bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 913: Erufosine simultaneously induces apoptosis and autophagy by modulating the mTOR signaling pathway in oral squamous cell carcinoma
Authors: Kapoor Vaishali , Zaharieva Maya M. , Berger Martin R. 
Published: August 2012

Abstract
Erufosine (erucylphospho-N, N, N-trimethylpropylammonium) is an i.v. injectable alkylphosphocholine analog, which is active against various hematological malignancies in vitro. In this study, we reveal activity in oral squamous carcinoma cell lines and down-regulation of the mTOR signaling cascade as novel mechanism underlying the anticancer activity of erufosine. To that purpose, four oral squamous cell carcinoma cell lines (Cal27, FaDu, SCC9 and SCC25) were exposed to erufosine and assessed for modulation of cell proliferation, colony formation, induction of autophagy/apoptosis, cell cycle distribution, and signaling of the mTOR pathway. In addition, combination effects of erufosine with decreased p-mTOR expression or cytotoxic drugs were investigated. Erufosine showed dose-dependent cytotoxicity in all cell lines as observed by MTT and clonogenicity assays. It simultaneously induced both autophagy and apoptosis via conversion of LC3BI to LC3BII, caspase 3/7 activation and PARP cleavage, respectively. In addition, G2 cell cycle arrest was observed along with cyclin D1 down-regulation. Subsequently, we observed that erufosine readily down-regulated in a dose-dependent manner the phosphorylation of components of the mTOR signaling pathway, like p-Akt, p-Raptor, p-mTOR, and its downstream substrates p-p70S6K and p-4EBP1. p-PRAS40 was reduced to undetectable levels at the highest concentrations of erufosine. Moreover, blockage of p-mTOR expression by siRNA, increased tumor cell sensitivity to erufosine and the resulting antiproliferative effect was comparable to the respective combination with cisplatin but superior to that with rapamycin. Further, erufosine showed additive tumor cell cytotoxicity in combination with 5-flourouracil and cisplatin. In conclusion, these data indicate that erufosine induces apoptosis, autophagy, cell cycle arrest and down-regulates mTOR signaling in oral cancer cell lines. Thus, it has potential as an anti-oral cancer drug either alone or in combination with other chemotherapeutic agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 913. doi:1538-7445.AM2012-913
Abstract 922: ABTL0812: A new drug class with oral antitumor action inhibiting mTOR activity and DHFR expression
Authors: Alfon Jose , Espadaler Jordi , García-Martínez Jose A. , Lizcano Jose Miguel , Domènech Carles 
Published: August 2012

Abstract
ABTL0812* is a lipid analogue that has shown high efficacy by the oral route in mouse models of cancer. Here we show that two clinically validated targets are responsible for the cytotoxic effect of ABTL0812: mTOR (mammalian target of rapamycin), as shown by the dramatic reduction in S6 phosphorylation, and dihydrofolate reductase (DHFR), as shown by its reduced expression, resulting in autophagic cell death. Moreover, the compound's cellular potency increases with incubation time, and it has a long lasting cytotoxic effect after removing the compound from the incubation medium. In vivo efficacy was determined in a human lung cancer xenograft model by subcutaneously injecting A549 human lung adenococarcinoma cells into nu/nu mice. ABT0812 was administered daily at two dose levels and its impact on tumor volume was measured. ABT0812 showed a similar efficacy to docetaxel but with much lower toxicity, and better efficacy than erlotinib. Histological analysis of the tumors revealed increased necrotic area, more inflammatory cells and fewer cells undergoing mitosis. Additionally, plasma levels of ABTL0812 were inversely correlated with tumor volume, reinforcing the concentration-effect relationship. A parallel study was performed to evaluate ABTL0812 efficacy in a pancreatic cancer model. Nu/nu mice were subcutaneously injected with MiaPaCa-2 cells and the volume of xenograft was used as a measurement of efficacy. Again, ABTL0812 showed a statistically significant reduction of tumor volume, increased tumor cell death, and better tolerance than gemcitabine in the mice. DMPK properties in rats and dogs showed very low in vitro hepatic metabolism, ∼50% bioavailability and half lives that calculate to single daily oral administration. Safety pharmacology studies with very high doses of the compound showed no impact on the central nervous system. Ongoing toxicological studies show that the margin between efficacy and toxicity is broad. In conclusion, ABTL0812 is a lipid analogue that hits two clinically validated targets: mTOR and DHFR. This multitarget property increases antitumor efficacy and reduces drug resistance. In addition, preliminary in vivo results indicate that the potential therapeutic margin will be high. * Protected by PCT WO 2010/106211, by Escribá Ruiz PV, et al., licensed to AB-Therapeutics, SL.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 922. doi:1538-7445.AM2012-922
Abstract 927: The ligand-gated Cl- channel GABA inhibits colon cancer invasion following activation by pharmacological treatments
Authors: Ceniccola Kristin E. , House Carrie D. , Bateman Ryan J. , Nguyen Amy , Obias Vincent , Ceryak Susan M. , Mendelowitz David , Lee Norman H. 
Published: August 2012

