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Iranian Journal of Pharmaceutical... 2018The aim of this study is to investigate the antitumor activity and possible molecular mechanism of () against Ehrlich ascites carcinoma and . , ascetic fluid volume,...
The aim of this study is to investigate the antitumor activity and possible molecular mechanism of () against Ehrlich ascites carcinoma and . , ascetic fluid volume, body weight, serum malondialdehyde (MDA) level and total antioxidant capacity (TAC) were determined using Ehrlich ascites carcinoma (EAC) bearing mice. MTT assay was used. RT-PCR was used to investigate role of in apoptosis by analyzing the expression of Bax, caspase-9, and Bcl-2 genes. The effect of on caspase-9 enzyme activity was also tested. and/or Doxorubicin (Dox) treatment significantly suppressed EAC growth as compared to EAC/oil control mice. treatment showed a dose-dependent inhibition of EAC cells as indicated by MTT assay. We found that significant increase in MDA level and decrease in TAC caused by Dox treatment were significantly reduced by combination with treatment. Bax, caspase-9 genes' expression and caspase-9 enzymatic activity were significantly increased, while Bcl-2 gene expression was significantly decreased in treated mice. may act as a promising anticancer agent either alone or more effectively in combination with Dox through apoptotic cell death induction.
PubMed: 30568691
DOI: No ID Found -
Antioxidants & Redox Signaling Jun 2016Chemotherapeutics target vital functions that ensure survival of cancer cells, including their increased reliance on defense mechanisms against oxidative stress compared...
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 H2O2 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 H2O2 level. Measuring peroxiredoxin-2 (Prx-2) oxidation as evidence of increased H2O2, 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 H2O2 production, it is determined that H2O2 produced during piperlongumine treatment acts synergistically with the compound to cause enhanced cysteine oxidation and subsequent toxicity. The importance of H2O2 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.
Topics: A549 Cells; Antineoplastic Agents; Apoptosis; Biosensing Techniques; Cell Survival; Dioxolanes; Drug Screening Assays, Antitumor; Glutathione; HEK293 Cells; HeLa Cells; Humans; Hydrogen Peroxide; Inhibitory Concentration 50; Isothiocyanates; NF-E2-Related Factor 2; Oxidative Stress
PubMed: 26905788
DOI: 10.1089/ars.2015.6482 -
Pharmaceutics Jan 2021It 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...
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's exposure to the sun. Herein, we prepared a topical gel containing 0.5% / 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.
PubMed: 33467626
DOI: 10.3390/pharmaceutics13010106 -
Pharmacological Research Dec 2016Epigenetic silencing of tumor suppressor genes is a phenomenon frequently observed in multiple cancers. Ras-association domain family 1 isoform A (RASSF1A) is a...
Epigenetic silencing of tumor suppressor genes is a phenomenon frequently observed in multiple cancers. Ras-association domain family 1 isoform A (RASSF1A) is a well-characterized tumor suppressor that belongs to the Ras-association domain family. Several studies have demonstrated that hypermethylation of the RASSF1A promoter is frequently observed in lung, prostate, and breast cancers. Phenethyl isothiocyanate (PEITC), a phytochemical abundant in cruciferous vegetables, possesses chemopreventive activities; however, its potential involvement in epigenetic mechanisms remains elusive. The present study aimed to examine the role of PEITC in the epigenetic reactivation of RASSF1A and the induction of apoptosis in LNCaP cells. LNCaP cells were treated for 5days with 0.01% DMSO, 2.5 or 5μM PETIC or 2.5μM azadeoxycytidine (5-Aza) with 0.5μM trichostatin A (TSA). We evaluated the effects of these treatments on CpG demethylation using methylation-specific polymerase chain reaction (MSP) and bisulfite genomic sequencing (BGS). CpG demethylation was significantly enhanced in cells treated with 5μM PEITC and 5-Aza+TSA; therefore, the latter treatment was used as a positive control in subsequent experiments. The decrease in RASSF1A promoter methylation correlated with an increase in expression of the RASSF1A gene in a dose-dependent