have shown potential as chemopreventive agents against several types of cancer. The aims of the present study were to study the potential of ITCs in chemoprevention and in potentiating the efficacy of cytotoxic drugs in gastric cancer treatment. The chemoprevention was studied in chemically induced mouse model of gastric cancer, namely N-methyl-N-nitrosourea (MNU) in drinking water, and in a genetically engineered mouse model of gastric cancer (the so-called INS-GAS mice). The pharmacological effects of ITCs with or without cisplatin were studied in human gastric cell lines MKN45, AGS, MKN74 and KATO-III, which were derived from either intestinal or diffused types of gastric carcinoma. The results showed that dietary phenethyl isothiocyanate (PEITC) reduced the tumor size when PEITC was given simultaneously with MNU, but neither when administrated after MNU nor in INS-GAS mice. Treatments of gastric cancer cells with ITCs resulted in a time- and concentration-dependent inhibition on cell proliferation. Pretreatment of gastric cancer cells with ITCs enhanced the inhibitory effects of cisplatin (but not 5-fluorouracil) in time- and concentration-dependent manners. Treatments of gastric cancer cells with PEITC plus cisplatin simultaneously at different concentrations of either PEITC or cisplatin exhibited neither additive nor synergetic inhibitory effect. Furthermore, PEITC depleted glutathione and induced G2/M cell cycle arrest in gastric cancer cells. In conclusion, the results of the present study showed that PEITC displayed anti-cancer effects, particularly when given before the tumor initiation, suggesting a chemopreventive effect in gastric cancer, and that pretreatment of PEITC potentiated the anti-cancer effects of cisplatin, possibly by reducing the intracellular pool of glutathione, suggesting a possible combination strategy of chemotherapy with pretreatment with PEITC.

This study concerns obesity-related atherosclerosis, hyperlipidemia, and chronic inflammation. We studied the anti-obesity and anti-atherosclerosis effects of phenethyl isothiocyanate (PEITC) and explored their underlying mechanisms. We established an animal model of high fat/cholesterol-induced obesity in C57BL/6 mice fed for 13 weeks. We divided the mice into five groups: control (CON), high fat/cholesterol (HFCD), HFCD with 3 mg/kg/day gallic acid (HFCD + G), and HFCD with PEITC (30 and 75 mg/kg/day, HFCD + P30 and P75). The body weight, total cholesterol, and triglyceride were significantly lower in the HFCD + P75 group than in the HFCD group. Hepatic lipid accumulation and atherosclerotic plaque formation in the aorta were significantly lower in both HFCD + PEITC groups than in the HFCD group, as revealed by hematoxylin and eosin (H&amp, E) staining. To elucidate the mechanism, we identified the expression of genes related to inflammation, reverse cholesterol transport, and lipid accumulation pathway in the liver. The expression levels of peroxisome proliferator activated receptor gamma (PPAR&gamma, ), liver-X-receptor &alpha, (LXR-&alpha, ), and ATP binding cassette subfamily A member 1 (ABCA1) were increased, while those of scavenger receptor A (SR-A1), cluster of differentiation 36 (CD36), and nuclear factor-kappa B (NF-&kappa, B) were decreased in the HFCD + P75 group compared with those in the HFCD group. Moreover, PEITC modulated H3K9 and H3K27 acetylation, H3K4 dimethylation, and H3K27 di-/trimethylation in the HFCD + P75 group. We, therefore, suggest that supplementation with PEITC may be a potential candidate for the treatment and prevention of atherosclerosis and obesity.