Abstract
Gamma-aminobutyric acid (GABA) receptors are ligand-gated ion channels that are essential for neurotransmitter function and neuronal cell homeostasis. Activation of these channels triggers the opening of a chloride-sensitive pore, which causes a hyperpolarization via an influx of chloride ions into the cell. The presence of these channels was recently implicated in several cancers, and the neurotransmitter GABA has been cited as a tumor suppressor. We propose that commercially available pharmacological treatments that manipulate GABA receptor function could be repurposed to target cancer. We have identified functional GABA receptors in a spectrum of colon cancer cell lines and examined the effects of the channels on invasion of the metastatic cell line SW620. Electrophysiological techniques were used to confirm that these channels have functional expression. Treatment with propofol, an agonist which slows the channel closing time, and GABA led to a decrease in invasive potential. Conversely, treatment with the antagonist gabazine, which allosterically blocks GABA from binding in the channel, facilitated invasion by preventing chloride influx. Curiously, treating the cells with bicuculline, which blocks GABA's inhibitory action, led to a decrease in invasion. In some situations bicuculline can also act as a GABA agonist by causing spontaneous gating of homomeric β3 channels. The expression of the β3 subunit was also confirmed through immunocytochemistry. In addition to colon cancer cell lines, β3 expression was detected at higher quantities in colon cancer patient samples compared to matched controls. To further understand how GABA signaling is implicated in cancer, we have looked at the association of GABA with the EGF signaling pathway, which is commonly dysregulated in cancer. The EGF pathway has also been linked with a loss of the glucagon receptor in liver cancer, suggesting that a common pathway may exist between GABA and glutamate that can be exploited for treatment. Altogether, our data suggest that ligand-gated GABA channels inhibit the metastatic potential of cancer cells and can be targeted to treat colon cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 927. doi:1538-7445.AM2012-927
Abstract 930: p38 MAPK is required for the antitumor activity of the vascular disrupting agent DMXAA
Authors: Lou Liguang , Wu Qiong , Quan Haitian , Xu Yongping 
Published: August 2012

