bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4403: Differential cytotoxic effects of atorvastatin in human hepatocellular carcinoma and pancreatic adenocarcinoma cells
Authors: Lai Maria B. , Bhardwaj Vikas , Lai James CK , Bhushan Alok 
Published: June 2012

Abstract
Statins are lipid-lowering drugs that inhibit 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting step in cholesterol synthesis. During cholesterol synthesis, isoprenoid intermediates are also formed which prenylate Ras and Rho proteins. Upon prenylation and transportation to the plasma membrane, Ras and Rho may interact with other molecules to partake in a signaling cascade that eventually lead to cell survival and proliferation. When statins inhibit cholesterol synthesis, they also inhibit the formation of these isoprenoid. Our studies focus on the potential anticancer effects of a statin (atorvastatin) in human hepatocellular carcinoma (HepG2) and pancreatic adenocarcinoma (AsPC-1) cells. We hypothesized that atorvastatin enhances cytotoxic effects of cisplatin in HepG2 and AsPC-1 treated cells. By utilizing a cell survival assay and western blot analysis, we found marked differences between the two cell lines after atorvastatin treatment. Our results indicate that treatment with atorvastatin at a concentration range of 0.1 µM to 20 µM for 48 and 72 hours significantly decreased cell survival of AsPC-1 cells, but not that of HepG2 cells. The IC50 value for atorvastatin in AsPC-1 treated cells was 3.5 µM; whereas, no effect on HepG2 cell survival was observed even at 20 µM concentration. Treatment with atorvastatin in combination with cisplatin in HepG2 cells did not potentiate the decrease in cell survival as compared to cisplatin treatment alone. However, treatment with 10 µM of atrovastatin in combination with 20 µM of cisplatin for 72 hours antagonized the effects of cisplatin treatment alone. After 48 hour treatments with atorvastatin, HepG2 and AsPC-1 cells had differential p-ERK expression, which could be an important factor in atorvastatin-induced cell death. Our preliminary findings suggest that statin treatment may be beneficial as a therapeutic avenue for pancreatic cancer but may not have the same benefits for liver cancer. The specific molecular mechanisms that decrease cancer cell survival following statin treatment have not been well understood and needs to be further studied. [Our project is supported by in part from NIH INBRE Grant P20RR016454].
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4403. doi:10.1158/1538-7445.AM2011-4403
Abstract 4409: A quantitative MSD assay to measure c-IAP1 degradation in PBMC, cell lines and tumor cells as a pharmacodynamic biomarker following antagonism of IAP family members
Authors: Kadel Edward E. , West Kristina , McNamara Erin , Low Justin , Khosraviani Mehraban , Mamounas Michael , Fairbrother Wayne J. , Darbonne Walter C. 
Published: June 2012

Abstract
The Inhibitor of Apoptosis (IAP) protein family members are widely expressed in many cancers, providing a mechanism to protect these cancer cells from apoptosis. The IAP proteins block activation of the canonical and non-canonical NF-kB pathway, the subsequent expression of TNFα and its initiation of the extrinsic apoptosis pathway. IAP proteins also directly bind and inhibit caspases activated during the induction of apoptosis. Using MDA-MB-231 cells as a model system to assess the effect of candidate IAP antagonists on markers of extrinsic and intrinsic pathway inhibition, we observe that the antagonism of the major IAP family members results in apoptosis in vitro and inhibits their tumor growth in nude mice in vivo. These effects are coincident with changes in the cellular levels of IAP family members such as c-IAP1, detected by Western analysis. These data are consistent with previously described autoubiquitination and subsequent proteasomal degradation of c-IAP1 following IAP antagonism. We have developed a high-throughput, quantifiable and sensitive assay to measure c-IAP1 levels in multiple cell lines, xenografts and in PBMCs using the MesoScale Discovery (MSD) Platform. The c-IAP1 MSD assay has a lower limit of quantification of 1.6 ng/ml of cell lysate, has precision of &lt;10% CV and is linear down to at least a 4-fold dilution of lysate. Quantifiable changes in cellular c-IAP1 protein may serve as an ideal proximal pharmacodynamic (PD) biomarker to measure IAP family inhibition and degradation in the cell, particularly in the evaluation of candidate inhibitors targeting the IAP pathway in the clinical setting.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4409. doi:10.1158/1538-7445.AM2011-4409
Abstract 441: Degree or extent of radially-aligned collagen fibrils in the tumor-stromal interface of rodent mammary tumor tissue is an indicator of chemotherapeutic potential of the EGFr inhibitor, Gefitinib
Authors: Ericson Marna E. , Nye Steffan , Bode Ann , Grubbs Clinton , Lubet Ron 
Published: June 2012

