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Shivendra V. Singh - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of Glycolysis in Prostate Cancer Chemoprevention by Phenethyl Isothiocyanate
Cancer prevention research (Philadelphia Pa.), 2018Co-Authors: Krishna B. Singh, Eun-ryeong Hahm, Lora H. Rigatti, Daniel P. Normolle, Jian-min Yuan, Shivendra V. SinghAbstract:We have shown previously that dietary administration of Phenethyl Isothiocyanate (PEITC), a small molecule from edible cruciferous vegetables, significantly decreases the incidence of poorly differentiated prostate cancer in Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice without any side effects. In this study, we investigated the role of c-Myc-regulated glycolysis in prostate cancer chemoprevention by PEITC. Exposure of LNCaP (androgen-responsive) and 22Rv1 (castration-resistant) human prostate cancer cells to PEITC resulted in suppression of expression as well as transcriptional activity of c-Myc. Prostate cancer cell growth inhibition by PEITC was significantly attenuated by stable overexpression of c-Myc. Analysis of the RNA-Seq data from The Cancer Genome Atlas indicated a significant positive association between Myc expression and gene expression of many glycolysis-related genes, including hexokinase II and lactate dehydrogenase A Expression of these enzyme proteins and lactate levels were decreased upon PEITC treatment in prostate cancer cells, and these effects were significantly attenuated by ectopic expression of c-Myc. A normal prostate stromal cell line (PrSC) was resistant to lactic acid suppression by PEITC treatment. Prostate cancer chemoprevention by PEITC in TRAMP mice was associated with a significant decrease in plasma lactate and pyruvate levels. However, a 1-week intervention with 10 mg PEITC (orally, 4 times/day) was not sufficient to decrease lactate levels in the serum of human subjects. These results indicated that although prostate cancer prevention by PEITC in TRAMP mice was associated with suppression of glycolysis, longer than 1-week intervention might be necessary to observe such an effect in human subjects. Cancer Prev Res; 11(6); 337-46. ©2018 AACR.
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Irreversible Inhibition of Glutathione S-Transferase by Phenethyl Isothiocyanate (PEITC), a Dietary Cancer Chemopreventive Phytochemical.
PloS one, 2016Co-Authors: Vandana Kumari, Marzena A. Dyba, Ryan J. Holland, Yu-he Liang, Shivendra V. SinghAbstract:Dietary Isothiocyanates abundant as glucosinolate precursors in many edible cruciferous vegetables are effective for prevention of cancer in chemically-induced and transgenic rodent models. Some of these agents, including Phenethyl Isothiocyanate (PEITC), have already advanced to clinical investigations. The primary route of Isothiocyanate metabolism is its conjugation with glutathione (GSH), a reaction catalyzed by glutathione S-transferase (GST). The pi class GST of subunit type 1 (hGSTP1) is much more effective than the alpha class GST of subunit type 1 (hGSTA1) in catalyzing the conjugation. Here, we report the crystal structures of hGSTP1 and hGSTA1 each in complex with the GSH adduct of PEITC. We find that PEITC also covalently modifies the cysteine side chains of GST, which irreversibly inhibits enzymatic activity.
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Phenethyl Isothiocyanate suppresses inhibitor of apoptosis family protein expression in prostate cancer cells in culture and in vivo.
The Prostate, 2011Co-Authors: Kozue Sakao, Sudhakar Desineni, Eun-ryeong Hahm, Shivendra V. SinghAbstract:BACKGROUND Cruciferous vegetable constituent Phenethyl Isothiocyanate (PEITC) causes apoptosis in prostate cancer cells through mechanisms not fully understood. The present study was designed to determine the role of inhibitor of apoptosis (IAP) family proteins in PEITC-induced apoptosis induction.