manner. To confirm that promoter demethylation was mediated by DNA methyltransferases (DNMTs), we analyzed the expression levels of DNMTs and histone deacetylases (HDACs) at the gene and protein levels. PEITC reduced DNMT1, 3A and 3B protein levels in a dose-dependent manner, and 5μM PEITC significantly reduced DNMT3A and 3B protein levels. HDAC1, 2, 4 and 6 protein expression was also inhibited by 5μM PEITC. The combination of 5-Aza and TSA, a DNMT inhibitor and a HDAC inhibitor, respectively, was used as a positive control as this treatment significantly inhibited both HDACs and DNMTs. The function of RASSF1A reactivation in promoting apoptosis and inducing G2/M cell cycle arrest was analyzed using flow-cytometry analysis with Annexin V and propidium iodide (PI). Growth inhibition effect on LNCaP cells were investigated by colony formation assay. In addition, we analyzed p21, caspase-3 and 7, Bax, and Cyclin B1 protein levels. Flow-cytometry analysis of cells stained with PI alone demonstrated that 5μM PEITC promotes early apoptosis and G2/M cell cycle arrest. Flow cytometry analysis of cells stained with Annexin V and PI also demonstrated an increased proportion of cells in early apoptosis in cells treated with 5μM PEITC or 5-Aza with TSA. PEITC and efficiently inhibit colony numbers and total area. In addition, 5μM PEITC significantly enhanced p21, caspase-3, 7 and Bax levels and reduced Cyclin B1 expression compared with the control group. Collectively, the results of our study suggest that PEITC induces apoptosis in LNCaP cells potentially by reactivating RASSF1A via epigenetic mechanisms.
Topics: Anticarcinogenic Agents; Apoptosis; Cell Line, Tumor; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Isothiocyanates; Male; Promoter Regions, Genetic; Prostatic Neoplasms; Tumor Suppressor Proteins
PubMed: 27818231
DOI: 10.1016/j.phrs.2016.10.021 -
Molecules (Basel, Switzerland) Nov 2018Glucosinolates (GSL) are naturally occurring β-d-thioglucosides found across the cruciferous vegetables. Core structure formation and side-chain modifications lead to... (Review)
Review
Glucosinolates (GSL) are naturally occurring β-d-thioglucosides found across the cruciferous vegetables. Core structure formation and side-chain modifications lead to the synthesis of more than 200 types of GSLs in Brassicaceae. Isothiocyanates (ITCs) are chemoprotectives produced as the hydrolyzed product of GSLs by enzyme myrosinase. Benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC) and sulforaphane ([1-isothioyanato-4-(methyl-sulfinyl) butane], SFN) are potential ITCs with efficient therapeutic properties. Beneficial role of BITC, PEITC and SFN was widely studied against various cancers such as breast, brain, blood, bone, colon, gastric, liver, lung, oral, pancreatic, prostate and so forth. Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a key transcription factor limits the tumor progression. Induction of ARE (antioxidant responsive element) and ROS (reactive oxygen species) mediated pathway by Nrf2 controls the activity of nuclear factor-kappaB (NF-κB). NF-κB has a double edged role in the immune system. NF-κB induced during inflammatory is essential for an acute immune process. Meanwhile, hyper activation of NF-κB transcription factors was witnessed in the tumor cells. Antagonistic activity of BITC, PEITC and SFN against cancer was related with the direct/indirect interaction with Nrf2 and NF-κB protein. All three ITCs able to disrupts Nrf2-Keap1 complex and translocate Nrf2 into the nucleus. BITC have the affinity to inhibit the NF-κB than SFN due to the presence of additional benzyl structure. This review will give the overview on chemo preventive of ITCs against several types of cancer cell lines. We have also discussed the molecular interaction(s) of the antagonistic effect of BITC, PEITC and SFN with Nrf2 and NF-κB to prevent cancer.
Topics: Animals; Anticarcinogenic Agents; Biomarkers; Chemoprevention; Glucosinolates; Humans; Isothiocyanates; NF-E2-Related Factor 2; NF-kappa B; Neoplasms; Reactive Oxygen Species; Signal Transduction; Vegetables
PubMed: 30445746
DOI: 10.3390/molecules23112983 -
The Journal of Medical Investigation :... 2012Bile and pancreatic juice contain a number of parameters for cancer chemoprevention. Indole-3-carbinol (I3C) and phenethyl isothiocyanate (PEITC), which are hydrolytic...
