bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5659: Down-regulation of hTERT sensitizes chemotherapeutic effects of docetaxel in human prostate cancer cells via suppression of PIM-1 oncogene
Authors: Rajendra Ashoka S. , Jagadeesh Shankar , Banerjee Partha P. 
Published: February 2011

Abstract
Taxanes comprise some of the most widely used cancer chemotherapeutic agents for various cancers. Docetaxel is an effective first-line treatment for hormone-refractory prostate cancer. However, despite the recently demonstrated survival benefits of docetaxel-based chemotherapy, most patients will move from response to progression within 6 months. Moreover, effective concentrations of docetaxel have side effects including localized erythema of the extremities with edema followed by desquamation, severe neuropathy, fatigue, and weakness which can have debilitating effects in patients with prostate cancer. One reason for disease progression is the up-regulation of PIM-1 expression following docetaxel treatment of prostate cancer cells. PIM-1 is a serine-threonine kinase that promotes survival by inhibiting the activity of apoptotic proteins. In a recent study, we observed that a telomerase suppressing small molecule MST-312, and hTERT siRNA down-regulated PIM-1 protein level in prostate cancer cells. These results prompted us to investigate whether combination of docetaxel with inhibition of telomerase by MST-312 or TERT siRNA would have synergistic effects on prostate cancer cell growth and induce death. Treatment of PC3 cells with 1 nM of docetaxel for 3 days substantially promoted the viability of cells compared to the control, with a 27% increase in cell number. This increase was associated with the up-regulation of PIM-1. Treatment of telomerase inhibitory concentration (2 μM) of MST-312 over 3 days resulted in a 51% decrease in cell viability relative to the 1 nM docetaxel treated groups, associated with a decrease in PIM-1 protein levels. More interestingly, treatment of 2 μM MST-312 with 1 nM docetaxel for 3 days resulted in 72% reduction in cell viability compared to docetaxel alone and 43% reduction in cell viability compared to MST-312 alone. This combined treatment also resulted in lower levels of PIM-1 activity than MST-312 or docetaxel treatment alone. These results suggest that there is synergy between the combination of telomerase inhibitor MST-312 with docetaxel in the treatment of metastatic prostate cancer. This can be explained by the down-regulation of PIM-1 kinase that promotes resistance to docetaxel treatment. These findings suggest potential clinical benefit by the combined use of docetaxel and telomerase inhibitors for prostate cancer treatment.
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 5659.
Abstract 5660: Galbanic acid downregulates androgen receptor and induces G1 arrest and apoptosis in LNCaP cells
Authors: Zhang Yong , Kim Kwan-Hyun , Lee Hyo-Jeong , Kim Sung-Hoon , Lü Junxuan 
Published: February 2011

Abstract
Studies have demonstrated that androgen receptor (AR) is crucial for the genesis and progression of human prostate cancer (PCa). Targeting AR signaling is an important approach for the prevention of PCa. Identification of novel herbal phytochemicals that target AR signaling from Oriental medicinal herbs holds the promise to deal with this malignant disease at the root. Ferula asafetida is used as a food spice and as a traditional herbal medicine for many illnesses in Asia, where the incidence of PCa is lower than that in USA. We report here, for the first time, that one of the main components of ferula asafetida, galbanic acid (GA) down-regulates AR and suppresses the growth of LNCaP cells via an induction of G1 arrest and apoptosis. After exposure to GA for 24h and 48h, GA dose-dependently decreased cellular AR level via posttranscriptional and posttranslational regulation in LNCaP cells. Consequently, GA dose-dependently reduced PSA protein expression and inhibited its AR-dependent promoter transactivation. Flow cytometric analysis showed that GA does-dependently induced G1 arrest accompanied by a decrease of CDK4, dephosphorylation of RB and inhibition of E2F1-dependent target gene products, but independent of p21 and p27. In addition, GA induced moderate apoptosis characterized by increased cleaved PARP, DNA fragmentation and annexinV staining as early as 6h after treatment. The induction of apoptosis was attenuated by a general caspase inhibitor (zVADfmk), supporting caspase-dependency. Furthermore, colony formation assay showed that GA suppressed the growth of LNCaP cells with an IC50 of approximate 7 microM. In contrast, GA did not affect the cell cycle distribution or apoptosis or growth of AR-independent DU 145 or PC-3 cells at the same doses of exposure. Taken together, these data suggests that GA exerts growth inhibitory effect against AR-dependent PCa with down-regulation of AR signaling and the induction of G1 arrest and apoptosis.
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 5660.
Abstract 5668: Nexrutine, a phellodendron amurense extract protects against breast cancer
Authors: Lanza-Jacoby Susan , Yan Guang , Wang Chenguang 
Published: February 2011

