bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A41: Butyl benzyl phthalate induces metastasis and angiogenesis of hepatocellular carcinoma through a nongenomic AhR/G protein signaling
Authors: Tsai Eing-Mei , Tsai Cheng-Fang 
Published: January 2014

Abstract
The widespread use of phthalates as plasticizers particularly in polyvinylchloride (PVC) products has raised public health concerns recently due to their adverse health effects, including cancer. Although sufficient evidences of animal investigations suggested the association of phthalates exposure and hepatoma, the mechanisms remain unclear. This study of the effects of phthalates on hepatoma cells progression through AhR shows that butyl benzyl phthalate (BBP) stimulates AhR at the cell surface, interacts with G protein, and triggers the downstream signaling cascade. The experimental results suggest that BBP activates AhR through a nongenomic action, involving G protein signaling other than the classical genomic AhR action. Further experiments have shown that BBP induces both in vitro and in vivo angiogenesis through the AhR/ERK/VEGF pathway. Moreover, the study also reveals that BBP treatment promotes migration, invasion in vitro and metastasis in vivo via AhR/Gβ/PI3K/Akt/NF-κB pathway. Collectively, the findings suggest a novel nongenomic AhR mechanism of phthalates that contributes to tumor progression in hepatoma. The finding will be useful when developing approaches for preventing and treating liver cancer.
Citation Format: Eing-Mei Tsai, Cheng-Fang Tsai. Butyl benzyl phthalate induces metastasis and angiogenesis of hepatocellular carcinoma through a nongenomic AhR/G protein signaling. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A41.
Abstract A42: Estradiol induced prostaglandin E2 expression to regulate cell proliferation through MAPK/PI3K/COX2 signal pathway in Her2/neu breast cancer cell
Authors: Tsai Eing-Mei , Hsieh Tsung-Hua 
Published: January 2014

Abstract
Prostaglandin E2 (PGE2), a product of cyclooxygenase-2 (COX-2) enzymatic activity, induced aromatase activity which converts androgens to estrogens and mediates cell biological function. However, the relationship between estradiol (E2), COX-2 and PGE2 signaling pathway in Her-2/neu breast cancer cell was still unclear. In this report, we elucidate the mechanisms that mediate COX-2 expression and define the relationship of E2 and PGE2 with clinicopathological characteristics in breast cancer patients. The results were presented to demonstrate that the high level of PGE2 (P=0.02) and E2 (P=0.09) was significantly correlated with histological grade. To further investigate the signaling pathways mediating COX-2 gene expression, the experiments were performed in human breast cancer cell lines. In vitro study we found that time and dose courses of COX-2 were induced by E2 treatment in human breast adenocarcinoma cell lines Her-18(Her-2/neu stable expression cell lines), but not in MCF-7 cell lines. Furthermore, the effect was eliminated by pretreatment with MAPK, P38, PI3K, Her-2 inhibitor and estrogen antagonist ICI 182,780. Collectively, our data indicate that MAPK/PI3K/COX-2 is the functional signaling pathway intermediates linking Her-2/neu and E2 and suggest that inhibitors of PGE2 synthesis will suppress cancer cell proliferation in human breast cancer cell lines.
Citation Format: Eing-Mei Tsai, Tsung-Hua Hsieh. Estradiol induced prostaglandin E2 expression to regulate cell proliferation through MAPK/PI3K/COX2 signal pathway in Her2/neu breast cancer cell. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A42.
Abstract A50: PAR-4 (prostate apoptosis response-4) modulates cell survival and chemosensitivity to docetaxel in MCF-7 breast cancer cells
Authors: Pereira Michelly C. , Bessa-Garcia Simone A. de , Nagai Maria A. 
Published: January 2014