Phenethyl isothiocyanate is widely present in cruciferous vegetables with multiple biological effects. Here we reported the antiatherogenic effects and the underlying mechanisms of JC-5411 (Phenethyl isothiocyanate formulation) in vitro and in vivo. Luciferase reporter assay showed that JC-5411 increased the activity of nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant response element (ARE). JC-5411 treatment significantly increased the protein expression of Nrf2 and its downstream target gene hemeoxygenase 1 (HO-1) in liver of apolipoprotein E deficient (ApoE−/−) mice. Importantly, JC-5411 treatment significantly reduced atherosclerotic plaque area in both en face aorta and aortic sinus when compared with model group in WD induced ApoE−/− mice. JC-5411 obviously decreased proinflammatory factors’ levels in serum of ApoE−/− mice, LPS stimulated macrophages and TNFα induced endothelial cells, respectively. JC-5411 significantly decreased the levels of total cholesterol (TC) and triglyceride (TG) in both serum and liver of ApoE−/− mice and hyperlipidemic golden hamsters. Mechanism studies showed that JC-5411 exerted anti-inflammatory effect through activating Nrf2 signaling and inhibiting NF-κB and NLRP3 inflammasome pathway. JC-5411 exerted regulating lipid metabolism effect through increasing cholesterol transfer proteins (ABCA1 and LDLR) expression, regulating fatty acids synthesis related genes (p-ACC, SCD1 and FAS), and increasing fatty acids β-oxidation (CPT1A) in vivo. Furthermore, JC-5411 treatment had a favorable antioxidant effect in ApoE−/− mice by increasing the antioxidant related genes expression. Taken together, we conclude that JC-5411 as a Nrf2 activator has anti-inflammatory, rebalancing lipid metabolism, and antioxidant effects, which makes it as a potential therapeutic agent against atherosclerosis.

Cell cycle, growth, survival and metabolism are tightly regulated together and failure in cellular regulation leads to carcinogenesis. Several signaling pathways like the PI3K, WNT, MAPK and NFKb pathway exhibit aberrations in cancer and help achieve hallmark capabilities. Clinical research and in vitro studies have highlighted the role of epigenetic alterations in cancer onset and development. Altered gene expression patterns enabled by changes in DNA methylation, histone modifications and RNA processing have proven roles in cancer hallmark acquisition. The reversible nature of epigenetic processes offers robust therapeutic targets. Dietary bioactive compounds offer a vast compendium of effective therapeutic moieties. Isothiocyanates (ITCs) sourced from cruciferous vegetables demonstrate anti-proliferative, pro-apoptotic, anti-inflammatory, anti-migratory and anti-angiogenic effect against several cancers. ITCs also modulate the redox environment, modulate signaling pathways including PI3K, MAPK, WNT, and NFkB. They also modulate the epigenetic machinery by regulating the expression and activity of DNA methyltransferases, histone modifiers and miRNA. This further enhances their transcriptional modulation of key cellular regulators. In this review, we comprehensively assess the impact of ITCs such as sulforaphane, phenethyl isothiocyanate, benzyl isothiocyanate and allyl isothiocyanate on cancer and document their effect on various molecular targets. Overall, this will facilitate consolidation of the current understanding of the anti-cancer and epigenetic modulatory potential of these compounds and recognize the gaps in literature. Further, we discuss avenues of future research to develop these compounds as potential therapeutic entities.

Phenylethyl isothiocyanate (PEITC) was reported as a useful antioxidant, anti-inflammatory, and chemopreventive agent. Due to technological and stability issues, it is necessary to be able to extract PEITC from its natural matrix (watercress) through sustainable and scalable methodologies. In this article, we explored, for the first time, the extractive capacity of aqueous micellar systems (AMSs) of two non-ionic surfactants. For this, we compared the AMSs with conventional organic solvents. Furthermore, we developed and optimised a new integral PEITC production and extraction process by a multifactorial experimental design. Finally, we analysed the antioxidant capacity by the oxygen radical absorbance capacity (ORAC) and ABTS methods. As results, the AMSs were able to extract PEITC at the same level as the tested conventional solvents. In addition, we optimised by response surface methodology the integrated process (2.0% m/m, 25.0 &deg, C, pH 9.0), which was equally effective (ca. 2900 &micro, g PEITC/g watercress), regardless of the surfactant used. The optimal extracts showed greater antioxidant capacity than pure PEITC, due to other antioxidant compounds extracted in the process. In conclusion, by the present work, we developed an innovative cost-effective and low environmental impact process for obtaining PEITC extracts from watercress by-products.