Abstract
Breast cancer is the most common cancer in women with over 40,000 deaths per year in the United States. Prognosis is poor for a subset of women with estrogen receptor (ER) negative or ErB2 overexpressing ER negative tumors because their cancers are aggressive and do not respond to conventional treatment. This emphasizes the importance of developing new agents and protocols for preventing breast cancer. Numerous epidemiological studies suggest that plant-based diets are protective against many types of cancer. Nexrutine, an herbal extract from the Chinese plant Phellodendron amurense, has been used for centuries in Chinese medicine to treat inflammation, gastroenteritis, abdominal pain, and diarrhea. The anti-inflammatory properity of Nexrutine is of particular relevance considering the relationship of inflammation to cancer. Many tumors including those of the breast have high levels of cyclooxygenase (COX)-2., which result in increased levels of the proinflammatory mediator prostaglandin (PG) E2.
In this study we investigated the anti-cancer effects of Nexrutine on several breast cancer cell lines. Nexrutine decreased activities of COX-2 and peroxisome proliferators activated receptor gamma (PPAR)γ; two potential biomarkers of breast cancer. Nexrutine reduced the production of PGE2, which was associated with decreased protein expression of microsomal PGE2 synthase (mPGES) and increased PG 15-dehydrogenase (15-PGDH). The Nexrutine decreased cell survival, which was accompanied by a G1 cell cycle arrest, increased autophagy, and cell death in SkBr3 and MDA-MB 231 cells. Analysis of the cell cycle regulators indicated a decrease in Cyclin D1, cdk 2, Cyclin E, and decreased phosphorylation of retinoblastoma protein and increase in p21 and p27. Based upon these findings, we propose that the use of Nexrutine could provide a novel approach for protection against breast cancer.
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 5668.
Abstract 5669: Aldose reductase is a novel therapeutic target to prevent oxidative stress-induced inflammatory signals in prostate cancer
Authors: Tammali Ravinder , Ramana Kota V. , Srivastava Satish K. 
Published: February 2011

Abstract
Prostate Cancer (PC) is one of the most common cancers in American men, especially as they age. Although PC initially responds to androgen therapy, as the cancer progresses it usually becomes androgen-independent and prone to metastasis and multi-drug resistance, which kills the majority of patients within 5 years of diagnosis. Therefore, it is necessary to develop better therapeutic strategies which could prevent both early and late stage PC. Our recent studies demonstrate that Aldose Reductase (AR) is the main mediator of inflammatory signals induced by growth factors, cytokines, chemokines, carcinogens etc. Since inflammation is known to play a central role in PC, we investigated the possible role of AR in heterogenous androgen-dependent, -independent, and multi-drug resistant PC cells. Using androgen -dependent LNCaP and -independent PC-3 cells, we have determined the effect of AR inhibition on growth factors such as IGF- and EGF -induced proliferation, cell cycle progression, and generation of reactive oxygen species (ROS). We also determined the effect of AR inhibition on the phosphorylation/expression of androgen receptor, PSA, AKT/PI3K, NF-kB etc in PC cells. Our results show that inhibition of AR by fidarestat significantly prevented the IGF -and EGF-induced proliferation and generation of ROS in both androgen -dependent (LNCaP) and -independent (PC3) PC cells. Cell cycle analysis suggested that inhibition of AR prevents IGF-induced entry of cells from G1 to S phase in PC3 cells. Inhibition of AR also prevented IGF-induced activation of AKT/PI3K and NF-kB. Results with androgen-dependent LNCaP cells showed that inhibition of AR prevented the phosphorylation of androgen receptor, and secretion and expression of PSA when cells were cultured in 5% serum. Further, inhibition of AR increased the drug-sensitivity of multi-drug-resistant PC3 cells against chemotherapeutic agents such as cisplatin, docetaxel, doxorubicin, and methotrexate. These results indicate that AR mediates oxidative stress -induced inflammatory signals in prostate carcinogenesis. Hence, AR inhibition could be a potential therapeutic target against prostate cancer.
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 5669.
Abstract 5670: Piceatannol, a catechol-type polyphenol, inhibits phorbol ester-induced NF-κB activation and cyclooxygenase-2 expression in human breast epithelial cells: Cys179 of IKKβ as a potential target
Authors: Son Phil-Soon , Park Sin-Aye , Na Hye-Kyung , Surh Young-Joon 
Published: February 2011