Abstract
There is an urgent need for unbiased evaluations of potential therapeutic treatments. An early indicator of treatment efficacy might allow for a more individualized and effective therapeutic regimen. In the present study we employed the MNU model of ER+ mammary tumors to address this question. Rats were treated with MNU at 50 days of age. When an animal developed a palpable mammary tumor it was randomized either to Iressa (6 mg/kg BW) or vehicle. Two days following this time animals were biopsied. Three days later animals were replaced on Iressa or vehicle for a period of 6 weeks. The objective was to determine whether tumors that responded to Iressa over a 6 week period exhibited changes in collagen fibril orientation relative to unresponsive tumors within two days of initial treatment. We examined collagen fibril orientation at the tumor-stromal interface. We employed a second harmonic generation (SHG) imaging protocol and examined collagen fiber orientation in normal glands, untreated tumors, tumors treated for 2 days which would then regress or not. We found that untreated tumors or non responsive tumors appeared to have a relatively disoriented pattern at the tumor-stromal interface whereas responding tumors within two days of treatment showed greater orientation of collagen fibrils oriented parallel to the tumor boundary. Thus the degree or extent of radially-aligned collagen fibrils in the tumor-stromal interface of rodent mammary tumor tissue is an indicator of chemotherapeutic potential of the EGFr inhibitor, Gefitinib (Iressa).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 441. doi:10.1158/1538-7445.AM2011-441
Abstract 4414: Clinical significance of CHD1L in hepatocellular carcinoma and therapeutic potentials of virus-mediated CHD1L depletion
Authors: Chen Leilei , Chan Hon Man , Guan Xin-Yuan 
Published: June 2012

Abstract
Background: Hepatocellular carcinoma (HCC) is among the most lethal of human malignancies. It is difficult to detect early, has a high recurrence rate and is refractory to chemotherapies. Amplification of 1q21 is one of the most frequent genetic alterations in HCC. CHD1L is a newly identified oncogene responsible for 1q21 amplicon. This study aims to investigate the role of CHD1L in predicting prognosis and chemotherapy response of HCC patients, its chemo-resistant mechanism and whether virus-mediated CHD1L silencing has therapeutic potentials for HCC treatment.
Methods: We assessed the clinical significance of CHD1L in a cohort of 109 HCC cases including 50 cases who received transarterial chemoembolization (TACE) treatment by clinical correlation and Kaplan-Meier analyses. CHD1L-overexpressing cell model was generated and the mechanism of CHD1L-involved chemo-resistance was investigated. Adenovirus-mediated silencing method was used to knockdown CHD1L and its effects on tumorigenicity as well as chemo-resistance were investigated in vivo and in vitro.
Results: Overexpression of CHD1L was significantly associated with tumor microsatellite formation (p=0.045), advanced tumor stage (p=0.018), overall survival (OS) time (p=0.002), OS time of patients who received TACE treatment (p=0.028) and chemo-resistance (p=0.020) in HCC. Interestingly, CHD1L could inhibit apoptosis induced by 5-fluorourail (5-FU) but not doxorubicin (DOX). The mechanistic study revealed that the involvement of Nur77-mediated pathway in chemotherapeutic agent-induced apoptosis can dictate if CHD1L could confer resistance to chemotherapy. Furthermore, adenoviral vector containing shRNAs against CHD1L (CHD1L-shRNAs) could suppress cell growth, clonogenicity and chemo-resistance to 5-FU. In vivo study found that CHD1L-shRNAs could inhibit xenograft tumor growth and increase the sensitivity of tumor cells to 5-FU in nude mice.
Conclusions: Our study highlighted for the first time the prognostic value of CHD1L in HCC and the potential application of virus-mediated CHD1L silencing in HCC therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4414. doi:10.1158/1538-7445.AM2011-4414
Abstract 4415: Inhibition of mammalian target of rapamycin (mTOR) signaling by Temsirolimus as a potential therapeutic strategy for esophageal cancer treatment
Authors: Takaoka Munenori , Nishikawa Toshio , Ohara Toshiaki , Tomono Yasuko , Fujiwara Yasuhiro , Shirakawa Yasuhiro , Nagatsuka Hitoshi , Fukazawa Takuya , Yamatsuji Tomoki , Bao Xiaohong , Hao Huifang , Shigemitsu Kaori , Morita Ichiro , Fujiwara Toshiyoshi , Naomoto Yoshio 
Published: June 2012

