bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1242: Green tea polyphenols inhibit the growth and induce death of melanoma cells by initiating DNA damage and inhibition of class I histone deacetylases
Authors: Prasad Ram , Katiyar Santosh K. 
Published: May 2015

Abstract
Melanoma remains a leading cause of death from skin diseases due to its propensity to metastasis, and is increasing rapidly in children. Although, melanoma is less common than other types of skin cancers, however, it causes the majority (75%) of skin cancer-related deaths. The average survival of patients with advanced stage of melanoma is less than a year because no effective strategies are available for metastatic melanoma. Since melanoma is a highly malignant cancer, an approach that can inhibit its growth and progression may facilitate the development of an effective strategy for its treatment or prevention. As green tea polyphenols (GTPs) have been shown to have anti-skin carcinogenic effects, we have examined the chemotherapeutic effect of GTPs on the growth of different melanoma cell lines and the molecular mechanisms underlying these effects using an in vitro model. Treatment of melanoma cells (A375 and Hs294t) with GTPs (0, 20, 40 and 60 µg/ml) for 24 and 48 h significantly inhibited histone deacetylase (HDAC) activity, reduced the levels of class 1 HDAC proteins (HDAC 1, 2, 3 and 8) and enhanced histone acetyltransferase (HAT) activity in a dose-dependent manner. These effects of GTPs on melanoma cells were associated with DNA damage, which was evident by Comet assay, and significant reduction in the viability of melanoma cells and induction of cell death. Concomitant treatment of melanoma cells with a proteasome inhibitor, MG132, prevented GTPs-induced degradation of class I HDACs, suggesting that GTPs reduced the levels of HDAC proteins in melanoma cells through proteasomal degradation. Valproic acid, an inhibitor of HDACs, exhibited a similar pattern of reduced viability and induction of death of melanoma cells (A375 and Hs294t). Treatment of A375 and Hs294t cells with GTPs resulted in an alteration of cell cycle regulatory proteins of G0/G1 phase, and that is a decrease in the levels of cyclin D1, D2 and E, and cyclin dependent kinases, CDK2, CDK4 and CDK6 in a dose-dependent manner. Simultaneously, it was also observed that the levels of p21 and p53 proteins were also increased in the cells after the treatment with GTPs, which may have a role in G0/G1 phase arrest and DNA damage. Together, our study provides new insights into the role of class I HDACs in the chemotherapeutic effects of green tea polyphenols on melanoma cells.
Citation Format: Ram Prasad, Santosh K. Katiyar. Green tea polyphenols inhibit the growth and induce death of melanoma cells by initiating DNA damage and inhibition of class I histone deacetylases. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1242. doi:10.1158/1538-7445.AM2014-1242
Abstract 1249: ERK1/2 targeting with magnolin as a chemopreventive agent
Authors: Lee Cheol-Jung , Lee Mee-Hyun , Lee Ji-Young , Song Ji Hong , Cho Yong-Yeon 
Published: May 2015

Abstract
Mitogen activated protein kinases (MAPKs) play a key role in cell proliferation, cell cycle progression and cell transformation, and activated Ras/ERKs/RSK2 signaling pathways have been widely identified in many solid tumors. In this study, we found that magnolin, a compound found in Magnolia species, directly targeted and inhibited ERK1 and ERK2 kinase activities with IC50 values of 87 nM and 16.5 nM by competing with ATP in an active pocket, respectively. Further, we demonstrated that magnolin inhibited EGF-induced p90RSKs phopshorylation at Thr359/Ser363, but not ERKs phosphorylation at Thr202/Tyr204, resulted in inhibition of cell proliferation by suppression of G1/S cell cycle transition. Additionally, p38 kinases, Jun N-terminal kinases, and Akts did not involved magnolin-mediated inhibitory signaling. Magnolin targeting on ERK1 and 2 activities suppressed the phosphorylation of RSK2 and downstream target proteins including ATF1 and c-Jun and AP-1, a dimer of Jun/Fos, and the transactivation activities of ATF1 and AP-1. Notably, ERKs inhibition by magnolin suppressed EGF-induced anchorage-independent cell transformation and colony growth of RasG12V- harboring A549 human lung cancer cells and NIH3T3 cells stably expressing RasG12V in soft agar. Taken together, these results demonstrated that magnolin might be a naturally occurring chemoprevention and therapeutic agent capable of inhibiting cell proliferation and transformation by targeting ERK1 and ERK2.
Citation Format: Cheol-Jung Lee, Mee-Hyun Lee, Ji-Young Lee, Ji Hong Song, Yong-Yeon Cho. ERK1/2 targeting with magnolin as a chemopreventive agent. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1249. doi:10.1158/1538-7445.AM2014-1249
Abstract 125: A novel OSM inhibition of cancer metastasis and epithelial-mesenchymal transition in lung adenocarcinoma through STAT1-mediated suppression of Slug
Authors: Pan Chih-Ming , Wang Mong-Lien , Wu Cheng-Wen 
Published: May 2015