Background Phenethyl isothiocyanate (PEITC) is a glucosinolate derived from cruciferous vegetables and is a cancer-chemopreventive reagent. Cancer stem cells (CSCs) have roles in cancer chemoresistance, invasion, metastasis, and recurrence. Here, we investigated whether PEITC can suppress the properties of CSCs using NCCIT cells and HCT116-derived cancer stem-like cells. Furthermore, we established a CSC xenograft prevention model using nude mice. Purpose The purpose of this study was to examine the actual cancer-preventive effects of PEITC in vitro and in a xenograft prevention model. Study Design We assessed the cancer-preventive effects of PEITC on CSCs using a novel xenograft prevention model. Methods NCCIT cells were treated with PEITC, and the expression of pluripotent markers was confirmed by reporter assays, western blotting, and qRT-PCR. In addition, to evaluate the effects of PEITC on CSC properties, sphere cells, which exhibit CSC properties, were established from the HCT116 cells. Furthermore, to examine the inhibitory effects and the underlying mechanism following daily intake of PEITC on CSCs, we performed an animal study in a mouse xenograft model and RNA-sequencing analysis. Results PEITC significantly reduced the CSC properties, including clonogenicity and the expression of pluripotent factors. Prior to CSC inoculation in vivo, the PEITC pre-treatment group showed a more effective reduction in the tumor growth rate and expression of CSC markers compared to the post-treatment groups. Furthermore, RNA-sequencing results showed that PEITC pre-treatment remarkably suppressed genes related to inflammatory and immune responses and chemokine-related signaling. Conclusion PEITC might contribute to the prevention or delay of colorectal cancer growth by inhibiting CSCs via the regulation of inflammatory chemokines, which can affect the tumor microenvironment. Thus, our study suggests that the daily intake of phytochemicals derived from vegetables or dietary supplements could have cancer-preventive effects through regulation of the host-tumor microenvironment.

The intestinal tract is a target for the deoxynivalenol (DON), which has adverse effects in animals and humans' health by affecting intestinal functions. Phenethyl isothiocyanate (PEITC) is an important degradation product of glucosinolates (GSLs), belonging to an anti-nutritional factor that affects the digestion and absorption of nutrients in the animals' intestinal. However, little attention has been paid to the interaction and its mechanism between DON and PEITC. Therefore, the purpose of this study was to assess the effects of PEITC on DON-induced cytotoxicity and inflammation, and explore the potential mechanisms in IPEC-J2 cells. Our results showed that DON exposure could decrease the cell viability and pro-inflammatory cytokine expression in IPEC-J2 cells in a dose-dependent manner. PEITC treatment at the concentrations of 1.25–5 μM had no significant effect on IPEC-J2 cells viability, but above 10 μM of PEITC treatment significantly reduced the cell viability. Interestingly, 1.25–5 μM of PEITC treatment could suppress 4 μM of DON-induced decrease in cell viability and increase in pro-inflammatory cytokine expression. Meanwhile, the protein ratios of p-p65/p-65 and p-IκBα/IκBα were markedly decreased in the groups treated with 1.25–5 μM PEITC compared to DON exposure alone. However, the protective effects of PEITC treatment were significantly blocked after pre-treatment with LPS, NF-κB activator, in IPEC-J2 cells. In conclusion, these findings indicated that the nontoxic dose of PEITC could alleviate DON-induced cytotoxicity and inflammation responses via suppressing the NF-κB signaling pathway in IPEC-J2 cells. Our results provide a new theoretical basis for the rational addition of rapeseed meal in animal feedstuff.

