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Shivendra V Singh - One of the best experts on this subject based on the ideXlab platform.
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z guggulsterone a constituent of ayurvedic medicinal plant commiphora mukul inhibits angiogenesis in vitro and in vivo
Molecular Cancer Therapeutics, 2008Co-Authors: Dong Xiao, Shivendra V SinghAbstract:Our previous studies have shown that z-guggulsterone, a constituent of Indian Ayurvedic medicinal plant Commiphora mukul , inhibits the growth of human prostate cancer cells by causing apoptosis. We now report a novel response to z-guggulsterone involving the inhibition of angiogenesis in vitro and in vivo . The z-guggulsterone treatment inhibited capillary-like tube formation ( in vitro neovascularization) by human umbilical vein endothelial cells (HUVEC) and migration by HUVEC and DU145 human prostate cancer cells in a concentration- and time-dependent manner. The z- and E-isomers of guggulsterone seemed equipotent as inhibitors of HUVEC tube formation. The z-guggulsterone–mediated inhibition of angiogenesis in vitro correlated with the suppression of secretion of proangiogenic growth factors [e.g., vascular endothelial growth factor (VEGF) and granulocyte colony–stimulating factor], down-regulation of VEGF receptor 2 (VEGF-R2) protein level, and inactivation of Akt. The z-guggulsterone–mediated suppression of DU145 cell migration was increased by knockdown of VEGF-R2 protein level. Ectopic expression of constitutively active Akt in DU145 cells conferred protection against z-guggulsterone–mediated inhibition of cell migration. Oral gavage of 1 mg z-guggulsterone/d (five times/wk) to male nude mice inhibited in vivo angiogenesis in DU145-Matrigel plug assay as evidenced by a statistically significant decrease in tumor burden, microvessel area (staining for angiogenic markers factor VIII and CD31), and VEGF-R2 protein expression. In conclusion, the present study reveals that z-guggulsterone inhibits angiogenesis by suppressing the VEGF–VEGF-R2–Akt signaling axis. Together, our results provide compelling rationale for further preclinical and clinical investigation of z-guggulsterone for its efficacy against prostate cancer. [Mol Cancer Ther 2008;7(1):171–80]
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diallyl trisulfide induced g2 m phase cell cycle arrest in human prostate cancer cells is caused by reactive oxygen species dependent destruction and hyperphosphorylation of cdc25c
Oncogene, 2005Co-Authors: Dong Xiao, Anna Hermanantosiewicz, Jedrzej Antosiewicz, Hui Xiao, Marni Brisson, John S Lazo, Shivendra V SinghAbstract:Molecular mechanism of cell cycle arrest caused by diallyl trisulfide (DATS), a garlic-derived cancer chemopreventive agent, has been investigated using PC-3 and DU145 human prostate cancer cells as a model. Treatment of PC-3 and DU145 cells, but not a normal prostate epithelial cell line (PrEC), with growth suppressive concentrations of DATS caused enrichment of the G2–M fraction. The DATS-induced cell cycle arrest in PC-3 cells was associated with increased Tyr15 phosphorylation of cyclin-dependent kinase 1 (Cdk1) and inhibition of Cdk1/cyclinB1 kinase activity. The DATS-treated PC-3 and DU145 cells also exhibited a decrease in the protein level of Cdc25C and an increase in its Ser216 phosphorylation. The DATS-mediated decrease in protein level and Ser216 phosphorylation of Cdc25C as well as G2–M phase cell cycle arrest were significantly attenuated in the presence of N-acetylcysteine implicating reactive oxygen species (ROS) in cell cycle arrest caused by DATS. ROS generation was observed in DATS-treated PC-3 and DU145 cells. DATS treatment also caused an increase in the protein level of Cdk inhibitor p21, but DATS-induced G2–M phase arrest was not affected by antisense-mediated suppression of p21 protein level. In conclusion, the results of the present study indicate that DATS-induced G2–M phase cell cycle arrest in human prostate cancer cells is caused by ROS-mediated destruction and hyperphosphorylation of Cdc25C.