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Slow but Steady Progress in Cancer Chemoprevention with Phenethyl Isothiocyanate: Fulfilled Promises and Translational Challenges
Nutraceuticals and Cancer, 2011Co-Authors: Anna A. Powolny, Ajay Bommareddy, Shivendra V. SinghAbstract:Population-based observational studies continue to support the premise that intake of certain fruits and vegetables may lower the risk of cancer, and this association is quite persuasive for the cruciferous vegetables. Inverse association between cruciferous vegetable intake and the risk of cancer has been noted for different types of malignancies, including stomach, prostate, lung, breast, colon, and bladder cancers. Epidemiological observations in “FOLKS” have undoubtedly sparked interest among cancer biologists to conduct “FLASK”-based bench investigations to identify bioactive anticancer compounds from cruciferous vegetables as well as to determine their efficacy through “FUR”-based preclinical research in rodents. Cancer protective effect of cruciferous vegetables is partly attributed to organic Isothiocyanates (ITC) with an –N = C = S functional group. Elucidation of the mechanism by which ITCs impart protection against cancer has been the topic of intense research in the past few decades. This article reviews bench-cage-bedside evidence supporting cancer chemopreventive potential of one such ITC compound, Phenethyl Isothiocyanate (PEITC). Future directions and challenges in clinical translation for PEITC are also highlighted.
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Differential Response of Normal (PrEC) and Cancerous Human Prostate Cells (PC-3) to Phenethyl Isothiocyanate-Mediated Changes in Expression of Antioxidant Defense Genes
Pharmaceutical research, 2010Co-Authors: Anna A. Powolny, Shivendra V. SinghAbstract:Purpose The present study was undertaken to test a hypothesis that differential sensitivity of normal and cancerous human prostate cells to prooxidant effect of Phenethyl Isothiocyanate (PEITC) is determined by altered expression of antioxidant defense genes.
J. W. Chiao - One of the best experts on this subject based on the ideXlab platform.
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Repression of androgen receptor in prostate cancer cells by Phenethyl Isothiocyanate
2015Co-Authors: L. G. Wang, X. M. Liu, J. W. ChiaoAbstract:Background: Prostate cancer usually progresses to andro-gen refractory after an initial anti-androgen treatment. The androgen receptor (AR) is a pivotal factor for the androgen-mediated growth and maintenance of the prostate. Abnormality of the AR, such as overexpression has been postulated to be related to the hormone independent growth of the cancer. Although we previously demonstrated that the AR expression could be modu-lated by Isothiocyanates, which are natural constituents of cruciferous vegetables, the mechanism, however, remained to be clarified. We have since investigated the mechanism of Phenethyl Isothiocyanate (PEITC) in AR regulation. Methods: A human androgen dependent prostate cancer cell line LNCaP (AD) and its sub-line LNCaP (AI), i.e. androgen independent but overexpress
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Mitochondrial structure alteration in human prostate cancer cells upon initial interaction with a chemopreventive agent Phenethyl Isothiocyanate
Cancer cell international, 2014Co-Authors: Chengsen Xue, Ha Pasolli, Irene Piscopo, Daniel J Gros, Christina Liu, Yamei Chen, J. W. ChiaoAbstract:Background Phenethyl Isothiocyanate (PEITC), present naturally in cruciferous vegetables, is a chemopreventive agent. It blocks initiation and post-initiation progression of carcinogenesis. Mechanism study in human prostate cancer cells revealed that PEITC is a dual inhibitor of aberrant DNA hypermethylation and histone deacetylases, reactivating silenced genes and regulating the androgen-mediated growth of tumor cells. The identity of the cellular organelle that initially interacts with PEITC has not been fully described.
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Phenethyl Isothiocyanate and paclitaxel synergistically enhanced apoptosis and alpha-tubulin hyperacetylation in breast cancer cells
Experimental hematology & oncology, 2014Co-Authors: Shundong Cang, J. W. Chiao, Delong LiuAbstract:Combination of Phenethyl Isothiocyanate (PEITC) and paclitaxel (taxol) has been shown to work synergistically to increase apoptosis and cell cycle arrest in breast cancer cells. In this report, we further explored the mechanisms for the synergistic activity of PEITC and taxol in MCF7 and MDA-MB-231 (MB) breast cancer cell lines. By Western blotting analysis, treatment of MCF7 cells with both PEITC and taxol led to a 10.4-fold and 5.96-fold increase in specific acetylation of alpha-tubulin over single agent PEITC and taxol, respectively. This synergistic effect on acetylation of alpha-tubulin was also seen in MB cells. The combination of PEITC and taxol also reduced expressions of cell cycle regulator Cdk1, and anti-apoptotic protein bcl-2, enhanced expression of Bax and cleavage of PARP proteins. In conclusion, this study provided biochemical evidence for the mechanism of synergistic effect between the epigenetic agent PEITC and the chemotherapeutic agent taxol.