Allyl isothiocyanate (AITC) induces stomatal closure accompanied by reactive oxygen species (ROS) production and glutathione (GSH) depletion in Arabidopsis thaliana. In this study, stomatal responses to three other isothiocyanates (ITCs), benzyl isothiocyanate (BITC), sulforaphane (SFN), and phenethyl isothiocyanate (PEITC), were investigated in A. thaliana. All these ITCs significantly induced stomatal closure, where PEITC and BITC were most effective. The selected ITCs also induced ROS accumulation, cytosolic alkalization, and GSH depletion in guard cells. Moreover, all ITCs increased the frequency of cytosolic free calcium ([Ca2+]cyt) spikes (transient elevation), while PEITC and BITC showed the highest frequency. There was a strong positive correlation between the number of [Ca2+]cyt spikes per guard cell and the decrease in stomatal aperture. Both cytosolic alkalization and GSH content have a positive correlation with the decrease in stomatal aperture, but ROS production did not have a significant correlation with the decrease in stomatal apertures. These results indicate that the molecules with a functional ITC group induce stomatal closure that is accompanied by GSH depletion, cytosolic alkalization, [Ca2+]cyt spikes, and ROS production, and that the former three cellular events, rather than ROS production, are highly correlated with the decrease in stomatal aperture.

Background:The effect of cruciferous vegetable intake on breast cancer survival is controversial at present. Glucosinolates are the naturally occurring constituents found across the cruciferous vegetables. Isothiocyanates are produced from the hydrolysis of glucosinolates and this reaction is catalysed by the plant-derived enzyme myrosinase. The main isothiocyanates (ITCs) from cruciferous vegetables are sulforaphane, benzyl ITC, and phenethyl ITC, which had been intensively investigated over the last decade for their antibreast cancer effects.Objective:The aim of this article is to systematically review the evidence from all types of studies, which examined the protective effect of cruciferous vegetables and/or their isothiocyanate constituents on breast cancer.Methods:A systematic review was conducted in Pubmed, EMBASE, and the Cochrane Library from inception to 27 April 2020. Peerreviewed studies of all types (in vitro studies, animal studies, and human studies) were selected.Results:The systematic literature search identified 16 human studies, 4 animal studies, and 65 in vitro studies. The effect of cruciferous vegetables and/or their ITCs intake on breast cancer survival was found to be controversial and varied greatly across human studies. Most of these trials were observational studies conducted in specific regions, mainly in the US and China. Substantial evidence from in vitro and animal studies was obtained, which strongly supported the protective effect of sulforaphane and other ITCs against breast cancer. Evidence from in vitro studies showed that sulforaphane and other ITCs reduced cancer cell viability and proliferation via multiple mechanisms and pathways. Isothiocyanates inhibited cell cycle, angiogenesis and epithelial mesenchymal transition, as well as induced apoptosis and altered the expression of phase II carcinogen detoxifying enzymes. These are the essential pathways that promote the growth and metastasis of breast cancer. Noticeably, benzyl ITC showed a significant inhibitory effect on breast cancer stem cells, a new dimension of chemo-resistance in breast cancer treatment. Sulforaphane and other ITCs displayed anti-breast cancer effects at variable range of concentrations and benzyl isothiocyanate appeared to have a relatively lower inhibitory concentration IC50. The mechanisms underlying the cancer protective effect of sulforaphane and other ITCs have also been highlighted in this article.Conclusion:Current preclinical evidence strongly supports the role of sulforaphane and other ITCs as potential therapeutic agents for breast cancer, either as adjunct therapy or combined therapy with current anti-breast cancer drugs, with sulforaphane appeared to display the greatest potential.