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role of mitogen activated protein kinases in phenethyl isothiocyanate induced apoptosis in human prostate cancer cells
Molecular Carcinogenesis, 2005Co-Authors: Dong Xiao, Sunga Choi, Yong J Lee, Shivendra V SinghAbstract:The present study was undertaken to examine the role of mitogen-activated protein kinases (MAPKs) in apoptosis induction by phenethyl isothiocyanate (PEITC), a cruciferous vegetable-derived cancer chemopreventive agent, with DU145 and LNCaP human prostate cancer cells as a model. The MAPK family of serine/threonine kinases, including extracellular signal-regulated kinase1/2 (ERK1/2), c-jun N-terminal kinase1/2/3 (JNK1/2/3), and p38 MAPK play an important role in cell proliferation and apoptosis in response to different stimuli. Exposure of DU145 and LNCaP cells to growth suppressive concentrations of PEITC resulted in activation of ERK1/2 and JNKs, but not p38 MAPK, in both cell lines. In DU145 cells, the apoptosis induction by PEITC was statistically significantly attenuated by pharmacological inhibition of JNKs with SP600125. Adenovirus-mediated overexpression of Flag-tagged JNK binding domain (JBD) of JNK-interacting protein-1 (JIP-1), an inhibitor of JNK, also inhibited PEITC-induced apoptosis in DU145 cells. On the other hand, inhibition of ERK1/2 activation with MEK1 inhibitor PD98059 failed to offer protection against PEITC-induced apoptosis in DU145 cells. In LNCaP cells, the PEITC-induced cell death was not affected by either pretreatment with PD98059 or SP600125 or overexpression of JBD of JIP-1. These results indicate that involvement of MAPKs in apoptosis induction by PEITC in human prostate cancer cells is cell line-specific.
Rajesh Agarwal - One of the best experts on this subject based on the ideXlab platform.
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anti tumor activity of oxypeucedanin from ostericum koreanum against human prostate carcinoma DU145 cells
Acta Oncologica, 2009Co-Authors: Tae Jin Kang, Rajesh Agarwal, Sook Yeon Lee, Rana P Singh, Dong Sool YimAbstract:Purpose. Oxypeucedanin has been reported to have various biological activities. We investigated the efficacy of a coumarin compound, oxypeucedanin, from Ostericum koreanum against the human prostate carcinoma cell line DU145. Material and methods. Oxypeucedanin (C16H14O5, mw: 286) was isolated through silica gel chromatography and characterized by NMR. The cells were treated with oxypeucedanin (25, 50, and 100 µM) for 24–72 hours, and cell growth and death were then assayed. The cell cycle progression and apoptotic effects were also assessed by western blotting. Results. Treatment with oxypeucedanin inhibited cell growth and induced cell death in DU145 cells. Furthermore, oxypeucedanin-induced cell growth inhibition was associated with an increase in G2-M arrest in cell cycle progression in DU145 cells in a dose and time-dependent manner. G2-M arrest by oxypeucedanin was associated with decreased levels of cyclin A, cyclin B1, Cdc2, and pCdc2. Oxypeucedanin-induced cell death was associated with significa...
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Fractionation of high molecular weight tannins in grape seed extract and identification of procyanidin B2-3,3'-di-O-gallate as a major active constituent causing growth inhibition and apoptotic death of DU145 human prostate carcinoma cells.
Carcinogenesis, 2007Co-Authors: Chapla Agarwal, Ravikanth Veluri, Manjinder Kaur, Shen-chieh Chou, John A. Thompson, Rajesh AgarwalAbstract:Several studies have documented the anticancer and chemopreventive efficacy of grape seed extract (GSE) against various malignancies including prostate cancer (PCA). GSE is a complex mixture of polyphenols including gallic acid (GA), catechin (Cat), epicatechin (Epi) and procyanidins-oligomers of Cat and Epi, some of which are esterified with GA. Initial studies to identify the GSE components cytotoxic to human prostate carcinoma (DU145) cells demonstrated that GA and several crude chromatographic fractions containing procyanidin dimers and trimers were biologically active. The focus of the present work was to purify 14 procyanidins from the fractions and to identify those with highest activity toward growth inhibition, cell death and apoptosis in DU145 cells. The most active procyanidin was identified by mass spectrometry and enzymatic hydrolysis as the 3,3'-di-O-gallate ester of procyanidin dimer B2 (Epi-Epi). B2-digallate exhibited dose-dependent effects on DU145 cells over the range 25-100 microM, whereas GA exhibited comparable activity at lower doses but was highly lethal at 100 microM. Structure-activity studies demonstrated that all three hydroxyl groups of GA are necessary for activity, but a free carboxylic acid group is not required even though esterification reduced the activity of GA. These data, and the fact that non-esterified B2 exhibited little or no activity, suggest that the galloyl groups of B2-digallate are primarily responsible for its effects on DU145 cells. Taken together, these data identify procyanidin B2-3,3'-di-O-gallate as a novel biologically active agent in GSE that should be studied in greater detail to determine its effects against PCA.