Abstract
We previously reported that mesenchymal stem cells (MSCs) secrete a multifunctional cytokine - Oncostatin M (OSM) which effectively inhibited the metastasis and growth of LAC cells, and induced the mesenchymal epithelial transition (MET) pathway, as evidenced by the reduction of several epithelial-mesenchymal transition related markers, including SLUG. However, the underlying mechanism of how OSM mediates the suppression of SLUG is still unknown.
To dissect the downstream effectors of OSM-dependent suppression of SLUG, we individually knocked down STAT1 (STAT1-KD) and STAT3 (STAT3-KD), the two well-known downstream transcription factors activated by OSM, in A549 and CL1-5 cells using lentiviral expressed short hairpin RNAs (shRNA). We demonstrated that knockdown of STAT1, but not STAT3, reversed the OSM suppressed SLUG level and resulted in a higher SLUG mRNA and protein in comparison to scrambled shRNA control. Consistently, knockdown of STAT1 in LAC cells rescued the OSM-mediated inhibition of cell migration, invasion, and proliferation, indicating that STAT1 is the effector of OSM-dependent induction of MET and suppression of cell motility.
Moreover, we constructed SLUG promoter-driven luciferase expression reporters and test the effect of OSM and STAT1 on SLUG promoter activity. We observed that STAT1-KD cells had increased SLUG promoter activity than control cells, while OSM treatment augments this difference. A mutation in the putative STAT1 binding sequence (gamma activated sequence) mapped at -599 bp upstream of STAT1 transcriptional start site diminished the SLUG promoter activity in STAT1-KD cells. We also showed STAT1 binding to SLUG promoter region after OSM treatment by using a chromatin immunoprecipitation assay. These data indicated that the OSM-dependent inhibition of SLUG and elevation of MET signaling is mediated, at least in part, by a STAT1-dependent pathway through a transcriptional control. Our findings revealed a novel paracrine effect of OSM and the underlying mechanism on cancer metastasis and MET in LAC.
Citation Format: Chih-Ming Pan, Mong-Lien Wang, Cheng-Wen Wu. A novel OSM inhibition of cancer metastasis and epithelial-mesenchymal transition in lung adenocarcinoma through STAT1-mediated suppression of Slug. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 125. doi:10.1158/1538-7445.AM2014-125
Abstract 1250: Inhibition of pancreatic carcinogenesis by t-CUPM, a dual inhibitor of c-Raf and soluble epoxide hydrolase
Authors: Liao Jie , Zhang Wanying , Hwng Sung Hee , Li Haonan , Wecksler Aaron T. , Ma Ke , Hammock Bruce D. , Yang Guang-Yu 
Published: May 2015

Abstract
Mutant Kras activated Raf-MAPK/ERK pathway and chronic pancreatitis are the most common pathogenic events involved in human pancreatic carcinogenesis. The soluble epoxide hydrolase (sEH), a pro-inflammatory enzyme, generally inactivates anti-inflammatory epoxyeicosatrienoic acids (EETs). Herein, we have synthesized a novel compound of trans-4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-cyclohexyloxy}-pyridine-2-carboxylic acid methylamide (t-CUPM) via modifying the central phenyl ring of sorafenib and confirmed its dual inhibition of sEH and c-Raf by recombinant kinase activity assay. Pharmacokinetic analysis revealed that oral dosing of t-CUPM resulted in the higher blood levels than that of sorafenib throughout the complete time course (48 h). The effect of t-CUPM on the development of pancreatitis and pancreatic intraepithelial neoplasia (mPanIN) was determined in the LSL-KrasG12D/Pdx1-Cre mice. The results showed that t-CUPM significantly reduced the severity of chronic pancreatitis, as measured for the extents of acini loss, inflammatory cell infiltration and stromal fibrosis. The progression of low-grade mPanIN I to high grade mPanIN II/III was significantly suppressed by t-CUPM treatment. Inhibition of mutant Kras-transmitted phosphorylations of MEK/ERK was demonstrated in pancreatic tissues and in vitro pancreatic cancer cells by Western blot assay. qPCR analysis revealed that t-CUPM treatment resulted in significantly decreasing the levels of inflammatory cytokines including TNF-α, MCP-1, as well as VCAM-1, and the levels of Shh and GLI1 (Hedgehog pathway). Analysis of eicosanoid profile revealed a significant increase of the EET/DHET ratio that further confirmed sEH inhibition by t-CUPM. These results indicate that simultaneous inhibition of sEH and c-Raf by t-CUPM is important in preventing chronic pancreatitis and carcinogenesis. (supported by NIH R01CA172431)
Note: This abstract was not presented at the meeting.
Citation Format: Jie Liao, Wanying Zhang, Sung Hee Hwng, Haonan Li, Aaron T. Wecksler, Ke Ma, Bruce D. Hammock, Guang-Yu Yang. Inhibition of pancreatic carcinogenesis by t-CUPM, a dual inhibitor of c-Raf and soluble epoxide hydrolase. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1250. doi:10.1158/1538-7445.AM2014-1250
Abstract 1253: Dual PI3K/mTOR inhibitor NVP-BEZ235 in combination with AKT inhibitor MK2206 in esophageal carcinoma cells
Authors: Yu Hao , Shi Ni , Pan Zui , Chen Tong 
Published: May 2015