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Synergistic effect of paclitaxel and epigenetic agent Phenethyl Isothiocyanate on growth inhibition, cell cycle arrest and apoptosis in breast cancer cells
Cancer cell international, 2013Co-Authors: Katherine Liu, Shundong Cang, J. W. ChiaoAbstract:This study examined whether combining paclitaxel (taxol) with a novel epigenetic agent Phenethyl Isothiocyanate (PEITC) will yield a synergistic effect on inhibiting breast cancer cells. Two drug-resistant breast cancer cell lines, MCF7 and MDA-MB-231, were treated with PEITC and taxol. Cell growth, cell cycle, and apoptosis were examined. The combination of PEITC and taxol significantly decreased the IC50 of PEITC and taxol over each agent alone. The combination also increased apoptosis by more than two fold over each single agent in both cell lines. A significant increase of cells in the G2/M phases was detected. In conclusion, the combination of PEITC and taxol exhibits a synergistic effect on growth inhibition in breast cancer cells. This combination deserves further study in vivo.
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prostate cancer chemopreventive activity of Phenethyl Isothiocyanate through epigenetic regulation review
International Journal of Oncology, 2010Co-Authors: L. G. Wang, J. W. ChiaoAbstract:Prostate cancer is one of the most commonly diagnosed cancers in men. The number of affected men is expected to rapidly increase as the population of males over the age of 50 grows worldwide. For patients who are not cured by local treatment and experience metastatic disease, neither androgen ablation nor chemotherapy can abrogate progression and death from androgen-independent/hormone-refractory disease. Therefore, finding strategies for the prevention of prostate cancer initiation and disease progression is a medical challenge. Consumption of cruciferous vegetables has been reported to be associated with reduced incidence of prostate cancer cases. The Isothiocyanates, including Phenethyl Isothiocyanate (PEITC), from cruciferous vegetables have been demonstrated as active components responsible for chemoprevention. In this review, we summarize the recent findings of PEITC on prostate cancer prevention with an emphasis on epigenetic mechanisms. Studies have indicated that PEITC mediates gene regulation, such as downregulation of androgen receptor expression and induction of endogenous cyclin-dependent kinase inhibitors, p21 and p27. The gene for detoxifying enzyme pi-class glutathione S-transferase (GSTP1), silenced in the vast majority of prostate tumor cells, could be reactivated and the enzymatic function recovered. This may be through epigenetic mechanisms as PEITC is a dual inhibitor of histone deacetylases and aberrant CpG island methylation of various genes. The epigenetic regulation may play a critical role, along with interactive mechanisms including the disruption of microtubule polymerization, in prostate cancer prevention by PEITC. These mechanisms target and correct the aberrations fundamental to the initiation and progression of carcinogenesis in cells, and restoring the cells to a more normal state. Inhibiting and eliminating cancer cells forms the basis of cancer prevention.
Ah-ng Tony Kong - One of the best experts on this subject based on the ideXlab platform.
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Transcriptomic Analysis of Histone Methyltransferase Setd7 Knockdown and Phenethyl Isothiocyanate in Human Prostate Cancer Cells.
Anticancer research, 2018Co-Authors: Chao Wang, Davit Sargsyan, Chengyue Zhang, Yuqing Yang, Ah-ng Tony KongAbstract: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.