Abstract
[Introduction] Mammalian target of rapamycin (mTOR) is an intracellular serine/threonine kinase involved in the control of translational initiation by activating its downstream molecules such as S6 kinase and 4E-BP1 and therefore plays a critical role for cell proliferation, survival and angiogenesis, each of which is infinitely activated during cancer progression. Recently, chemical inhibitors against mTOR have been synthesized and Temsirolimus, an analog of rapamycin, has been approved for clinical usage to renal cell carcinomas. Since esophageal cancer is one of the most aggressive cancers with poor prognosis, we aimed to explore a potential effectiveness of Temsirolimus as a new therapeutic option to treat esophageal cancer.
[Methods] Firstly, we performed immunohistochemistry for phosphorylated mTOR in fifty-eight cases of surgically resected esophageal squamous cell carcinoma (ESCC) tissues and cultured ESCC cell lines (TE-1, TE-8, and TE-10) to compare its expression to normal esophageal epithelial tissues or primary esophageal epithelial cells. Next we treated these ESCC cells with a novel mTOR inhibitor, temsirolimus to determine its inhibitory effects on the expression of the downstream molecules and cancer cell growth. Furthermore, we administered temsirolimus weekly to nude mice with subcutaneous or orthotopic xenograft with TE-8 cells to obtain its antitumor effects and a benefit of prolonged survival.
[Results] The expression of phosphorylated mTOR was increased in 46 of 58 ESCC tumors (79.3%) and appeared to get strengthened with tumor progression. All of ESCC cell lines revealed an increase of mTOR phosphorylation, accompanied with the upregulation of hypoxia inducible factor-I alpha (HIF-1α), one of the downstream effectors of mTOR. Temsirolimus treatment apparently suppressed mTOR phosphorylation and the activation of its downstream effectors, resulting in the reduced ability of ESCC cell proliferation. Finally, the weekly administration of temsirolimus significantly diminished the size of subcutaneous tumors in nude mice and effectively prolonged orthotopic esophageal cancer-bearing mice.
[Conclusion] As the increased activity of mTOR signaling can be critical for ESCC progression, our study may contribute to developing an alternative therapeutic strategy for ESCC, by targeting mTOR with Temsirolimus.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4415. doi:10.1158/1538-7445.AM2011-4415
Abstract 4416: Significance of IGF-1R and Its signaling pathways in human sarcoma
Authors: Yang Jia Lin , DasGupta Romi , Hopkins Alyse , Luk Frederick , Goldstein David , Crowe Philip 
Published: June 2012