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growth inhibitory and apoptotic effects of linarin linarin acetate and acacetin on human prostate carcinoma cells
Cancer Research, 2004Co-Authors: Rana P Singh, Puja Agrawal, Dong S Yim, Rajesh AgarwalAbstract:739 This study was carried out to assess the anticancer efficacy of linarin (LN), linarin acetate (LA) and acacetin (AC), the flavonoid compounds with same flavone ring structure but different substitution, against human prostate cancer (PCA) cells. LN was isolated and purified from Chrysanthemum zawadaskii var, Latilobum (Compositae); LA was synthesized from LN; and acacetin was obtained commercially, which is abundant in Cirsium rhinoceros Nakai (Compositae). LNCaP and DU145 PCA cells were treated with LN, LA and AC in the range of 5-100 μM doses for 24-72 h, and cell growth and death was determined by cell counting. Cell cycle progression and apoptosis were analyzed by saponin/propidium iodide (PI) and annexin V/PI staining followed by flow cytometry analysis, respectively. Higher doses of LN were effective in inhibiting growth of DU145 cells whereas LA did not show any growth inhibition. Interestingly, LN showed a significant cell growth inhibition at 24 h of treatment in LNCaP cells, which decreased progressively with an increase in treatment time. Conversely, LA followed a reverse trend showing a time-dependent increase in LNCaP cell growth inhibition when compared with LN. Both these compounds were also effective in causing PCA cell death. LN caused up to 5-7-fold increase in cell death at 24 h of treatment in both cell lines that decreased with the time; however, LA enhanced cell death by 2-3-fold with the increase in treatment time. Further, we observed that LN-induced cell death was associated with apoptosis induction in both cell lines; however, LA caused a moderate increase in apoptotic cell death only in DU145 cells. The third compound, AC showed a strong and both time- as well as –dose-dependent cell growth inhibition, which was more prominent in LNCaP cells (43-77%) as compared to DU145 cells (39-49%). Similarly, AC also increased cell death, which was associated with a strong and significant increase in apoptosis (up to 5 fold in LNCaP cells and up to 3 fold in DU145 cells). In cell cycle analysis, LN and LA did not show any profound effect on cell cycle arrest in both the cell lines; only a moderate increase in G1 arrest by LA in LNCaP cells at 24-72 h of treatment, and a slight increase in S phase arrest by LA in DU145 cells at 72 h of treatment were observed. Conversely, AC showed a strong effect on cell cycle arrest in both the cell lines. In LNCaP cells, lower doses (5-50 μM) of AC showed G2-M arrest whereas 100 μM dose resulted in a strong G1 arrest following 24 h treatment. At higher treatment times (48 and 72 h), lower doses of AC showed G1 arrest whereas its higher doses (50-100 μM) caused G2-M arrest. In DU145 cells, however, AC showed an increase in G1 arrest at 5-50 μM doses, and G2-M arrest at 50-100 μM doses after 24 h of treatment; higher treatment times showed only G2-M arrest. The findings in the present study reveal the structural determinants in anticancer efficacy of these three novel flavonoids against PCA cells.