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Phenethyl Isothiocyanate peitc suppresses prostate cancer cell invasion epigenetically through regulating microrna 194
Molecular Nutrition & Food Research, 2016Co-Authors: Chengyue Zhang, Tin Oo Khor, Limin Shu, Hyuck Kim, Ah-ng Tony KongAbstract:Scope Tumor metastasis greatly contributes to the mortality of prostate cancer. The glucosinolate-derived Phenethyl Isothiocyanate (PEITC) has been widely documented to reduce the risk of prostate cancer by modulating multiple biologically relevant processes. Emerging evidence suggests that PEITC may exert its anti-cancer effects through epigenetic mechanisms including microRNAs. Altered levels of miRNA have been linked to tumor malignancy due to their capacity to regulate functional gene expression in carcinogenesis. Here, we assessed the effects of PEITC on miRNA expression which is related to PCa cell invasiveness. Methods and results Utilizing oligonucleotide microarray first identified the most affected miRNAs in LNCaP cells after PEITC treatment. Several top altered miRNAs were further validated using quantitative PCR. Interestingly, overexpression of miR-194 suppressed PC3 cell invasion in matrigel-coated Transwell chambers. Bone morphogenetic protein 1 (BMP1) was shown to be a direct target of miR-194. Downregulation of BMP1 by miR-194 or PEITC led to decreased expression of key oncogenic matrix metalloproteinases, MMP2 and MMP9. This in turn resulted in the suppression of tumor invasion. Conclusion Our results indicate that miR-194 downregulates the expression of oncogenic MMP2 and MMP9 by targeting BMP1, which suggests a potential new mechanistic target by which PEITC suppresses prostate cancer cell invasiveness.
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Molecular Targets of Dietary Phenethyl Isothiocyanate and Sulforaphane for Cancer Chemoprevention
The AAPS journal, 2009Co-Authors: Ka Lung Cheung, Ah-ng Tony KongAbstract:Development of cancer is a long-term and multistep process which comprises initiation, progression, and promotion stages of carcinogenesis. Conceivably, it can be targeted and interrupted along these different stages. In this context, many naturally occurring dietary compounds from our daily consumption of fruits and vegetables have been shown to possess cancer preventive effects. Phenethyl Isothiocyanate (PEITC) and sulforaphane (SFN) are two of the most widely investigated Isothiocyanates from the crucifers. Both have been found to be very potent chemopreventive agents in numerous animal carcinogenesis models as well as cell culture models. They exert their chemopreventive effects through regulation of diverse molecular mechanisms. In this review, we will discuss the molecular targets of PEITC and SFN potentially involved in cancer chemoprevention. These include the regulation of drug-metabolizing enzymes phase I cytochrome P450s and phase II metabolizing enzymes. In addition, the signaling pathways including Nrf2–Keap 1, anti-inflammatory NFκB, apoptosis, and cell cycle arrest as well as some receptors will also be discussed. Furthermore, we will also discuss the similarities and their potential differences in the regulation of these molecular targets by PEITC and SFN.
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Synergistic Effect of Combination of Phenethyl Isothiocyanate and Sulforaphane or Curcumin and Sulforaphane in the Inhibition of Inflammation
Pharmaceutical research, 2008Co-Authors: Ka Lung Cheung, Tin Oo Khor, Ah-ng Tony KongAbstract:Purpose Accumulating evidence from epidemiologic and clinical studies indicates that chronic inflammatory disorders harbor an increased risk of cancer development. Curcumin (CUR) has been strongly linked to the anti-inflammatory effect. On the other hand, Isothiocyanates such as sulforaphane (SFN) and Phenethyl Isothiocyanate (PEITC) are strong phase-II detoxifying/antioxidant enzymes inducer. Therefore it is interesting to see if combination of these drugs can inhibit inflammation with higher combined efficacies.