Abstract
There are multiple lines of evidence supporting that inflammation is linked to carcinogenesis. Nuclear factor-κB (NF-κB), a master redox-sensitive transcription factor responsible for the induction of a wide array of proinflammatory genes, is frequently overactivated in many tumors. Moreover, constitutive activation of IκB kinase (IKK), a key regulator of NF-κB, has been implicated in inflammation-associated tumorigenesis. Piceatannol (3,5,3′4′-tetrahydroxy-trans-stilbene: PIC) derived from grapes, Rhubarb, and sugar cane, exhibits immunosuppressive and antitumorigenic activities in several cell lines, but the underlying mechanisms are poorly understood. In the present study, we found that PIC inhibited migration and anchorage-independent growth of human mammary epithelial cells (MCF-10A) treated with the prototypic tumor promoter, 12-O-tetracecanoylphorbol-13-aceate (TPA). PIC treatment suppressed the TPA-induced activation of NF-κB and cyclooxygenase-2 (COX-2) expression in MCF-10A cells. We hypothesize that an electrophilic quinone formed as a consequence of oxidation of PIC bearing the catechol moiety may directly interact with critical cysteine thiols of IKKβ, thereby inhibiting its catalytic activity. The reducing agent dithiothreitol and the antioxidant N-acetylcysteine abrogated inhibitory effects of PIC on TPA-induced activation of NF-κB and expression of COX-2. PIC incubated with whole cell lysate from MCF-10A cells stimulated with TPA inhibited IKKβ kinase activity. The inhibitory effect of PIC was reversed when DTT was cotreated. In addition, the inhibitory effects of PIC on NF-κB signaling and COX-2 induction were blunted in cells expressing mutant IKKβ (C179A) in which cysteine 179 was replaced by alanine. In conclusion, our results suggest that modification of cysteine residues of IKKβ by PIC blocks NF-κB activation signaling and COX-2 induction in TPA-treated MCF-10A cells and also migration and transformation of these cells.
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 5670.
Abstract 5677: Inhibition of Azoxymethane-induced aberrant crypt foci in C57BL/6 mice by the Chinese medicinal herb Scutellaria barbata
Authors: Wong Brian Yuen Yau , Kim Lucas Y. , Kim Brian Y. , Jung Jeeyoon , Nishikawa Christal Y. , Zima Alyssa K. , Hausted Randy P. 
Published: February 2011