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dietary feeding of silibinin inhibits advance human prostate carcinoma growth in athymic nude mice and increases plasma insulin like growth factor binding protein 3 levels
Cancer Research, 2002Co-Authors: Rana P Singh, Chapla Agarwal, Sivanandhan Dhanalakshmi, Anil K Tyagi, Daniel C F Chan, Rajesh AgarwalAbstract:We have reported recently the anticancer effect of flavonoid antioxidant silymarin, the major part of milk thistle extract, against advanced human prostate carcinoma DU145 cells (X. Zi et al. , Cancer Res., 58: 1920–1929, 1998) and later identified that silibinin is the main active component in silymarin responsible for its effect in cell culture studies. On the basis of these observations, here we assessed in vivo growth inhibitory potential of silibinin against advanced human prostate cancer (PCA). Dietary feeding of silibinin at 0.05 and 0.1% doses (w/w) for 60 days, 24 h after s.c. DU145 tumor xenograft implantation in athymic male nude mice, significantly inhibited tumor volume by 35 and 58% ( P < 0.05), and wet weight of tumor by 29 and 40% ( P < 0.05), respectively. In a second experiment where mice were fed with these test diets for 3 weeks before tumor xenograft implantation and continued on these diets for a total of 63 days, tumor volume and wet weight of tumor were reduced by 53–64% ( P < 0.001–0.05) and 31–52% ( P < 0.05), respectively. In both studies, animals did not show weight loss or reduced food consumption. These in vivo anticancer effects of silibinin were associated with an increased accumulation (up to 5.8 fold; P < 0.05) of human insulin-like growth factor-binding protein-3 in mouse plasma. In additional studies assessing biological availability of silibinin in nude mice and its antiproliferative activity at such doses in DU145 cells in culture, silibinin levels in plasma and prostate were found to be in the range of 7–13 μg/ml and 3.7–4.6 μg/g, respectively. At these biologically achievable silibinin concentrations, increased IGFBP-3 level in DU145 cell culture medium and a strong DU145 cell growth inhibition were observed that were irreversible in the absence of silibinin in culture medium. These findings extend and translate our observations on in vitro anticancer effect of silibinin/silymarin to an in vivo preclinical PCA model, which may form the basis for a Phase I clinical trial in PCA patients.
In-kyu Lee - One of the best experts on this subject based on the ideXlab platform.
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Scoparone exerts anti-tumor activity against DU145 prostate cancer cells via inhibition of STAT3 activity.
PloS one, 2013Co-Authors: Jeong Kook Kim, Joon Young Kim, Han Jong Kim, Keun-gyu Park, Robert A. Harris, Won-jea Cho, Jae Tae Lee, In-kyu LeeAbstract:Scoparone, a natural compound isolated from Artemisia capillaris, has been used in Chinese herbal medicine to treat neonatal jaundice. Signal transducer and activator of transcription 3 (STAT3) contributes to the growth and survival of many human tumors. This study was undertaken to investigate the anti-tumor activity of scoparone against DU145 prostate cancer cells and to determine whether its effects are mediated by inhibition of STAT3 activity. Scoparone inhibited proliferation of DU145 cells via cell cycle arrest in G1 phase. Transient transfection assays showed that scoparone repressed both constitutive and IL-6-induced transcriptional activity of STAT3. Western blot and quantitative real-time PCR analyses demonstrated that scoparone suppressed the transcription of STAT3 target genes such as cyclin D1, c-Myc, survivin, Bcl-2, and Socs3. Consistent with this, scoparone decreased phosphorylation and nuclear accumulation of STAT3, but did not reduce phosphorylation of janus kinase 2 (JAK2) or Src, the major upstream kinases responsible for STAT3 activation. Moreover, transcriptional activity of a constitutively active mutant of STAT3 (STAT3C) was inhibited by scoparone, but not by AG490, a JAK2 inhibitor. Furthermore, scoparone treatment suppressed anchorage-independent growth in soft agar and tumor growth of DU145 xenografts in nude mice, concomitant with a reduction in STAT3 phosphorylation. Computational modeling suggested that scoparone might bind the SH2 domain of STAT3. Our findings suggest that scoparone elicits an anti-tumor effect against DU145 prostate cancer cells in part through inhibition of STAT3 activity.
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Scoparone suppresses anchorage-independent growth invitro and xenograft tumor growth of DU145 cells in nude mice.