Abstract
PAWR (PKC apoptosis WT1 regulator) also known as prostate apoptosis response-4 (PAR-4) was first identified in prostate cancer cells undergoing apoptosis. It encodes a 332-amino-acid protein that induces cancer cell apoptosis, and causes tumor regression by activating Fas/FasL and inhibiting NF-κB activity. Experimental evidence indicates that PAR-4 is a central actor in cancer cell survival and may be a target for cancer-selective targeted therapeutics, however, little is currently known regarding its role in breast cancer tumorigenesis. In this study, we sought to investigate the effects of PAR-4 over-expression and suppression on cell proliferation, apoptosis, and drug sensitivity in breast cancer cells. MCF-7 cells were stably transfected with expression vectors for PAR-4 over-expression, or transiently transfected with siRNA for PAR-4 knockdown. Proliferation assays were performed using MTT, and apoptosis was evaluated using acridine orange staining, fluorescence microscopy, and flow cytometry. PAR-4 over-expression reduced MCF-7 proliferation rates compared with parental or control cells. Conversely, PAR-4 knockdown led to increased MCF-7 proliferation. Par-4 down-regulation also led to increased BCL-2 and reduced BID transcripts. PAR-4 over-expression did not affect the cell cycle profile. However, MCF-7 cells with increased Par-4 expression showed reduced ERK phosphorylation, suggesting that the inhibition of cell proliferation promoted by Par-4 is mediated by the MAPK/ERK1/2 pathway. MCF-7 cells with increased Par-4 expression showed an increased proportion of early apoptotic cells. Increased Par-4 expression also enhanced the sensitivity of MCF-7 breast cancer cells to docetaxel. PAR-4 has inhibitory effects on breast cancer cell proliferation and survival, and may increase breast cancer cells' chemosensitivity.
Supported by FAPESP and CNPq.
Citation Format: Michelly C. Pereira, Simone A. de Bessa-Garcia, Maria A. Nagai. PAR-4 (prostate apoptosis response-4) modulates cell survival and chemosensitivity to docetaxel in MCF-7 breast cancer cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A50.
Abstract A70: Ginger phytochemicals exhibit robust synergy to inhibit prostate cancer cell proliferation
Authors: Gundala Sushma Reddy , Brahmbhatt Meera , Aneja Ritu 
Published: January 2014

Abstract
An emerging notion accepts cancer as a preventable lifestyle disease. Fruits and vegetables offer non-toxic therapeutic options for prostate cancer in particular, since its slow growth offers a wide window for chemopreventive intervention. Fruits and vegetables contain various phytochemicals, including polyphenols and flavonoids that are well-known for their anti-inflammatory, and antiproliferative roles. However, the failure of several single-agent clinical trials has fueled a paradigm shift to appreciate that health benefits of fruits and vegetables are not ascribable to individual phytochemicals but rather to synergistic interactions among them. We recently reported the growth-inhibiting and apoptosis-inducing properties of whole ginger extract (GE) in in vitro and in vivo prostate cancer models. Nevertheless, the nature of interactions among the constituent ginger biophenolics, viz. 6-gingerol (6G), 8-gingerol (8G), 10-gingerol (10G), and 6-shogoal (6S), remains elusive. Here we show the antiproliferative efficacy of the most-active biophenolics present in GE as single-agents and in binary combinations, and investigate nature of their interactions using the Chou-Talalay combination-index (CI) method. Our data demonstrate that binary combinations of ginger phytochemicals synergistically inhibit cellular proliferation of human prostate cancer PC-3 cells with CI values ranging from 0.03 to 0.88. To appreciate synergy among ginger phytochemicals present in GE, the natural relative abundance of ginger biophenolics was quantitated using LC-UV/MS methods. Interestingly, combining GE with its constituents (in particular, 6G) resulted in significant augmentation of GE's antiproliferative activity. These data generate compelling grounds for further preclinical evaluation of GE alone and in combination with individual ginger biophenols for prostate cancer management.
Citation Format: Sushma Reddy Gundala, Meera Brahmbhatt, Ritu Aneja. Ginger phytochemicals exhibit robust synergy to inhibit prostate cancer cell proliferation. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A70.
Abstract A71: Curcubitacin B exhibits cytotoxic effects by inhibiting Integrin-HER2 signaling in breast cancer cells
Authors: Gupta Parul Gupta , Srivastava Sanjay K. 
Published: January 2014