Resistance to chemotherapy and radiation therapy is considered a major therapeutic barrier in breast cancer. Cancer stem cells (CSCs) play a prominent role in chemo and radiotherapy resistance. The established chemo and radio-resistant triple-negative breast cancer (TNBC) cell line MDA-MB-231/IR displays greater CSC characteristics than the parental MDA-MB-231 cells. Escalating evidence demonstrates that metadherin (MTDH) is associated with a number of cancer signaling pathways as well as breast cancer therapy resistance, making it an attractive therapeutic target. Kaplan&ndash, Meier plot analysis revealed a correlation between higher levels of MTDH and shorter lifetimes in breast cancer and TNBC patients. Moreover, there was a positive correlation between the MTDH and CD44 expression levels in The Cancer Genome Atlas breast cancer database. We demonstrate that MTDH plays a pivotal role in the regulation of stemness in MDA-MB-231/IR cells. Knockdown of MTDH in MDA-MB-231/IR cells resulted in a reduction in the CSC population, aldehyde dehydrogenase activity, and major CSC markers, including &beta, catenin, CD44+, and Slug. In addition, MTDH knockdown increased reactive oxygen species (ROS) levels in MDA-MB-231/IR cells. We found that phenethyl isothiocyanate (PEITC), a well-known pro-oxidant phytochemical, suppressed stemness in MDA-MB-231/IR cells through ROS modulation via the downregulation of MTDH. Co-treatment of PEITC and N-Acetylcysteine (a ROS scavenger) caused alterations in PEITC induced cell death and CSC markers. Moreover, PEITC regulated MTDH expression at the post-transcriptional level, which was confirmed using cycloheximide, a protein synthesis inhibitor.

Bladder cancer (BC) is a representative of urological cancer with a high recurrence and metastasis potential. Currently, cisplatin-based chemotherapy and immune checkpoint inhibitors are used as standard therapy in patients with advanced/metastatic BC. However, these therapies often show severe adverse events, and prolongation of survival is unsatisfactory. Therefore, a treatment strategy using natural compounds is of great interest. In this review, we focused on the anti-cancer effects of isothiocyanates (ITCs) derived from cruciferous vegetables, which are widely cultivated and consumed in many regions worldwide. Specifically, we discuss the anti-cancer effects of four ITC compounds—allyl isothiocyanate, benzyl isothiocyanate, sulforaphane, and phenethyl isothiocyanate—in BC; the molecular mechanisms underlying their anti-cancer effects; current trends and future direction of ITC-based treatment strategies; and the carcinogenic potential of ITCs. We also discuss the advantages and limitations of each ITC in BC treatment, furthering the consideration of ITCs in treatment strategies and for improving the prognosis of patients with BC.

The oxidative stress response (OSR) in yeast is under the control of oxidation-sensitive cysteines in the Yap1p transcription factor, and fusion of the Yap1p-dependent OS-induced promoter of the YKL071w gene (OSI1) to a luciferase coding sequence makes a sensitive reporter for OS induced by electrophiles. In mammalian cells, the OSR induced by electrophiles is coordinated in a mechanistically similar way via oxidation-sensitive cysteines in the kelch-like ECH-associated protein 1 (Keap1)&ndash, nuclear factor erythroid 2-related factor 2 / antioxidant response element ( Nrf2/ARE) system. Many electrophilic oxidants have already been independently shown to trigger both the Yap1 and Keap1 systems. Here, we investigated the responses of Yap1 and Keap1 reporters to sulforaphane (SFN), allyl isothiocyanate (AITC), phenylethyl isothiocyanate (PEITC), previously known to stimulate Keap1&ndash, Nrf2/ARE but not known to activate Yap1, and as a positive control, allicin, previously reported to stimulate both Yap1 and Nrf2. We have compared the reciprocal responsiveness of the respective reporter systems and show that the yeast reporter system can have predictive value for electrophiles that stimulate the mammalian Keap1&ndash, Nrf2/ARE system.