2013Co-Authors: Jeong Kook Kim, Joon Young Kim, Han Jong Kim, Keun-gyu Park, Robert A. Harris, Won-jea Cho, Jae Tae Lee, In-kyu LeeAbstract:A. Scoparone inhibits anchorage-independent growth of DU145 cells. DU145 cells were grown for 3 weeks in 0.25% agarose gel containing vehicle or scoparone. The number of colonies lager than 2 mm in diameter was counted and data represent the means ± S.E.M. of three independent experiments, each performed in duplicate. *P
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Scoparone suppresses proliferation of DU145 prostate cancer cells by inducing G1-phase cell-cycle arrest.
2013Co-Authors: Jeong Kook Kim, Joon Young Kim, Han Jong Kim, Keun-gyu Park, Robert A. Harris, Won-jea Cho, Jae Tae Lee, In-kyu LeeAbstract:A and B. Scoparone inhibits proliferation of human cancer cell lines. Prostate cancer cells (DU145 and PC-3), RWPE-1 (an immortalized human prostate epithelial cell line), and breast cancer cells (MCF-7 and MDA-MB-231) were serum starved for 24 h. Cells were then incubated in growth medium supplemented with 10% FBS in the presence of vehicle (0.1% DMSO) or the indicated concentrations of scoparone for 72 h, and cell proliferation was determined by WST-8 assay. Data are expressed as percentages of the vehicle control (defined as 100%) and represent the means ± S.E.M. of three independent experiments, each performed in triplicate. B. Scoparone induces cell-cycle arrest at G1 phase in DU145 cells. Serum-starved DU145 cells were stimulated with 10% FBS in the presence of vehicle or scoparone (0.5 and 1 mmol/L) for 28 h, and then subjected to flow cytometric analysis of the cell cycle. Bar graph indicates the percentage of cells in G1 phase. The data are the means ± S.E.M. of three independent experiments, each performed in duplicate. *P
Santosh K Katiyar - One of the best experts on this subject based on the ideXlab platform.
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berberine a natural product induces g1 phase cell cycle arrest and caspase 3 dependent apoptosis in human prostate carcinoma cells
Molecular Cancer Therapeutics, 2006Co-Authors: Sudheer K Mantena, Som D Sharma, Santosh K KatiyarAbstract:Berberine, a naturally occurring isoquinoline alkaloid, has been shown to possess anti-inflammatory and antitumor properties in some in vitro systems. Here, we report that in vitro treatment of androgen-insensitive (DU145 and PC-3) and androgen-sensitive (LNCaP) prostate cancer cells with berberine inhibited cell proliferation and induced cell death in a dose-dependent (10-100 micromol/L) and time-dependent (24-72 hours) manner. Treatment of nonneoplastic human prostate epithelial cells (PWR-1E) with berberine under identical conditions did not significantly affect their viability. The berberine-induced inhibition of proliferation of DU145, PC-3, and LNCaP cells was associated with G1-phase arrest, which in DU145 cells was associated with inhibition of expression of cyclins D1, D2, and E and cyclin-dependent kinase (Cdk) 2, Cdk4, and Cdk6 proteins, increased expression of the Cdk inhibitory proteins (Cip1/p21 and Kip1/p27), and enhanced binding of Cdk inhibitors to Cdk. Berberine also significantly (P < 0.05-0.001) enhanced apoptosis of DU145 and LNCaP cells with induction of a higher ratio of Bax/Bcl-2 proteins, disruption of mitochondrial membrane potential, and activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase. Pretreatment with the pan-caspase inhibitor z-VAD-fmk partially, but significantly, blocked the berberine-induced apoptosis, as also confirmed by the comet assay analysis of DNA fragmentation, suggesting that berberine-induced apoptosis of human prostate cancer cells is mediated primarily through the caspase-dependent pathway. The effectiveness of berberine in checking the growth of androgen-insensitive, as well as androgen-sensitive, prostate cancer cells without affecting the growth of normal prostate epithelial cells indicates that it may be a promising candidate for prostate cancer therapy.