Abstract
Integrins have recently been shown to play an important role in promotion of cell motility and survival in various cancers through cooperative signaling with EGFRs. Integrins transmit cell survival signals through ILK-Paxillin complex and further play role in activating AKT signaling. Curcubitacin B (CuB) is a steroidal class of chemical present in the plants belonging to cucurbitaceae family. CuB has shown cytotoxic potential in several cancers by causing G2/M cell cycle arrest and inhibition of JAK/STAT3 pathway. However, the exact mechanism of CuB and its role in metastasis and cell survival is not known. Our results show that CuB significantly suppressed the growth of MDA-MB-231, SKBR3, HCC1806 and MCF-7 breast cancer cells in a concentration and time-dependent manner. CuB also induced apoptosis and down-regulated ILK1 expression. In addition, CuB down-regulated ITGB4 and ITGA6 protein expression and suppressed the phosphorylation of AKT at Ser473, paxillin at Tyr118. Previous studies have shown that TGFβ mediates physical association of ITGB4 and HER2, through Src kinase to enhance cell survival and motility. Interestingly we observed significant downregulation of Src, EGFR and HER2 in different breast cancer cells, suggesting that CuB suppresses cooperative signaling of Integrins and HER2. We also observed that TGFβ pretreatment imparted protection from CuB's cytotoxic effects, indicating that CuB modulates TGFβ mediated Integrin signaling. Taken together our results indicate the anti-cancer effects of CuB in breast cancer cells by targeting ITGB4/ITGA6, Src, ILK and TGFβ. Further detailed mechanistic work is in progress. [Supported in part by R01 grants CA106953 and CA129038 (to S.K.S) awarded by the National Cancer Institute].
Citation Format: Parul Gupta Gupta, Sanjay K. Srivastava. Curcubitacin B exhibits cytotoxic effects by inhibiting integrin-HER2 signaling in breast cancer cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A71.
Abstract A72: Efficacy and safety of multiple doses of polyphenon E in prostate cancer using TRAMP mice
Authors: Ha Jick Hwan , Kim Seung Joon , Lee Hea Yon , Yeo Chang Dong , Park Chan Kwon , Lee Sang Haak , Park Jong Y. 
Published: January 2014

Abstract
Purpose: The purpose of this study was to assess the efficacy and safety of polyphenon E as a chemopreventive agent against prostate cancer using the transgenic adenocarcinoma of mouse prostate (TRAMP) mice model.
Experimental Design: Seven week old 128 male control C57BL/6 mice and 128 male TRAMP mice were treated with 3 different doses of polyphenon E orally at a human achievable dose. Animals were sacrificed at 12, 22, and 32 weeks of age. For the safety study, complete blood counts with leukocyte differentials and blood chemistry levels for liver and kidney functions were determined. For the efficacy study, weight of the prostate, tumor progression and metastasis, and histopathological evaluation of all organs were assessed. Prostate histology was assessed separately for each lobe of the prostate (i.e., the anterior, dorsal, lateral, and ventral lobes) since lesions progress differently in each lobe of the mouse.
Results: Polyphenon E treatment significantly inhibited prostate cancer progression and metastasis in TRAMP mice model. As expected, metastases were observed in all untreated TRAMP mice (100%, 8 of 8) at 32 weeks of age. However, significant reductions were found in all three polyphenon E treated groups with a dose response manner. 50% (6 of 12), 27% (3 of 11), and 12.5% (2 of 12) of low, intermediate, and high dose treated groups exhibited metastasis of prostate cancer to distant organ sites, respectively. Furthermore, treated TRAMP mice resulted in significant delay in tumor progression from 12 to 32 weeks of age with a dose response manner. No adverse effect in polyphenon E treatment group was found in control C57BL/6 mice up to 32 weeks of age regardless amount of polyphenone E treatment.
Conclusion: Polyphenon E was an effective chemopreventive agent in the progression of prostate cancer in the animal model. Polyphenon E also showed minimal toxicity in the mice model.
Citation Format: Jick Hwan Ha, Seung Joon Kim, Hea Yon Lee, Chang Dong Yeo, Chan Kwon Park, Sang Haak Lee, Jong Y. Park. Efficacy and safety of multiple doses of polyphenon E in prostate cancer using TRAMP mice. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A72.
Abstract A75: Metabolites of ginger component [6]-shogaol remain bioactive in cancer cells and have low toxicity in normal cells: Biotransformation, chemical synthesis and biological evaluation
Authors: Chen Huadong , Zhu Yingdong , Soroka Dominique , Warin Renaud , Sang Shengmin 
Published: January 2014