Abstract
5, 6-Dimethylxanthenone-4-acetic acid (DMXAA), a potent vascular disrupting agent, selectively destroys established tumor vasculature, causing a rapid collapse in blood flow that ultimately leads to inhibition of tumor growth. In this study, we explored the role of p38 MAPK in the antitumor activity of DMXAA. It was found that p38 MAPK was critically involved in DMXAA-induced cytoskeleton reorganization in endothelial cells and TNF-α production in macrophages, both of which were essential for DMXAA-induced vascular disruption. Inhibition of p38 MAPK significantly attenuated DMXAA-induced actin cytoskeleton reorganization in human umbilical vein endothelial cells and TNF-α production in macrophages. In vivo, p38 MAPK inhibition attenuated the immediate reduction in tumor blood flow induced by DMXAA treatment (&lt;30 min) by inhibiting actin cytoskeleton reorganization in tumor vascular endothelial cells, and blunted the long-lasting (&gt;4 h) DMXAA-induced shutdown of the tumor vasculature by inhibiting intratumoral TNF-α production. Our results indicate that p38 MAPK is required for DMXAA-induced endothelial cell cytoskeleton reorganization and TNF-α production, and thus regulates DMXAA-induced antitumor activity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 930. doi:1538-7445.AM2012-930
Abstract 931: The combination of the dual mTORC1/mTORC2 inhibitor AZD2014 and paclitaxel in human ovarian cancer models
Authors: Stewart Adam , Thavasu Parames , Heaton Simon , Banerjee Susana , Kaye Stan B. , Banerji Udai 
Published: August 2012

Abstract
Background Weekly administration of paclitaxel is increasingly used to treat patients with platinum-resistant ovarian cancer. We have previously reported that activation of the phosphatidylinositide-3-kinase pathway as measured by p-p70S6K is associated with resistance to chemotherapy in studies using ovarian cancer cells isolated from ascites (Carden et al, 101st AACR Annual Meeting, 2010; Abstract no. 788). We thus set out to explore the combination of paclitaxel and an inhibitor of the mTORC1/2 complex, AZD2014, in ovarian cancer cell line models. Purpose We aimed to study the effects of combining paclitaxel and the mTORC1/2 inhibitor AZD2014 on growth inhibition in a panel of human ovarian cancer cell lines. We also studied the effects of drug administration schedule on growth inhibition. Methods A panel of 5 human ovarian cell lines was studied: A2780, CH1, SKOV3, IGROV and OVCAR-3. The effects of paclitaxel and AZD2014 administered concomitantly on cell growth were studied using 96hr sulforhodamine B assays. Combination indices (CI) were calculated using median effect analysis and a one-sided t-test was performed to calculate significant differences from a hypothetical value of 1 (indicating additivity). All experiments were carried out in triplicate. Results The combination was additive when drugs were administered concomitantly. In addition, in A2780 and SKOV3 cell lines exposed to paclitaxel followed by AZD2014 the combination indices were 1.112 and 1.099 respectively. Conclusion AZD2014, a novel mTORC1/2 inhibitor, and paclitaxel have additive growth inhibitory effects in a panel of ovarian cancer cell lines when administered concomitantly. Further experiments to understand the effects of this combination on apoptosis and signal transduction are ongoing. The combination of AZD2014 and paclitaxel has potential applications in the treatment of ovarian cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 931. doi:1538-7445.AM2012-931
Abstract 935: Lapatinib and other tyrosine kinase inhibitors greatly potentiate doxorubicin-induced damage to cardiac myocytes
Authors: Hasinoff Brian B. , Patel Daywin , Wu Xing 
Published: August 2012