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Chemoprevention of familial adenomatous polyposis in ApcMin/+ mice by Phenethyl Isothiocyanate (PEITC)
Molecular carcinogenesis, 2008Co-Authors: Tin Oo Khor, Auemduan Prawan, William Cheung, Bandaru S. Reddy, Ah-ng Tony KongAbstract:Phenethyl Isothiocyanate (PEITC) is an Isothiocyanate which is a major constituent of watercress and other cruciferous vegetables. Its chemopreventive potential has been previously shown in various rodent models of cancer. In this study, we investigated the chemopreventive efficacy of PEITC in the ApcMin/+ mouse model. ApcMin/+ mice were fed with diet supplemented with 0.05% of PEITC for 3-wk. Our results clearly demonstrated that ApcMin/+ mice fed with PEITC supplemented diet developed significantly less (31.7% reduction) and smaller polyps in comparison to mice fed with the standard AIN-76A diet. Subsequent mechanistic study using Western blotting shows that inhibition of growth of adenomas by PEITC is associated with increase of apoptosis (cleaved-caspase-3, -caspase-7, and PARP). Treatments also led to the inhibition of cell cycle-related biomarkers such as the cyclins (D1, A, and E) and activation of p21. However, PEITC has no effect on the expression of p-Erk, p-JNK or p-p38. In conclusion, our results demonstrate that PEITC is a potent natural dietary compound for chemoprevention of gastrointestinal cancers. Its mechanism of actions may include induction of apoptosis and cell cycle arrest. © 2007 Wiley-Liss, Inc.
Fung-lung Chung - One of the best experts on this subject based on the ideXlab platform.
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A click chemistry approach to identify protein targets of cancer chemopreventive Phenethyl Isothiocyanate
RSC advances, 2014Co-Authors: Miloslav Sanda, Shana Silverstein, Monika Aggarwal, Deyun Wang, Pankaj Gupta, Radoslav Goldman, Daniel H. Appella, Fung-lung ChungAbstract:Here we report the identification of protein targets of chemopreventive Phenethyl Isothiocyanate (PEITC) via “click” chemistry in the A549 human lung cancer cell line, using a novel alkyne-tagged PEITC which was also found to show potent in vitro anticancer activity.
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Abstract 2591: Global gene expression regulated by Phenethyl Isothiocyanate in human colon cancer SW480 cells.
Prevention Research, 2013Co-Authors: Xiantao Wang, Fung-lung ChungAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Phenethyl Isothiocyanate (PEITC), a promising chemopreventive compound originated from cruciferous vegetables, is known to inhibit proliferation of colon cancer cells through inducing apoptosis and cell cycle arrest. Although exact mechanisms are unclear, it seems that PEITC may have multiple molecular targets and play multiple roles in a variety of events. Some of our recent studies indicate that a key mechanism of apoptosis induction by PEITC may be through covalent modification of its target proteins, such as tubulin. Numerous studies also reported that PEITC may induce apoptotic signals through gene transcriptional regulation. However, systematic studies on PEITC-induced gene expression profile, particularly in colon cancer cells, are rare. In this study, we examined overall gene expression profile of SW480 cells at different time points after PEITC treatment using cDNA microarray. Results showed that PEITC induced significant changes in expression of several apoptosis-related genes, such as BIM, DEDD2, GADD45B, HSPB8, SYK, PIK3C2A, CTNNB1, LGALS8, and NOXA. Furthermore, these changes were confirmed by real-time polymerase chain reaction at transcript level and immunoblot at protein level. Considering significant roles of these genes in signaling transduction leading to downstream events, such as apoptosis, the findings of this study may shed lights on the molecular mechanisms by which PEITC exert its anti-carcinogenic effects. (Supported by NCI grant CA100853) Citation Format: Lixin Mi, Xiantao Wang, Xin Li, Fung-Lung Chung. Global gene expression regulated by Phenethyl Isothiocyanate in human colon cancer SW480 cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2591. doi:10.1158/1538-7445.AM2013-2591