Abstract
It is now well accepted that natural compounds provide the opportunity to interfere in early stages of cancer or prevent its development altogether. However, these types of compounds do have their limitations, such as short half-life and fast metabolism once ingested. Often, presence of the compound can only be assessed by quantification of metabolites, suggesting that these metabolites circulate in the body for a certain amount of time and potentially interact with biological processes. In the present study, we investigated the biotransformation of [6]-shogaol, a bioactive component in ginger (Zingiber officinale Rosc.), in cancer cells, mice and humans. Our results indicated that [6]-shogaol is extensively metabolized in cancer cells and in vivo. To further investigate whether these metabolites retain bioactivity, we synthesized the major metabolites of [6]-shogaol and evaluate their anti-cancer activities. Twelve metabolites of [6]-shogaol (M1, M2, and M4-M13) were successfully synthesized using simple and easily accessible chemical methods. Growth inhibition assays showed most metabolites of [6]-shogaol had measurable activities against human cancer cells HCT-116 and H-1299. In particular, metabolite M2 greatly retained the biological activities of [6]-shogaol. The toxicity evaluation of the synthetic metabolites (M1, M2, and M4-M13) against human normal fibroblast colon cells CCD-18Co and human normal lung cells IMR-90 demonstrated a detoxifying metabolic biotransformation of [6]-shogaol. The most active metabolite M2 had almost no toxicity to CCD-18Co and IMR-90 normal cells. TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) assay indicated apoptosis was triggered by metabolites M2, M13, and its two diastereomers M13-1 and M13-2. There was no significant difference between the apoptotic effect of [6]-shogaol and those of M2 and M13 at 6 hour time point treatment. (This project is supported by NIH grants CA138277 and CA138277-S1 to S. Sang).
Citation Format: Huadong Chen, Yingdong Zhu, Dominique Soroka, Renaud Warin, Shengmin Sang. Metabolites of ginger component [6]-shogaol remain bioactive in cancer cells and have low toxicity in normal cells: Biotransformation, chemical synthesis, and biological evaluation. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A75.
Abstract A76: Diet versus drug paradigm for the prevention of colorectal cancer: Isorhamnetin and resveratrol versus sulindac and DFMO
Authors: Saud Shakir , Kim Young , Bobe Gerd , Colburn Nancy H. , Young Matthew R. 
Published: January 2014