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proanthocyanidins from grape seeds inhibit expression of matrix metalloproteinases in human prostate carcinoma cells which is associated with the inhibition of activation of mapk and nfκb
Carcinogenesis, 2004Co-Authors: Praveen K Vayalil, Anshu Mittal, Santosh K KatiyarAbstract:Prostate cancer (PCA) is the second most frequently diagnosed and leading cause of cancer-related deaths in men in the USA. The recognition that matrix metalloproteinases (MMPs) facilitate tumor cell invasion and metastasis of PCA has led to the development of MMP inhibitors as cancer therapeutic agents. As part of our efforts to develop newer and effective chemopreventive agents for PCA, we evaluated the effect of proanthocyanidins from grape seeds (GSP) on metastasis-specific MMP-2 and -9 in human prostate carcinoma DU145 cells by employing western blot and gelatinolytic zymography. Treatment of GSP dose-dependently inhibited cell proliferation (15-100% by 5-80 microg/ml of GSP), viability (30-80% by 20-80 microg/ml of GSP) and fibroblast conditioned medium (FCM)-induced expression of MMP-2 and -9 in DU145 cells. Since the signaling cascade of mitogen-activated protein kinases (MAPK) have been shown to regulate the expression of MMPs in tumor cells, we found that the treatment of DU145 cells with GSP (20-80 microg/ml) resulted in marked inhibition of FCM-induced phosphorylation of extracellular signal regulated kinase (ERK)1/2 and p38 but had little effect on c-Jun N-terminal kinase under similar experimental conditions. GSP treatment (20-80 microg/ml) to DU145 cells also dose-dependently inhibited FCM-induced activation of NF kappa B concomitantly with inhibition of MMP-2 and -9 expression in the same system. Additionally, the treatment of inhibitors of MEK (PD98059) and p38 (SB203580) to DU145 cells resulted in the reduction of FCM-induced phosphorylation of ERK1/2 and p38 concomitantly marked reduction in MMP-2 and -9 expressions. In further studies, treatment of androgen-sensitive LNCaP cells with a synthetic androgen R1881, resulted in an increase of MMP-2 and -9, which were completely abrogated in the presence of GSP (20-60 microg/ml). These data suggest that inhibition of metastasis-specific MMPs in tumor cells by GSP is associated with the inhibition of activation of MAPK and NF kappa B pathways, and thus provides the molecular basis for the development of GSP as a novel chemopreventive agent for both androgen-sensitive and -insensitive prostate cancer therapies.
Dong Xiao - One of the best experts on this subject based on the ideXlab platform.
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z guggulsterone a constituent of ayurvedic medicinal plant commiphora mukul inhibits angiogenesis in vitro and in vivo
Molecular Cancer Therapeutics, 2008Co-Authors: Dong Xiao, Shivendra V SinghAbstract:Our previous studies have shown that z-guggulsterone, a constituent of Indian Ayurvedic medicinal plant Commiphora mukul , inhibits the growth of human prostate cancer cells by causing apoptosis. We now report a novel response to z-guggulsterone involving the inhibition of angiogenesis in vitro and in vivo . The z-guggulsterone treatment inhibited capillary-like tube formation ( in vitro neovascularization) by human umbilical vein endothelial cells (HUVEC) and migration by HUVEC and DU145 human prostate cancer cells in a concentration- and time-dependent manner. The z- and E-isomers of guggulsterone seemed equipotent as inhibitors of HUVEC tube formation. The z-guggulsterone–mediated inhibition of angiogenesis in vitro correlated with the suppression of secretion of proangiogenic growth factors [e.g., vascular endothelial growth factor (VEGF) and granulocyte colony–stimulating factor], down-regulation of VEGF receptor 2 (VEGF-R2) protein level, and inactivation of Akt. The z-guggulsterone–mediated suppression of DU145 cell migration was increased by knockdown of VEGF-R2 protein level. Ectopic expression of constitutively active Akt in DU145 cells conferred protection against z-guggulsterone–mediated inhibition of cell migration. Oral gavage of 1 mg z-guggulsterone/d (five times/wk) to male nude mice inhibited in vivo angiogenesis in DU145-Matrigel plug assay as evidenced by a statistically significant decrease in tumor burden, microvessel area (staining for angiogenic markers factor VIII and CD31), and VEGF-R2 protein expression. In conclusion, the present study reveals that z-guggulsterone inhibits angiogenesis by suppressing the VEGF–VEGF-R2–Akt signaling axis. Together, our results provide compelling rationale for further preclinical and clinical investigation of z-guggulsterone for its efficacy against prostate cancer. [Mol Cancer Ther 2008;7(1):171–80]