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abstract 4858 mutant p53 depletion a possible mechanism of inhibition of human prostate cancer by dietary Phenethyl Isothiocyanate
Cancer Research, 2013Co-Authors: Thomas T.y. Wang, Xiantao Wang, Haiqiu Huang, Arnetta Fletcher, Fung-lung ChungAbstract:Phenethyl Isothiocyanate (PEITC) derived from cruciferous vegetables has been shown to inhibit tumor growth by induction of apoptosis. Previously, we demonstrated that PEITC can selectively deplete mutant p53, but not the wild type. However, whether p53, wild type or mutant, plays functional roles in PEITC-induced growth inhibition, remains unsettled. We hypothesize that the direct binding to mutant p53 by PEITC followed by conformational changes, subsequently leading to its depletion or/and restoration to the wild type may constitute a mechanism by which PEITC induces apoptosis. To determine whether PEITC can deplete mutant p53 in vivo and whether its depletion is correlated with tumor inhibition and apoptosis, in this xenograft model study BALB-C Nu/Nu mice carrying prostate tumor cells with either mutant (DU145) or wild type p53 (LNCap) were fed diets with and without PEITC (5 micromol per gram diet) for 8 weeks. Tumors were harvested at the end of bioassay for immunohistochemistry and immunoblot studies. Results showed that the tumor volumes of both LNCap and DU145 were significantly decreased in the PEITC-treated animals, compared with that on a diet without PEITC. The p53 level detected by immunoblot showed a moderate, yet significant, decrease in DU145 tumors, but not in LNCap tumors. Immunohistochemistry assays were carried out to examine the apoptotic markers, such as TUNEL, and anti-proliferation marker Ki67 in tumors from the PEITC-treated vs. untreated mice. This study provides the first in vivo evidence that mutant p53 can be depleted in tumors of mice fed PEITC-containing diet and its depletion seems to correlate with growth inhibition in the mutant p53 tumors. These findings suggest that mutant p53 maybe further investigated as a possible novel target for cancer chemoprevention and therapy by PEITC. (Supported by NCI grant CA100853) Citation Format: Lixin Mi, Thomas T.Y. Wang, Haiqiu Huang, Arnetta Fletcher, Lu Yu, Xiantao Wang, Fung-Lung Chung. Mutant p53 depletion: a possible mechanism of inhibition of human prostate cancer by dietary Phenethyl Isothiocyanate. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4858. doi:10.1158/1538-7445.AM2013-4858
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Phenethyl Isothiocyanate sensitizes human cervical cancer cells to apoptosis induced by cisplatin.
Molecular nutrition & food research, 2011Co-Authors: Xiantao Wang, Sudha Govind, Shyama Prasad Sajankila, Rabindra Roy, Fung-lung ChungAbstract:Naturally-occurring chemopreventive agent Phenethyl Isothiocyanate (PEITC), derived primarily from watercress, has been shown to inhibit cell growth and induce apoptosis in cancer cells. In this study, we examined the potential of PEITC in enhancing cisplatin-induced apoptosis in cervical cancer cells. HeLa cells were exposed to PEITC, cisplatin or both. Pretreatment of cells with PEITC strongly enhanced cisplatin-induced cytotoxicity. PEITC activated the mitogen-activated protein kinases, including JNK, ERK, and p38. The synergistic induction of apoptosis was significantly attenuated by MEK1/2 inhibitor U0126, but not by JNK or p38 inhibitor, suggesting that ERK activation is responsible for the synergistic effect. We found that NF-κB signaling pathway is not involved in the synergistic effect. Sulforaphane and benzyl Isothiocyanate, two other members of the Isothiocyanate family, also sensitize HeLa cells to apoptosis induced by cisplatin. Furthermore, we found that the synergistic effect was not seen in normal cells. Finally, we demonstrated that Noxa induction was associated with apoptosis induced by PEITC plus cisplatin. Taken together, this study shows that PEITC can sensitize cancer cells to apoptosis induced by cisplatin and this effect is mediated through ERK activation, suggesting the potential of PEITC to be used as an adjuvant with cisplatin in combination therapeutic treatments.