Abstract
The long-term goal of our research is to investigate the molecular carcinogenesis of esophageal squamous cell carcinoma and to develop strategies for esophageal cancer prevention. Previous studies in our laboratory demonstrated an association between activation of PI3K/AKT/mTOR pathways and the development of N-nitrosomethylbenzylamine (NMBA)-induced tumors in the rat esophagus. The objective of current study is to evaluate the effects of NVP-BEZ235, a dual PI3K/mTOR inhibitor, and MK2206, an AKT inhibitor, alone or in combination in esophageal cancer cell lines, KYSE-70, -150, -270 and -410. The cancer cell lines were treated with different doses of NVP-BEZ235 (1, 10, 50, 100, 1000 nMol/L) and MK2206 (0.5, 1, 3, 10, 20 uMol/L), or NVP-BEZ235 100 nMol/L plus MK2206 3 uMol/L. Western blot was performed to assess the activation of PI3K/AKT/mTOR pathways. Cell proliferation, apoptosis and cell cycle were analyzed by WST1 and flow cytometry. We found that the combination of NVP-BEZ235 and MK2206 significantly reduced the phosphorylation of p-AKTT308, p-AKTS473, p-mTORS2448, p-S6S235/236 and p-4EBP1T37/46, when compared to NVP-BEZ235 (1000 nMol/L) and MK2206 (20 uMol/L) alone (p&lt;0.05). The cell proliferation rate was reduced by NVP-BEZ235 1000 nMol/L, MK2206 20 uMol/L, or NVP-BEZ235 plus MK2206 to 20% (p&lt;0.01), 24% (p&lt;0.01) and 17% (p&lt;0.01), respectively. The NVP-BEZ235 1000 nMol/L and MK2206 10 uMol/L induced apoptosis in esophageal cancer cells to 30% and 20% (p&lt;0.01), respectively. NVP-BEZ235 plus MK2206 induced apoptosis in esophageal cancer cells to 45% (p&lt;0.01). The combination treatment increased the proportion of cells at G0/G1 phase compared to cells treated with NVP-BEZ235 or MK2206 alone. Our results indicate that co-targeting the PI3K/mTOR and AKT signaling pathways produces synergistic activity against esophageal carcinoma cell growth. This in-vitro study provides evidence to test the efficacy of NVP-BEZ235 in combination with MK2206 in inhibition of esophageal tumor development in vivo. (Supported by NIH/NCI R01 CA131073-01A1).
Citation Format: Hao Yu, Ni Shi, Zui Pan, Tong Chen. Dual PI3K/mTOR inhibitor NVP-BEZ235 in combination with AKT inhibitor MK2206 in esophageal carcinoma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1253. doi:10.1158/1538-7445.AM2014-1253
Abstract 1254: Novel acetal and halogen oridonin analogues potently induce apoptosis in prostate cancer cell lines via induction of p53/p73 and PUMA expression
Authors: Ke Yu , Liu Zhongbo , Liu Hong-Min , Zi Xiaolin 
Published: May 2015