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diallyl trisulfide induced g2 m phase cell cycle arrest in human prostate cancer cells is caused by reactive oxygen species dependent destruction and hyperphosphorylation of cdc25c
Oncogene, 2005Co-Authors: Dong Xiao, Anna Hermanantosiewicz, Jedrzej Antosiewicz, Hui Xiao, Marni Brisson, John S Lazo, Shivendra V SinghAbstract:Molecular mechanism of cell cycle arrest caused by diallyl trisulfide (DATS), a garlic-derived cancer chemopreventive agent, has been investigated using PC-3 and DU145 human prostate cancer cells as a model. Treatment of PC-3 and DU145 cells, but not a normal prostate epithelial cell line (PrEC), with growth suppressive concentrations of DATS caused enrichment of the G2–M fraction. The DATS-induced cell cycle arrest in PC-3 cells was associated with increased Tyr15 phosphorylation of cyclin-dependent kinase 1 (Cdk1) and inhibition of Cdk1/cyclinB1 kinase activity. The DATS-treated PC-3 and DU145 cells also exhibited a decrease in the protein level of Cdc25C and an increase in its Ser216 phosphorylation. The DATS-mediated decrease in protein level and Ser216 phosphorylation of Cdc25C as well as G2–M phase cell cycle arrest were significantly attenuated in the presence of N-acetylcysteine implicating reactive oxygen species (ROS) in cell cycle arrest caused by DATS. ROS generation was observed in DATS-treated PC-3 and DU145 cells. DATS treatment also caused an increase in the protein level of Cdk inhibitor p21, but DATS-induced G2–M phase arrest was not affected by antisense-mediated suppression of p21 protein level. In conclusion, the results of the present study indicate that DATS-induced G2–M phase cell cycle arrest in human prostate cancer cells is caused by ROS-mediated destruction and hyperphosphorylation of Cdc25C.
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role of mitogen activated protein kinases in phenethyl isothiocyanate induced apoptosis in human prostate cancer cells
Molecular Carcinogenesis, 2005Co-Authors: Dong Xiao, Sunga Choi, Yong J Lee, Shivendra V SinghAbstract:The present study was undertaken to examine the role of mitogen-activated protein kinases (MAPKs) in apoptosis induction by phenethyl isothiocyanate (PEITC), a cruciferous vegetable-derived cancer chemopreventive agent, with DU145 and LNCaP human prostate cancer cells as a model. The MAPK family of serine/threonine kinases, including extracellular signal-regulated kinase1/2 (ERK1/2), c-jun N-terminal kinase1/2/3 (JNK1/2/3), and p38 MAPK play an important role in cell proliferation and apoptosis in response to different stimuli. Exposure of DU145 and LNCaP cells to growth suppressive concentrations of PEITC resulted in activation of ERK1/2 and JNKs, but not p38 MAPK, in both cell lines. In DU145 cells, the apoptosis induction by PEITC was statistically significantly attenuated by pharmacological inhibition of JNKs with SP600125. Adenovirus-mediated overexpression of Flag-tagged JNK binding domain (JBD) of JNK-interacting protein-1 (JIP-1), an inhibitor of JNK, also inhibited PEITC-induced apoptosis in DU145 cells. On the other hand, inhibition of ERK1/2 activation with MEK1 inhibitor PD98059 failed to offer protection against PEITC-induced apoptosis in DU145 cells. In LNCaP cells, the PEITC-induced cell death was not affected by either pretreatment with PD98059 or SP600125 or overexpression of JBD of JIP-1. These results indicate that involvement of MAPKs in apoptosis induction by PEITC in human prostate cancer cells is cell line-specific.