Bile and pancreatic juice contain a number of parameters for cancer chemoprevention. Indole-3-carbinol (I3C) and phenethyl isothiocyanate (PEITC), which are hydrolytic products of brassica plants, have been established to be anti-cancer agents. Here, we developed a method for the continuous and selective sampling of bile and pancreatic juice, and the effects of I3C and PEITC on bile and pancreatic excretion and γ-glutamyl transpeptidase (γ-GTP) activity in the samples were investigated. Male Fisher 344 rats (eight weeks of age) were challenged intragastrically with I3C (150 mg/kg) or PEITC (160 mg/kg) for five days. Twenty-four hours after the final administration, cannulation was undertaken into the rats' bile and pancreatic ducts, and the bile and pancreatic juice were separately collected for 48 h. In this rat model, bile was stably excreted, and the bile and pancreatic excretion of the control rats was 21.9 ± 1.4 ml/48 h and 12.8 ± 1.7 ml/48 h, respectively. Bile excretion for the first 24 h significantly increased in the I3C- or PEITC-treated rats compared with the control rats. In the case of pancreatic juice, excretion during the first 24 h significantly increased in the PEITC-treated rats. In bile, γ-GTP activity was significantly increased for the first 24 h in the I3C- and PEITC-treated rats, but no difference was observed in the pancreatic juice. Increases of bile excretion and γ-GTP activity in bile might be a factor involved in the anti-cancer effect of I3C and PEITC. Our rat model described here is a useful tool for the study of cancer chemoprevention.
Topics: Animals; Anticarcinogenic Agents; Bile; Indoles; Isothiocyanates; Male; Pancreatic Juice; Rats; Rats, Inbred F344; gamma-Glutamyltransferase
PubMed: 23037195
DOI: 10.2152/jmi.59.246 -
Biochemistry and Biophysics Reports Sep 2021The common marmoset encodes two glutathione transferase (GST) enzymes with ketosteroid double-bond isomerase activity. The most active enzyme is CjaGST A3-3 showing a...
The common marmoset encodes two glutathione transferase (GST) enzymes with ketosteroid double-bond isomerase activity. The most active enzyme is CjaGST A3-3 showing a specific activity with 5-androsten-3,17-dione (Δ-AD) of 62.1 ± 1.8 μmol min mg, and a k value of 261 ± 49 s. The second ketosteroid isomerase CjaGST A1-1 has a 30-fold lower specific activity with Δ-AD and a 37-fold lower k value. Thus, the marmoset CjaGST A3-3 would be the main contributor to the biosynthesis of the steroid hormones testosterone and progesterone, like the human ortholog HsaGST A3-3. Two residues differ in the H-site of the 91.4% sequence identical CjaGST A1-1 and CjaGST A3-3, and modeling of the structures suggests that the bulky phenyl ring of Phe111 in CjaGST A1-1 causes steric hindrance in the binding of the steroid substrate. Tributyltin acetate (IC=0.16 ± 0.004 μM) and ethacrynic acid (IC=3.3 ± 0.2 μM) were found to be potent inhibitors of CjaGST A3-3, as previously demonstrated with the human and equine orthologs.
PubMed: 34286113
DOI: 10.1016/j.bbrep.2021.101078 -
Molecules (Basel, Switzerland) Nov 2021Phenethyl isothiocyanate isolated from root oil and its derivatives were tested at different doses in a bioassay designed to evaluate repellency against individual...
Phenethyl isothiocyanate isolated from root oil and its derivatives were tested at different doses in a bioassay designed to evaluate repellency against individual nymphs. Among the tested compounds, benzyl isothiocyanate exhibited repellency against nymphs at the lowest dose of 0.00625 mg/cm, followed by phenethyl isothiocyanate (0.0125 mg/cm) and phenyl isothiocyanate (0.025 mg/cm). The behavioral responses of 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/cm, whereas pure benzyl isothiocyanate showed repellency up to 60 min post-application at 0.1 mg/cm. The present study suggests that benzyl isothiocyanate is a potential repellent for protection against nymphs, and encapsulation in yeast cells may enhance the repellency effect.