Isothiocyanates are derived from their naturally-occurring glucosinolate precursors, which are abundant in cruciferous vegetables. Numerous scientific studies beginning more than half a century ago have documented the chemoprotective activities of these compounds. Isothiocyanates have numerous protein targets through which they exert protection in the context of various diseases such as cancer, neurodegeneration, inflammatory disease, metabolic disease and infection. The major mechanisms by which the isothiocyanates confer protection involve induction of stress response pathways that restore the cellular redox and protein homeostasis, and contribute to resolution of inflammation. However, high concentrations of isothiocyanates cause cell cycle arrest and selectively kill cancer cells by inducing apoptosis, autophagy or necrosis. In this review, we present readers with a detailed overview of isothiocyanates functions and discuss their molecular targets and antineoplastic effects. Furthermore, we provide an up-to-date summary of the evidence on the chemoprotective activities of the most widely-studied isothiocyanates: sulforaphane, phenethyl isothiocyanate (PEITC) and benzyl isothiocyanate (BITC).

Background/aim Transcriptomic analysis was performed to evaluate the differential gene expression profiles of Setd7 knockdown (KD) and the effects of phenethyl isothiocyanate (PEITC) in human prostate cancer (PCa) LNCaP cells. Materials and methods RNA isolated from wild-type and Setd7-KD LNCaP cells in the presence or absence of PEITC was subjected to microarray analysis followed by Ingenuity® Pathway Analysis (IPA). Results Setd7 KD impacted a larger set of genes and caused a higher fold change compared to PEITC treatment. Several signaling pathways were altered particularly inflammation-related TNFR signaling and PTEN/PI3K/AKT signaling by Setd7 KD and PEITC. Interestingly, PEITC and Setd7 KD at a small subset of genes that could be potential molecular targets. Conclusion This study offers new insights into the mechanisms of action of the epigenetic modifier Setd7 and the effects of PEITC treatment in PCa cells and enhances our understanding of the potential cancer preventive/treatment effects of isothiocyanate compounds such as PEITC in PCa.

The aim of this study is to confirm the toxic effect of phenylethyl isothiocyanate (PEITC) on porcine kidney cells (PK-15) and explore the effect of oxidative damage mediated by reactive oxygen species (ROS) induced by PEITC in PK-15 cells. Porcine kidney cell line (PK-15) was treated with PEITC (2, 5, and 10 µM) for 24 hours, and the oxidative damage mediated by PEITC through ROS was investigated. The survival rate of PK-15 cells decreased in a dose-dependent manner after the treatment of PEITC in a dose-dependent manner. A high concentration of PEITC (10 µM) can change cell morphology, increase the content of malondialdehyde, ROS, and lactate dehydrogenase, and decrease the activity of SOD, CAT, GSH-PX, and GSH. PEITC has a toxic effect on PK-15 cells by inducing oxidative stress in PK-15 cells through the generation of ROS.

Cancer stem cells (CSCs) are considered to play essential roles in the process of origination, proliferation, migration, and invasion of cancer, and their properties are regulated by Wnt/β-catenin pathway. Phenethyl isothiocyanate (PEITC) is a natural product obtained from cruciferous vegetables with anticancer activities. The present study aimed to investigate the inhibitory effect and the underlying mechanisms of PEITC on colorectal CSCs. In this study, we found that PEITC can significantly reduce the size and number of colorectal cancer cell spheroids in serum-free medium. With increasing PEITC concentrations (10-40 μM), the number of spheroids was reduced to about 10% of the control group, and the percentage of CD133+ cells was decreased by about 3-16 folds. PEITC also decreased the expression of CSC markers. Meanwhile, inhibition of proliferation as well as induction of apoptosis of colorectal CSCs was observed after PEITC treatment. Furthermore, through activating Wnt/β-catenin pathway with LiCl, the inhibitory effects of PEITC on colorectal CSCs were diminished. Our data suggested that PEITC can be an effective inhibitor of colorectal CSCs by targeting Wnt/β-catenin pathway.