Abstract
A 5-year 50% survival rate reflects the inadequacy of available therapies. We aimed to investigate the relationship of IGF-1R signaling factor expression with clinicopathological parameters of soft tissue sarcoma (STS) and patient outcome, as well as the therapeutic effect of targeting IGF-1R combined with chemotherapy in sarcoma cell lines.
Tissue-microarray and immunohistochemistry were used to detect expression of IGF-1R and its signaling factors, pAkt, pERK, pp38, pJNK and pSTAT3 in 93 samples from 89 STS patients. Combination therapy using IGF-1R inhibitor and each of 5 chemotherapueutic agents was investigated in 11 sarcoma cell lines and analysed by Chou-Talalay method. Mechanism studies were also performed.
A strong link between stage and grade with expression of IGF-1R (p&lt;0.033 and p&lt;0.042), pAkt (p&lt;0.004 and p&lt;0.001) and pERK (p=0.002 and p&lt;0.001) in STS was found. Decreased survival correlated with pAkt expression (Multivariate Cox regression p=0.043). Combination treatment of IGF-1R inhibitor with individual chemotherapeutic agents achieved synergistic anti-proliferative effect for all drugs except gemcitabine in some sarcoma cell lines (5/11 carboplatin, 3/11 ifosfamide, 3/11 docetaxel, and 3/11 doxorubicin), accompanied by apoptosis and cytotoxicity. Furthermore, characterisation of IGF-1R signaling interaction by downstream pathway inhibition revealed the importance of activated PI3K and p38 for chemoresistance in a pair of liposarcoma cell lines (synergistic, 778 and antagonistic, SW872). IGF-1R, pAkt and pERK may be predictors of the aggressiveness of STS. IGF-1R inhibition in combination with chemotherapy is a worthwhile strategy to pursue in anti-sarcoma therapy. These results provide a rationale for further clinical evaluation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4416. doi:10.1158/1538-7445.AM2011-4416
Abstract 4419: Effect of sphingosine kinase 1 inhibition in validated syngeneic mouse breast cancer metastasis model
Authors: Nagahashi Masayuki , Rashid Omar M. , Ramachandran Subramanian , Milstien Sheldon , Spiegel Sarah , Takabe Kazuaki 
Published: June 2012

Abstract
INTRODUCTION: Sphingosine kinase 1 (SphK1) is one of the two enzymes that generate sphingosine-1-phosphate (S1P), which promotes cancer growth, migration and angiogenesis. S1P is also known to have important roles in immune responses. Therefore, we utilized syngeneic models which better recapitulate the involvement of the host immune response to examine the role of SphK1 in breast cancer progression in vivo. The aims of this study are i) to critically evaluate syngeneic models to determine which is most appropriate for metastatic breast cancer drug development, and ii) to investigate the effect of inhibition of SphK1 on cancer progression using that model.
METHODS: One of the major challenges in preclinical cancer research is the identification of animal models that adequately mimic the human disease. Three commonly used syngeneic (implantation of 4T1-luc2 luciferase-tagged murine breast cancer cells into immune-competent mice) models were compared: cells implanted subcutaneously (Sq); cells implanted Orthotopically under direct vision with Surgery (OS); cells implanted Orthotopically with Percutaneous injection blindly into the area under a nipple (OP). Bioluminescence was used for macroscopic analysis, together with pathological analysis, and genome-wide microarrays for gene expression profiling, with confirmation by qPCR. An isozyme-specific inhibitor of SphK1 (SK1-I) was administered intraperitoneally. Tumor burden were quantified using an in vivo imaging system (IVIS 200).
RESULTS: Orthotopic implantation under direct vision with Surgery produced significantly more consistent tumors with less variability, more rapid cancer progression and metastasis, faster mortality, and more relevant clinical endpoints than OP or Sq models. There were significant differences between the genetic profiles of the tumors from OS compared to Sq tumors. Three fourth of the differentially expressed genes between OS and Sq are relevant to cancer biology. Using this OS model, we found that SK1-I treatment decreased tumor burden significantly.
CONCLUSIONS: Use of the OS model, in place of more commonly used Sq model, may improve the efficiency of cancer drug development. Our results support the notion that SphK1 play a critical role in breast cancer progression and suggest that SK1-I is a promising candidate for breast cancer targeted therapy. This work was supported by Sumitomo Life Social Welfare Services Foundation grant to MN, NIH (K12HD055881) and Susan G. Komen for the Cure (KG090510) to KT, and NCI (R01CA61774) to SS.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4419. doi:10.1158/1538-7445.AM2011-4419
Abstract 4425: Regulation of gamma-secretase in breast cancer cells
Authors: Li Yueming , Chien Jennifer 
Published: June 2012