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Abstract 1629: Restoration of the wild type function to mutant p53 by chemopreventive agent Phenethyl Isothiocyanate
Experimental and Molecular Therapeutics, 2010Co-Authors: Xiantao Wang, Sudha Govind, York Tomita, Anthony J. Di Pasqua, Fung-lung ChungAbstract:p53 mutations occur in more than 50% of all human tumor. Mutant p53 is incapable of activating downstream target genes necessary for cell cycle arrest and apoptosis. Phenethyl Isothiocyanate (PEITC), a cruciferous vegetable-derived compound, has been shown to possess anti-cancer property by causing cell growth arrest or apoptosis in tumor cell lines and animal models. Recently, we have found that PEITC can selectively reduce mutant p53, but not wild type protein levels in a variety of tumor cell lines. Here, we demonstrate that PEITC can increase sequence specific DNA binding of p53 in NSCLC H596 cells expressing mutant p53 and induce the expression of p53-dependent target proteins, such as p21 and Noxa. Similar effects were observed in human glioblastoma T98G cells which also express mutant p53. H596 cells incubated with sulforaphane (SFN), another widely studied ITC compound with much weaker cytotoxicity, showed no increased specific DNA binding of p53. In addition, PEITC induced p53-responsive p21 and Noxa promoter luciferase activity. Blocking mutant p53 protein expression with shRNA in T98G cells entirely prevented p21 protein induction triggered by PEITC. Immunoprecipitation studies with conformation-specific p53 antibodies (Pab1620 and Pab240) show that treatment with PEITC alters mutant p53 to wild type conformation in H596 cells. Currently, we are investigating the significance of function restoration to mutant p53 by Phenethyl Isothiocyanate in the regulation of apoptosis by PEITC or other conventional chemotherapeutic drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1629.
Charles Y.f. Young - One of the best experts on this subject based on the ideXlab platform.
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Phenethyl Isothiocyanate inhibits STAT3 activation in prostate cancer cells.
Molecular nutrition & food research, 2009Co-Authors: Aiyu Gong, Donkena Krishna Vanaja, Ping Yin, R. Jeffrey Karnes, Charles Y.f. YoungAbstract:This study was undertaken to investigate the mechanism by which Phenethyl Isothiocyanate (PEITC), a natural compound from cruciferous vegetables, exhibits antitumor effect on prostate cancer cells. Cell proliferation, cell cycle, Western blot, gene transfer, and reporter assays were used to test the effects of PEITC on the growth and IL6/JAK/STAT3 pathway in prostate cancer. The result showed that PEITC significantly inhibited DU145 cell proliferation in a dose-dependent manner and induced the cell arrest at G2-M phase. PEITC inhibited both constitutive and IL-6-induced STAT3 activity in DU145 cells. IL-6-stimulated phosphorylation of JAK2, an STAT3 upstream kinase, was also attenuated by PEITC. Moreover, an antioxidant reagent, N-acetyl-L-cysteine (NAC) which suppresses reactive oxygen species (ROS) generation, reversed the early inhibitory effects of PEITC on cell proliferation, constitutive or IL-6-mediated JAK-STAT3 phosphorylation in PCa cells. Taken together, our data demonstrated that PEITC can inhibit the activation of the JAK-STAT3 signal-cascade in prostate cancer cells and the underlying mechanism may be partially involved with blocking cellular ROS production during the early stage of the signaling activation by IL-6.
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Phenethyl Isothiocyanate induces cell cycle arrest and reduction of α- and β- tubulin isotypes in human prostate cancer cells
Cell biology international, 2008Co-Authors: Ping Yin, Donkena Krishna Vanaja, Tomoya Kawamura, Charles Y.f. YoungAbstract:This study was to investigate the effect of Phenethyl Isothiocyanate (PEITC), a constituent of many edible cruciferous vegetables, on the expression of α- and β-tubulins, which are the main components of microtubules in prostate cancer cells. Flow cytometry, light microscopy and western blot were used to study the cell cycle distribution, morphology changes and the expression of α- and β-tubulins in prostate cancer cells treated with PEITC. The results showed that PEITC-induced G2–M cell phase arrest and inhibited the expression of α- and β-tubulin proteins in a number of human prostatic carcinoma cell lines. Further, it is showed that this inhibitory effect could be reversed by antioxidant N-acetyl cysteine and proteasome inhibitor MG132. Finally, it is concluded that PEITC inhibited the expression of α- and β-tubulins in prostate cancer cells, which is at least related to the oxygen reaction species and protein degradation.