Topics: Animals; Armoracia; Behavior, Animal; Drug Carriers; Drug Compounding; Drug Synergism; Insect Repellents; Isothiocyanates; Ixodidae; Nymph; Oils, Volatile; Plant Oils; Plant Roots; Saccharomyces cerevisiae
PubMed: 34833912
DOI: 10.3390/molecules26226817 -
BMC Cancer Aug 2014The cytokine TRAIL (tumor necrotic factor-related apoptosis-inducing ligand) selectively induces apoptosis in cancer cells, but cancer stem cells (CSCs) that contribute...
BACKGROUND
The cytokine TRAIL (tumor necrotic factor-related apoptosis-inducing ligand) selectively induces apoptosis in cancer cells, but cancer stem cells (CSCs) that contribute to cancer-recurrence are frequently TRAIL-resistant. Here we examined hitherto unknown effects of the dietary anti-carcinogenic compound phenethyl isothiocyanate (PEITC) on attenuation of proliferation and tumorigenicity and on up regulation of death receptors and apoptosis in human cervical CSC.
METHODS
Cancer stem-like cells were enriched from human cervical HeLa cell line by sphere-culture method and were characterized by CSC-specific markers' analyses (flow cytometry) and Hoechst staining. Cell proliferation assays, immunoblotting, and flow cytometry were used to assess anti-proliferative as well as pro-apoptotic effects of PEITC exposure in HeLa CSCs (hCSCs). Xenotransplantation study in a non-obese diabetic, severe combined immunodeficient (NOD/SCID) mouse model, histopathology, and ELISA techniques were further utilized to validate our results in vivo.
RESULTS
PEITC attenuated proliferation of CD44(high/+)/CD24(low/-), stem-like, sphere-forming subpopulations of hCSCs in a concentration- and time-dependent manner that was comparable to the CSC antagonist salinomycin. PEITC exposure-associated up-regulation of cPARP (apoptosis-associated cleaved poly [ADP-ribose] polymerase) levels and induction of DR4 and DR5 (death receptor 4 and 5) of TRAIL signaling were observed. Xenotransplantation of hCSCs into mice resulted in greater tumorigenicity than HeLa cells, which was diminished along with serum hVEGF-A (human vascular endothelial growth factor A) levels in the PEITC-pretreated hCSC group. Lung metastasis was observed only in the hCSC-injected group that did not receive PEITC-pretreatment.
CONCLUSIONS
The anti-proliferative effects of PEITC in hCSCs may at least partially result from up regulation of DR4 and possibly DR5 of TRAIL-mediated apoptotic pathways. PEITC may offer a novel approach for improving therapeutic outcomes in cancer patients.
Topics: Animals; Anticarcinogenic Agents; Apoptosis; Cell Culture Techniques; Cell Proliferation; HeLa Cells; Humans; Isothiocyanates; Lung Neoplasms; Mice; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells; Receptors, TNF-Related Apoptosis-Inducing Ligand; Xenograft Model Antitumor Assays
PubMed: 25127663
DOI: 10.1186/1471-2407-14-591 -
Oxidative Medicine and Cellular... 2020Osteosarcoma is the most common primary malignancy of the skeleton in children and adults. The outcomes of people with osteosarcomas are unsatisfied. -Phenethyl...
-Phenethyl Isothiocyanate Induces Cell Death in Human Osteosarcoma through Altering Iron Metabolism, Disturbing the Redox Balance, and Activating the MAPK Signaling Pathway.
Osteosarcoma is the most common primary malignancy of the skeleton in children and adults. The outcomes of people with osteosarcomas are unsatisfied. -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 and . The results showed that PEITC reduced cell viability, inhibited proliferation, and caused G/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.
Topics: Animals; Cell Death; Humans; Iron; Isothiocyanates; MAP Kinase Signaling System; Male; Mice; Mice, Nude; Osteosarcoma; Reactive Oxygen Species
PubMed: 32322335
DOI: 10.1155/2020/5021983