Abstract
Isodon rubescens (a Chinese herb named “Donglingcao”) has been used as a folk, botanical medicine for treatment of inflammatory diseases and cancer for many years. Oridonin, a complex ent-kaurane diterpenoid that was isolated from this herb, has been demonstrated as a promising anti-cancer agent. However, the anti-cancer potency of oridonin and its in vivo stability remains unsatisfactory for its clinical development. Therefore, we have designed and synthesized a series of acetal and halogen oridonin analogues at the 20 position of the chemical skeleton. All these analogues have demonstrated improved potency over oridonin against the growth of bladder, breast, colon, lung and prostate cancer cell lines with low micromolar to submicromolar IC50 values. In particular, compound 10 potently induces apoptosis in both androgen-sensitive and castration-resistant prostate cancer cell lines, including LAPC4, LNCaP, 22Rv1, PC3 and DU145. Compound 10 increased the expression of YAP1 and its phosphorylation, as well as expression of p73 and p53, which further led to upregulation of p73/p53 target gene PUMA. The apoptotic effect of compound 10 is at least in part dependent on the existence of p53 and PUMA. These results demonstrated the potential of compound 10 as a novel apoptosis inducer for treatment of prostate cancer. The evaluation of the in vivo anti-tumor efficacy of compound 10 is in progress.
Note: This abstract was not presented at the meeting.
Citation Format: Yu Ke, Zhongbo Liu, Hong-Min Liu, Xiaolin Zi. Novel acetal and halogen oridonin analogues potently induce apoptosis in prostate cancer cell lines via induction of p53/p73 and PUMA expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1254. doi:10.1158/1538-7445.AM2014-1254
Abstract 1257: From chemoprevention strategy to identification of potential therapeutic targets and biomarkers for breast cancer
Authors: Ouhtit Allal , Shanmuganathan Somya , Gupta Ishita , Al-Riyami Hamad , Raj Madhwa 
Published: May 2015

Abstract
Over the years, several phyto-compounds have been extensively used in Complementary Alternative Medicine (CAM) studies, individually and often at higher doses to kill cancer cells. Based on the combination and synergism theory, we had previously demonstrated that a combination of Resveratrol and Indole-3-Carbinol synergized and killed a maximum number of Breast Cancer cells. In the present study, we have tested various combinations of 10 well known phytochemicals, used at bioavailable levels, for their effect on cell growth and proliferation of the MDA-MB-231; breast cancer (BC) cell line and MCF-10A; normal breast epithelium as control cell line. The results revealed a super combination of 7 phyto-compounds (7SC), that synergized and induced 100% clearance of the BC cells but did not affect the normal breast epithelial cells. Next, in order to understand the underlying molecular mechanisms of this ‘synergism’ effect, microarray analysis will be conducted on the mRNA collected from the 7SC treated and control cells at 12 and 24 hour time points. Ongoing in vivo experiments aim to evaluate the efficacy of the 7SC phyto-compound treatment in preventing tumor growth using xenograft mouse BC model, and further validate the functional relevance of these genes in BC cell growth and survival. The data supports our hypothesis that the 7SC could be used in CAM as a dietary supplement approach against BC, and further identify genes that have the potential to serve as biomarkers and gene candidate to guide the design of appropriate anti-BC therapeutic strategies.
Note: This abstract was not presented at the meeting.
Citation Format: Allal Ouhtit, Somya Shanmuganathan, Ishita Gupta, Hamad Al-Riyami, Madhwa Raj. From chemoprevention strategy to identification of potential therapeutic targets and biomarkers for breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1257. doi:10.1158/1538-7445.AM2014-1257
Abstract 1258: Knockdown or inhibition of Aldo-keto reductase 1B10 inhibits pancreatic carcinogenesis via modulating Kras-E-cadherin pathway
Authors: Zhang Wanying , Li Haonan , Ma Ke , Liao Jie , Yang Guang-Yu 
Published: May 2015