Abstract
Scutellaria barbata (SB) is a perennial herb of the mint family which has been used to treat appendicitis, hepatitis, pulmonary abscess, and cancers of the liver, lung, and colon in Chinese medicine. Our early studies showed that SB contained phytochemicals that inhibited mutagenesis, DNA binding, and metabolism of aflatoxin B1 (AFB1) and benzo[a]pyrene bioactivated by Arcoclor 1254-induced rat S9. It also inhibited the mutagenicity of AFB1 bioactivated by either non-induced or DXM-induced hepatic S9, suggesting its effect via an inhibition of CYP3-mediated metabolism of [3H]AFB1. Recent oral feeding data demonstrated that SB could delay prostate tumor development in TRAMP mice. Complementary in vitro data indicated that SB may exert this function via up-regulating the apoptotic pathway and down-regulating the survival pathway in murine (TRAMP-C1) and human (LNCaP) prostate cancer cells. Inhibitory effects of SB were also observed in inducing cell death in human (LoVo) colon cancer cells. This study investigated the effects of SB on azoxymethane (AOM)-induced aberrant crypt foci (AFC) formation in C57BL/6 mice. Thirty C57BL/6 mice of 9 wks old were randomized into three groups (N=10). Mice of the positive control and experimental groups were injected with AOM (5 mg/kg body wt) at the beginning and second wk of the 8-wk duration while the negative control group received no injection. Animals in the experimental group received daily oral feedings of 24 mg SB since day 1 while mice in the other two groups were given sterilized-water placebo. SB feeding significantly reduced the number of AOM-induced ACF in the proximal colon (25 mm) compared with the water-fed positive control AOM-induced group (8.35 ± 5.56 &lt; 32.1 ± 9.86; P&lt; 0.000047). The negative non-induced group had minimal ACF (2.0 ± 1.56) compared to the experimental and positive control groups (P&lt; 0.0056; P&lt; 0.0000034 respectively). The potency index of the herb was calculated as 3.84. Significant percent inhibition (74%) of AOM-induced ACF formation was obtained with SB treatment. Mice in all three groups had gained wt (% increase) in the course of the experiment (negative control, 16.2 ± 4.32 &lt; experimental, 20.7 ± 10.39 &lt; positive control, 35.78 ± 16.79). These in vivo data suggest the potential chemopreventive and treatment potential of SB.
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 5677.
Abstract 5679: Differential phosphorylation of EGFR in response to PUFA supplementation
Authors: Hernandez Karla , Rogers Kristina R. , Kikawa Keith D. , Mouradian Michael , Pardini Ronald S. 
Published: February 2011

Abstract
Epidermal Growth Factor Receptor (EGFR) is a 170 kDa transmembrane glycoprotein responsible for the initiation of a variety of cellular signaling cascades governing cell proliferation and survival, which are initiated by specific phosphorylation sites in its tyrosine-kinase domain (TKD). Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid (PUFA) that has been demonstrated to have positive effects on human health, including the inhibition of tumor growth in various cancer cell lines, both in vivo and in vitro. Preliminary data in our laboratory has shown that supplementation with both DHA, and the omega-6 PUFA, linoleic acid (LA), are capable of upregulating total EGFR phosphorylation in the TKD. Subsequent investigations have identified that increased EGFR phosphorylation in DHA treatments is largely due to enhanced phosphorylation at one particular site, the tyrosine 1068 residue. However, because EGFR has numerous activation sites, a systematic evaluation of the changes in EGFR phosphorylation upon supplementation with DHA and LA is necessary. The current research demonstrates specific EGFR phosphorylation events that are altered by PUFA supplementation. This data will provide critical insight into how PUFAs may be exerting some of the many other signaling changes that have been associated with their use (i.e. decreased p38, MAPK, pAkt, etc.).
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 5679.
Abstract 5681: Flavokawain B down-regulates SKP2 through a proteasome-dependent and ubiquitin-independent pathway, and acts synergistically with Bortezomib on inhibition of Skp2 expression and prostate cancer cell growth
Authors: Li Xuesen , Liu Zhongbo , Simoneau Anne R. , Zi Xiaolin 
Published: February 2011