Abstract
Increase in polyamine synthesis and inflammation is associated with increased risk in colon carcinogenesis. In patients with a high risk for colon cancer a combination treatment with difluoromethylornithine (DFMO), a selective inhibitor of polyamine synthesis, and sulindac, a nonsteroidal anti-inflammatory drug, resulted in a synergistic reduction in adenoma recurrence. However, this drug combination has some toxicities and should be limited to those individuals with a positive benefit to risk ratio.
Bioactive food components have been shown to modulate inflammation and polyamine synthesis and can influence the risk of developing colon cancer with less toxicity. In this study we demonstrated that the chemopreventive activity of isorhamnetin (a plant flavonoid), and resveratrol (a naturally occurring polyphenolic compound) may mimic the effects of sulindac and DFMO. In a mouse model for colitis-associated colon carcinogenesis where mice are treated with the chemical carcinogen azoxymethane (AOM) and then exposed to colonic irritant dextran sodium sulfate (DSS), a diet enriched in isorhamnetin or resveratrol resulted in a reduction in tumor incidence by 22 and 29 percent, respectively. Furthermore, analysis of biomarkers revealed both anti-proliferative and anti-inflammatory properties of both isorhamnetin and resveratrol in vivo. More intriguingly, we found that isorhamnetin mimics sulindac activity by inhibiting Src kinase activity and interfering with Wnt/beta catenin signaling both in culture and in mice. In addition, our metabolomic analyses suggest that resveratrol mimics DFMO activity by inhibiting ornithine decarboxylase (ODC) activity in the mouse colon. Inhibition of ODC by resveratrol was confirmed in culture. It will be interesting to see if the combination of isorhamnetin and resveratrol will have a synergistic effect on prevention of colon cancer. These findings suggest that isorhamnetin and resveratrol could be used as a safer alternative to sulindac and DMFO for the prevention of colon cancer.
Citation Format: Shakir Saud, Young Kim, Gerd Bobe, Nancy H. Colburn, Matthew R. Young. Diet versus drug paradigm for the prevention of colorectal cancer: Isorhamnetin and resveratrol versus sulindac and DFMO. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A76.
Abstract A83: Inhibition of hypoxia inducible factor alpha and astrocyte elevated gene-1 mediates cryptotanshionone induced anti-tumor activity in hypoxic PC-3 cells
Authors: Kim Sung Hoon , Lee Hyojeong , Kim Hanna Hyun , Jung Deok Beom , Sohn Eunjung 
Published: January 2014

Abstract
Although cryptotanshinone (CT) from Salvia miltiorrhiza Bunge was known to exert antitumor activity in liver, breast and prostate cancers, its molecular mechanism under hypoxia still remain unclear. Thus, in the present study, the roles of astrocyte elevated gene 1 (AEG-1) and HIF-1α in crytotanshinone induced antitumor activity were investigated in PC-3 prostate cancer cells under hypoxia. Cryptotanshinone exerted cytotoxicity against prostate cancer cells and suppressed HIF-1α accumulation and transcriptional activity and AEG-1 expression in hypoxic PC-3 cells. Also, AGE-1 was overexpressed in prostate cancer cells and also upregulated along with HIF-1α in hypoxic PC-3 cells. Interestingly, HIF-1α siRNA transfection blocked AEG-1 expression and activated caspase 9/3 and PARP cleavage, while AEG-1 siRNA transfection did not affect HIF-1α activity in hypoxic PC-3 cells. Of note, HIF prolyl hydroxylase inhibitor, dimethyloxalylglycine enhanced the stability of AEG-1 and HIF-1α during hypoxia. In addition, CT also significantly reduced cellular levels of VEGF, a downstream of HIF-1α, and disturbed tube formation in human umbilical vein endothelial cells maintained in conditioned medium of hypoxic PC-3 cells. Consistently, ChIP assay revealed that CT inhibited the binding of HIF-1α to VEGF promoter. Furthermore, CT at 10 mg/kg suppressed the growth of PC-3 cells in BALB/c athymic nude mice by 46.4% compared to untreated control. Consistently, immunohistochemistry revealed decreased expression of Ki-67(proliferation), CD34 (blood vessel), VEGF (angiogenesis), carbonic anhydrase(CA)IX (hypoxic marker) and AEG-1 indices in CT-treated group compared to untreated control. Overall, our findings suggest that CT exerts antitumor activity via inhibition of HIF-1α, AEG1 and VEGF as a potent chemotherapeutic agent.
Citation Format: Sung Hoon Kim, Hyojeong Lee, Hanna Hyun Kim, Deok Beom Jung, Eunjung Sohn. Inhibition of hypoxia inducible factor alpha and astrocyte elevated gene-1 mediates cryptotanshionone induced antitumor activity in hypoxic PC-3 cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A83.