Abstract
Lapatinib (Tykerb) is dual tyrosine kinase inhibitor targeting the HER2 (ERBB2) and EGFR (ERBB1, HER1) pathways. Lapatinib has been shown in a clinical trial to produce low levels of cardiotoxicity that is reversible. Using a neonatal rat cardiac myocyte model we have investigated the ability of lapatinib alone, and in combination with doxorubicin, to damage myocytes. Lapatinib alone at pharmacological concentrations only slightly induced myocyte damage. However, doxorubicin-induced myocyte damage was greatly potentiated by the addition of low nanomolar lapatinib concentrations. Because trastuzumab also targets ERBB2 receptors, the lapatinib/doxorubicin combination also provides a good model to probe the mechanism of the increased cardiotoxicity caused by the concurrent use of trastuzumab and doxorubicin. Lapatinib treatment alone had little or no effect on myocyte mitochondrial membrane potential, on oxidation of intracellular DCF (dichlorofluorescein), on intracellular ATP levels, or on caspase 3/7 induction. While the doxorubicin cardioprotective agent dexrazoxane was able to greatly reduce doxorubicin-induced myocyte damage, it could only partially reduce the increase in myocyte damage produced by the lapatinib/doxorubicin treatment. Lapatinib alone had little effect on the phosphorylation status of ACC (acetyl-coenzyme A carboxylase) and AKT. Lapatinib alone decreased phosphorylated ERK (MAPK), which may have, in part, contributed to the increased doxorubicin-mediated myocyte damage. As measured by flow cytometry lapatinib-treated myocytes demonstrated an increased accumulation of doxorubicin. As lapatinib is a strong inhibitor of several ATP-dependent ABC-type efflux transporters, this likely occurred because lapatinib blocked doxorubicin efflux, thereby increasing intracellular doxorubicin concentrations. These results suggest that the clinical use of concurrent doxorubicin and lapatinib should be approached with care due to the possibility of lapatinib increasing doxorubicin cardiotoxicity. Several other kinase inhibitors (imatinib, dasatinib, sorafenib, sunitinib, gefitinib, pazopanib, nilotinib, erlotinib, vandetanib and canertinib) were also examined for their ability to potentiate doxorubicin-induced myocyte damage and induce an increase in intracellular doxorubicin levels. Support: CIHR and a Canada Research Chair in Drug Development to BBH.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 935. doi:1538-7445.AM2012-935
Abstract 959: ERα1 represses breast cancer EMT by inhibiting EGFR-mediated downregulation of E-cadherin
Authors: Thomas Christoforos , Rajapaksa Gayani , Nikolos Fotis , Hao Ruixin , Katchy Anne , Bondesson Maria , Krishnamurty Savitri , Esteva Francisco , Gustafsson Jan-Ake 
Published: August 2012

Abstract
Although epithelial to mesenchymal transition (EMT) is associated with specific breast cancer phenotypes, such as the basal-like and claudin-low tumors, there is a lack of validated markers, which can distinguish tumors with poor clinical outcome and high metastatic potential. Estrogen receptor beta (ERα) has been shown to regulate invasion in prostate cancer. However, it is still unclear if ERα by influencing invasion can predict metastasis in breast cancer. Here we show that wild-type ERα (ERα1) inhibits EMT and invasion in basal-like breast cancer cells when they grow either in vitro or in vivo in zebrafish. This correlates with an ERα1-mediated upregulation of miR-200a, miR-200b and miR-429 and the subsequent repression ZEB1 and SIP1, which results in increased expression of E-cadherin. Downregulation of the basal marker EGFR was found to be involved in the ERα1-mediated mesenchymal to epithelial transition since induction of EGFR expression or treatment with EGF abolished the ability of ERα1 to sustain the epithelial phenotype. This inverse correlation of ERα1 with EGFR and its positive association with epithelial markers was additionally observed in breast cancer specimens. These results strengthen the association of ERα1 with the regulation of EMT and propose the receptor as potential crucial marker in predicting survival and metastasis in breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 959. doi:1538-7445.AM2012-959
Abstract 96: From genome-wide association studies (GWAS) to functional genomics of prostate cancer: exploring the role of candidate transcripts through RNAi-based analysis
Authors: Tang Wei , Jones Tamara L. , Pitt Jason , Ambs Stefan , Caplen Natasha J. , Prokunina Ludmila 
Published: August 2012