Abstract
The E3 ubiquitin ligase SKP2 (S-phase kinase-associated protein 2), an oncogenic protein, was found to be overexpressed in 557 of 622 (89.2%) primary prostate cancer (PCa) samples and in 64 of 74 samples (86.4%) high-grade prostatic intra-epithelial neoplasia lesions. In addition, a transgenic mouse model with prostatic over-expression of SKP2 develops low-grade adenocarcinomas. These results suggest that SKP2 could be a potential target for PCa chemoprevention. In a search for SKP2 targeting agents for PCa chemoprevention, we found that Flavokawain B, a chalcone found in multiple edible plants- including roots of Alpinia speciosa (family Zingiberaceae) and Piper methysticum Forst (kava kava), potently down-regulates the protein expression of SKP2 in several prostate cancer cell lines (LNCaP, C4-2B, DU145 and PC3) at a concentration of 8.8 µM. More importantly, Flavokawain B reduces the cell viability of transfected PC3 cell line stably overexpressing SKP2 compared to vector control-transfected PC3 cells (IC50s are 7 and 26.4 µM, respectively), which suggest that flavokawain B may target SKP2 for its growth inhibitory effect. Flavokawain B treatment did not decrease the promoter activity and mRNA levels of SKP2. Instead, Flavokawain B decreases the protein levels of both a native and a myc-tagged SKP2 in PC3 cells through promoting its degradation. The degradation of the myc tagged SKP2 can be recovered by a proteasome inhibitor MG132. MG132 treatment resulted in an increase of ubquitinated SKP2, whereas Flavokawain B did not affect SKP2 ubquitination. These data suggest that the degradation of SKP2 by Flavokawain B may be through a proteasome-dependent and ubquitination-independent pathway. Interestingly, proteasome inhibitors (MG132 and Bortezomib) also down-regulate SKP2 mRNA expression through transcriptional inhibition, and combination of Bortezomib or MG132 with Flavokawain B exhibits a synergistic effect on SKP2 down-regulation and cell growth inhibition via induction of G2M arrest in PCa cell lines. Taken together, Flavokawain B is a novel SKP2 target agent and deserves further investigation for PCa chemoprevention and therapy.
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 5681.
Abstract 5686: Linoleic acid supplementation upregulates phosphatidylinositol-3-kinase signaling by increasing the association between Gab1 and EGFR
Authors: Kikawa Keith D. , Johnson Eric D. , McKinnon Kristen M. , Rogers Kristina R. , Pardini Ronald S. 
Published: February 2011

Abstract
The omega-6 polyunsaturated fatty acid, linoleic acid (LA), is prevalent in Western diets and is known to enhance the tumorigenesis of mammary cancer models; with previous work demonstrating an upregulation of phosphatidylinositol-3-kinase (PI3K) signaling may play a key role. The Grb2-associated binding protein 1 (Gab1) is a scaffolding protein that can complex with the epidermal growth factor receptor (EGFR) to activate PI3K signaling. Recent studies in our laboratory reveal LA supplementation of the breast cancer cell lines MDA-MB-231 and BT-474 greatly increases the association between Gab1 and EGFR, while at the same time dramatically decreasing Gab1 protein levels. These changes are concomitant with increases in activated Akt (pAkt), a downstream signaling component in the PI3K signaling pathway. Moreover, inhibitors of EGFR and Gab1-specific siRNAs are capable of reversing LA-induced upregulation of pAkt, as well as observed increases in cell proliferation for these models. Finally, we were able to confirm these findings in the A549 lung cancer cell line, validating the potential relevance to tissues other than breast cancer cell lines. These data establish Gab1 as major target in LA-induced enhancement of tumorigenesis.
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 5686.
Abstract 5689: Phtalates toxicity on normal lymphocytes
Authors: Rosado Carlos A. , Velez Christian , Zayas Beatriz 
Published: February 2011

Abstract
The main purpose of this study is to determine the toxicity and cell death mechanism of the phthalate Di-ethylhexyl (DEHP) and its principal metabolite, Mono-ethylhexyl (MEHP) on the TK-6 human lymphocytic cell line. Phthalates are a family of compounds used widely in the manufacturing industry and in the production of plastics. Exposure to these compounds can be through plastic items and personal care products. Phthalates are considered estrogen disrupters and effects on the reproductive and respiratory systems have also been reported by the scientific community. Studies, of the effect of phthalates on the immune system however are limited. The analysis of the effects of phthalates on normal lymphocytes could allow the development biomarkers of exposure to phthalates. TK-6 lymphocytes cells were cultured on 25cm2 flasks on modified RPMI culture media with 10% FBS, and incubated at 37oC and 5% CO2. TK-6 cells were exposed to DEHP or MEHP at doses ranging from 5μM, to 350μM for 48 and 72 hours. Cytotoxicity, ROS generation and mitochondrial membrane permeabilization were measured by Trypan Blue exclusion, DCFH-DA ROS assay and Mito PT assay respectively. Cytotoxicity results indicated higher resistance of TK-6 to the parent compound DEHP in comparison to the metabolite MEHP with IC50s of 100uM and 75uM respectively. Preliminary ROS generation analyses suggest induction of ROS generation by both parent and metabolite. mitochondrial membrane permeability analysis also indicated some degree of mitochondrial interaction.
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 5689.