Abstract
Gamma-secretase inhibitors are being actively pursued in preclinical and clinical studies for treatment of breast and other cancers. However, little is known on the regulation gamma-secretase in breast cancer cells. A better understanding of gamma-secretase and its involvement in breast cancer will be critical for the development of target-based therapies. A thorough investigation on gamma-secretase related research has been hampered due to the complexity of this protease and technical challenges. Gamma-secretase is a macromolecular complex composed of at least four proteins: presenilin (PS), Nicastrin (Nct), Pen2 and Aph1. Remarkably, only a small fraction of the four protein complex is catalytically active and total amount of PS protein is not always correlated with gamma-secretase activity. Therefore, detection of the level of individual subunits doesn't necessary reflect the activity of gamma-secretase. In addition, detection of gamma-secretase activity requires either large quantities of cells for membrane preparation or transitionally and stably expression of the substrates. These assays limit the ability to quickly characterize γ-secretase activity in multiple cancer cell lines and primary cells. To overcome these barriers, we have developed a variety of the activity-based probes and assays that allow us to investigate the active gamma-secretase complex and real-time inhibition of gamma-secretase in any cellular system. We have characterized gamma-secretase in basal A and B as well as luminal type of breast cancer cell lines and their sensitivity toward structurally distinct gamma-secretase inhibitors. We have found that different types of breast cancer cells exhibit distinctive gamma-secretase activity. Inhibition of gamma-secretase activity suppressed the migration, invasion and metastasis of aggressive breast cancer cell lines. An in depth examination of the function and regulation of gamma-secretase in breast cancer cells could lead to the development of more effective treatments of breast cancer and other malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4425. doi:10.1158/1538-7445.AM2011-4425
Abstract 4436: Biological evaluation of folate prodrugs with a highly toxic derivative of doxorubicin
Authors: Ajaj Khalid Abu , El-Abadla Naser , Welker Pia , Azab Samar , Zeisig Reiner , Fichtner Iduna , Kratz Felix 
Published: June 2012

Abstract
Folic acid is itself not biologically active but it is essential for the proliferation of cells. Cellular uptake of folate in the body is primarily mediated by the folate receptor (FR), a membrane-bound protein for which three isomers have been identified. The isomer FR-α is highly over-expressed in many human tumors. Since FR-α has a high affinity for binding and transporting physiologic levels of folic acid into cells, coupling a drug through a cleavable linker to folic acid can yield a prodrug that can be delivered inside tumor cells. Many studies have focused on reducible or acid-sensitive based linkers that are cleaved in the endosomes and/or cytoplasm.
For the development of new folate receptor-targeted prodrugs, the highly active doxorubicin derivative N-(5,5-diacetoxybut-1-yl)doxorubicin was chosen to avoid potential saturation of the folate receptor. This acyclic doxorubicin diacetate undergoes an ester-mediated hydrolysis producing 2-pyrrolinodoxorubicin that is 500-1000 times more active than doxorubicin. Two prodrugs were designed to contain an acid-sensitive hydrazone bond (1) or in addition a disulfide bond (2) in order to elucidate the importance of the pre-determined breaking point for their in vitro and in vivo activity.
In a 24h MTT assay, 1 was 5-fold more active than 2 in folate-positive KB cells in the nanomolar range whereas no activity was observed in the folate-negative A549 lung cancer cells, an observation that correlated well with the uptake of 1 and 2 in fluorescence microscopy studies.
In subsequent in vivo studies in the folate-positive KB model, 1 was as active as the free drug but significantly less toxic when dosed at twice the dose of the free drug whereas 2 showed no anticancer efficacy. As an explanation, we could show by HPLC that prodrug 2 that additionally contains a disulfide bond undergoes rapid disulfide exchange in murine and human plasma in the order of 40% after 5 h at 37°C in contrast to 1 which was essentially stable after a 5 h incubation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4436. doi:10.1158/1538-7445.AM2011-4436