Abstract
Aldo-keto reductase 1B10 (AKR1B10) is an essential enzyme in the metabolism of carbonyls, retinal and farnesal/geranylgeranial for maintaining cellular homeostasis of retinal-retinoid acid, detoxifying the active carbonyls, and recycling key intermediate products of cholesterol synthesis. All of these biologic processes are crucial contributing to carcinogenesis, particularly the reduction of farnesal/geranylgeranial involves in protein prenylation and for mutant K-ras activity. Mutant K-ras is a most common oncogene in pancreatic cancer, and over expression of AKR1B10 has been identified in pancreatic cancer. To determine the role of AKR1B10 in pancreatic carcinogenesis, silencing of AKR1B10 was achieved in CD18 human pancreatic carcinoma cell line using shRNA knockdown approach. Silencing of AKR1B10 resulted in a significant inhibition of anchor-dependent growth (shRNA AKR1B10 knockdown cells compared to vector-control cells 67 ± 9.5 colonies/HPF vs 170 ± 3.7 colonies/HPF, P &lt; 0.01), invasion index (0.27 vs. 1.00, p&lt;0.05), and cell migration (at 16 hours 9.2 ± 1.2% vs 14.0 ± 1.8%, at 24 hours 21.0 ± 1.1% vs 30.5 ± 3.5%, and at 48 hours 51.9 ± 5.7% vs 88.9 ± 3.0%, P &lt; 0.01). Oleanolic acid (OA), a naturally occurring triterpenoid compound, showed a potent inhibition of AKR1B10 activity and a dose-dependent inhibition of cell growth with IC50 at 30µM. K-ras pull-down and Western blot analysis revealed a significant down-regulation of active form K-ras and phosphorylated C-Raf, and ErK,as well as an up-regulation of E-cadherin by either AKR1B10 knockdown or inhibition. A significant reduction of in vivo tumor growth was observed in nude mice implanted the CD18 pancreatic carcinoma cells with shRNA AKR1B10 knockdown (tumor weight: 0.25 ± 0.06g vs. 0.52 ± 0.07g, P = 0.01), and with AKR1B10 inhibitor OA (tumor weight: 0.35 ± 0.05g vs. 0.52 ± 0.07g, P = 0.05). Our findings indicate AKR1B10 is a unique enzyme involved in pancreatic carcinogenesis possibly via modulation of protein prenylation (KRAS)-E-Cadherin pathway. (supported by NIH R01CA164041)
Note: This abstract was not presented at the meeting.
Citation Format: Wanying Zhang, Haonan Li, Ke Ma, Jie Liao, Guang-Yu Yang. Knockdown or inhibition of Aldo-keto reductase 1B10 inhibits pancreatic carcinogenesis via modulating Kras-E-cadherin pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1258. doi:10.1158/1538-7445.AM2014-1258
Abstract 1259: Gut microbiota and mucosal inflammation and colorectal neoplasia
Authors: Keku Temitope O. , Bonakdar Romin , Perez Felix Araujo , McCoy Amber N. , Edmundson Patrick , Smith Kevin 
Published: May 2015

Abstract
Colorectal cancer (CRC) is a leading cause of cancer death in the United States. Chronic inflammation has been linked to colorectal neoplasia. More recent studies also implicate imbalances in the gut microbiota (bacteria) CRC. We sought to understand the relationship between the gut microbiota, mucosal inflammation and colorectal adenomas, CRC precursors. We hypothesized that the gut microbiota promotes inflammation via activation of mucosal immune cells to elevate adenoma risk. We examined the relationship between adherent gut bacteria, mucosal immune cells, namely T cells (CD4+ and CD8+), macrophages (CD11b+) and natural killer cells (CD57+) and adenomas in a case control study.
Methods: Participants were consenting screening colonoscopy patients at UNC Hospitals without history or diagnosis of inflammatory bowel disease. Subjects were defined as cases (n=42) or controls (n=35) based on the presence or absence of adenomas. High throughput deep sequencing method was used to assess the microbiota in normal colonic mucosa of cases and controls. Immune cells were assessed by immunohistochemistry and automated image analysis using Aperio software. Differences in microbiota abundance or mucosal immune cell numbers between cases and controls were evaluated by t-tests. Diversity was measured by Shannon diversity. Correlation between bacteria and immune cells was performed using Spearman's correlation.
Results: Cases had higher WHR than controls (p=0.0001). No difference was observed for age, sex, BMI among cases and controls. The abundance of several bacteria taxa differed significantly between cases and controls. We observed a positive relationship between mucosal immune cell density and adenomas. In particular, CD 4+ density and CD4/CD8 ratio were higher in cases than controls (CD4; 1.44 case, 0.69 control p = 0.001; CD4/CD8 1.66 case, 0.56 control, p= 0.002). There were no statistically significant differences in CD 57+, CD11b or CD 8+ cell density between cases and controls. The correlation patterns between the gut microbiota and immune cells differed markedly for cases and controls. There was a positive correlation between Proteobacteria and CD4 or CD4/CD8+ cells among cases but not controls.
Conclusions: our results suggest that the gut bacteria and immune cells are interacting differently depending on adenoma status. These findings suggest activation of mucosal immune cells by bacteria may promote local inflammation and contribute to the etiology of colorectal cancer.
Citation Format: Temitope O. Keku, Romin Bonakdar, Felix Araujo Perez, Amber N. McCoy, Patrick Edmundson, Kevin Smith. Gut microbiota and mucosal inflammation and colorectal neoplasia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1259. doi:10.1158/1538-7445.AM2014-1259