Abstract
Recent genome-wide association studies (GWAS) have identified multiple genomic regions that harbor single nucleotide polymorphisms (SNPs) associated with human prostate cancer. Determining the biological basis of association data requires the identification of molecular phenotypes that correlate to these sequence variants. However, many of these variants are located in intergenic regions or gene deserts, making it difficult to identify the underlying biological mechanisms these association studies suggest. Two SNPS identified by prostate cancer GWAS include rs10486567 located within intron 2 of JAZF1 gene on chromosome 7p15.2, and rs4430796 located on chromosome 17 near the HNF1B gene. JAZF1 (JAZF zinc finger 1) is a putative transcriptional repressor. SNPs in JAZF1 have also been associated with height body stature, and risk of type-2 diabetes and systemic lupus erythematosus. HNF1B (HNF1 homeobox B) is a homeodomain containing transcription factor; SNPs at this locus show an inverse association with risk of type-2 diabetes and this locus has also been identified as associated with endometrial cancer susceptibility. As the function of JAZF1 and HFNB1 is poorly characterized we are using RNAi based loss-of-function analysis, initially in a prostate cancer cell line, to assess the molecular consequences of silencing these genes. First the transfection conditions for the prostate cancer cell line LNCAP were optimized for synthetic siRNA transfection and multiple siRNAs (from two different vendors) corresponding to JAZF1 and HFN1B were assessed for efficiency of gene specific silencing. To assess the functional consequence of silencing in an unbiased manner we have generated gene specific expression profiles for JAZF1 and HFN1B in LNCAP cells. Briefly, gene expression microarray analysis was conducted on RNA prepared 72 hours post siRNA transfection and expression profiles were generated from data using three different siRNAs corresponding to each gene transfected in triplicate compared to negative control transfected cells. Following silencing of JAZF1 approximately 150 genes were identified as showing significant changes in gene expression, with over 500 other genes showing evidence of altered expression but not at significant level. Following silencing of HFN1B, over 250 genes were identified as showing significant changes in gene expression, with over 400 other genes showing evidence of altered expression but not at significant level. Further analysis and validation of these expression profiles is ongoing.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 96. doi:1538-7445.AM2012-96
Abstract 970: Multi-layer and integrative analysis of the whole transcriptome in Asian gastric cancer: AMPKβ modulation in cancer progression
Authors: Kim Yon Hui , Liang Han , Liu Xiuping , Izzo Julie , Lemos Robert , Lee Ju-Seog , Cho Jae Yong , Cheong Jae Ho , Kim Hoguen , Li Min , Downey Thomas J. , Dyer Matthew D. , Sun Yongming , Sun Jingtao , Beasley Ellen M. , Chung Hyun Cheol , Noh Sung Hoon , Weinstein John N. , Liu Chang-gong , Powis Garth 
Published: August 2012

Abstract
We performed whole-transcriptome profiling of gastric cancer_the most common cancer in developing countries and the second leading cause of cancer deaths in the world. Applying a innovative SOLiD RNA-Seq approach to 24 gastric tumor samples and 6 noncancerous samples, we generated 3.0 billion short reads to quantitatively measure the abundance of mRNAs and small non-coding RNAs. We then developed a multi-layer analysis to identify differentially expressed mRNAs and microRNAs, and novel single-nucleotide mutations candidates associated with gastric cancer. With the insights from the multi-layer analysis, we experimentally demonstrated a critical role for AMPKβ modulation in gastric cancer progression. This work provides a multi-faceted portrait of the Asian gastric cancer transcriptome, which facilitates the elucidation of molecular mechanisms of gastric carcinogenesis and the development of targeted therapies. By integrating data obtained on the expression of both mRNa and miRNa molecules, we were able to identify certain gene signatures uniquely expressed in gastric cancer. This gene signatures along with gastric cancer-related therapeutic target gene signature, showed molecular changes as robust biological markers. Integration of differentially expressed mRNAs and microRNA profiles allowed us to identify potential miRNA drivers of disease progression. We demonstrated the translational relevance of AMPKβ as a potential therapeutic target for treatment and for prediction of early stage gastric cancer. This work lays a critical foundation for the identification of molecular mechanisms of gastric carcinogenesis and the development of related targeted therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 970. doi:1538-7445.AM2012-970