bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 800: Formation of chemotherapy resistance-inducing fatty acids by mesenchymal stem cells depends on COX-1, thromboxane synthase and intracellular calcium
Authors: Houthuijzen Julia M. , Roodhart Jeanine M.L. , Daenen Laura G.M. , Voest Emile E. 
Published: August 2012

Abstract
The development of resistance to chemotherapy is considered to be one of the most important obstacles to continued effective treatment of cancer in patients. We recently have identified an important mechanism that is responsible for systemic resistance to chemotherapy. Circulating mesenchymal stem cells (MSCs) activated by chemotherapy secrete specific polyunsaturated fatty acids that confer resistance to a broad spectrum of anti-cancer agents. These factors were identified to be two distinct platinum-induced polyunsaturated fatty acids (PIFAs) 12-S-keto-5,8,10-heptadecatrienoic acid (KHT) and 4,7,10,13-hexadecatetraenoic acid (16:4(n-3)) that were able to induce chemotherapy resistance in picomolar concentrations. Interestingly, the production of these PIFAs is restricted to MSCs and mouse embryonic fibroblasts (MEFs), other stem cells like hematopoietic stem cells and cancer stem cells are not able to form the PIFAs after cisplatin stimulation. Research from our lab showed that the production of these PIFAs can be blocked by cyclooxygenase-1 (COX-1), thromboxane A synthase (TXAS) and intracellular calcium inhibitors, suggesting that these are important in the production of the PIFAs, and indicating that the PIFAs are formed in the pathways of arachidonic acid (AA) and eicosapentaenoic acid (EPA). Lipid peroxidation with subsequent release of oxygen radicals could be a trigger for the formation of PIFA. We therefore tested whether reactive oxygen species (ROS) were involved in the production of the PIFAs. Neither increasing ROS by hydrogen peroxide, nor scavenging of ROS by glutathione in the MSCs influenced the level of resistance to chemotherapy in mice. In addition, intracellular ROS levels in the MSCs treated with cisplatin for various intervals did not change as was determined by DCFDA fluorescence. Our findings provide a new paradigm on how MSCs can induce a systemic protection against chemotherapy through the secretion of two distinct fatty acids that are formed in response to platinum-containing chemotherapy.
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 800. doi:1538-7445.AM2012-800
Abstract 803: HOXB7 functions as a co-activator of estrogen receptor in the development of tamoxifen resistance
Authors: Jin Kideok , wen Teo Wei , Yoshida Takahiro , Park Sunju , Sukumar Saraswati 
Published: August 2012

Abstract
Multiple factors including long term treatment with tamoxifen are involved in the development of selective estrogen receptor modulator (SERM)-resistance in ERα positive breast cancer. Increased expression of HER family members can also directly alter cellular responses to tamoxifen, but the mechanism underlying the increased expression of the HERs is not clear. In this report we show that HOXB7 interacts with ERα, and together they bind to the promoter or enhancer regions of ERα-regulated genes to enhance their transcription activity. We found a number of novel HOXB7 binding sites at promoter regions, intron regions and adjacent to ER-binding sites in ER-regulated genes through HOXB7 ChIP on chiP using an Affymetrix promoter array. Potentially, HOXB7 and ERα may co-regulate about 84% of ERα-target genes. HOXB7 overexpression renders MCF-7 cells resistant to tamoxifen. Overexpression of HOXB7 results in upregulation of HER2 and ERα target genes while knockdown of HOXB7 with siRNA in tamoxifen-resistant cell lines causes decrease of HER2 and ERα target genes expression and loss of tamoxifen resistance. Our data shows that to mediate upregulation of HER2 and ER-target genes occurring in tamoxifen resistance, the HOXB7-ERα complex recruits ERα coactivators and promotes HER2- and ER-target genes transcriptional activity through direct binding to the HER2 enhancer and regulatory regions of ER target genes. However, depletion of HOXB7 negatively affects the binding affinity of its cofactors to the HER2 enhancer element and ER-binding sites. Also, we found that miR196a might control HOXB7 expression; reducing miR196a levels in tamoxifen-resistant cells causes an increase of HOXB7 expression. Further, miRNA 196a is regulated by c-MYC which undergoes stabilization through the EGFR-HER2 signaling pathway. These findings implicate overexpression of HOXB7 as a key event in the initiation and maintenance of tamoxifen resistance. These studies suggest that HOXB7 acts as a key regulator orchestrating two major groups of target molecules, ERα and HER2, in the oncogene hierarchy. Therefore, we have provided additional evidence that supports the thesis that functional antagonism of HOXB7 has the potential to circumvent tamoxifen resistance.
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 803. doi:1538-7445.AM2012-803
Abstract 804: The impact of aromatase inhibitor therapy on ER co-regulator expression and interaction
Authors: Bourgo Ryan J. , Greene Geoffrey L. 
Published: August 2012

Abstract
Estrogen receptor alpha (ERα) is a member of the nuclear receptor family and is currently recognized as the most defining metric in breast cancer diagnosis and treatment. Roughly 70% of all breast cancer patients present with ERα-positive, hormone sensitive disease, and the majority of these women are post-menopausal. Because post-menopausal women require the aromatase enzyme for estrogen synthesis, the first line of treatment for these patients is aromatase inhibitor (AI) therapy. Despite the number of women whose primary disease responds positively, a significant fraction of patients fail to gain any clinical benefit due to intrinsic resistance, or eventually relapse due to acquired resistance to AI therapy. Currently, the biochemical changes underlying both intrinsic and acquired resistance to AI therapy is yet unknown; thus, resistance to AI therapy remains a significant clinical obstacle for a large fraction of breast cancer patients. Here, we investigate the impact of ERα co-regulators on intrinsic and acquired AI resistance in breast cancer. In vitro administration of testosterone to wild-type MCF-7, T47-D, or ZR75-1 cells is capable of offering a significant ERα-dependent proliferative advantage, suggesting an active role for aromatase in these cells. Interestingly, aromatase inhibitor (Anastrazole) treatment of these cells alters the expression of specific ERα co-regulators independent of ligand. Furthermore, interaction between ERα and individual co-regulators is altered after treatment with estradiol or testosterone, and is impacted by Anastrazole treatment acutely. While these findings are preliminary, further investigation is on-going and promises to provide critical insight into the contributions of ERα co-regulators to the short- and long-term response to AI-mediated estrogen deprivation, as well as establish the alterations in ERα-mediated promoter occupancy and gene regulation that contribute to intrinsic and acquired AI resistance.
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 804. doi:1538-7445.AM2012-804
Abstract 820: Somatic mutations to identify tumors for highly selective chemosensitization by Nrf2 depletion
Authors: Batist Gerald , Wu JianHui , Abdulkassim Tahar , Bendavit Gabriel , Abramovitz Mark 
Published: August 2012

Abstract
Therapeutic resistance remains a critical challenge in cancer treatment. Effective chemosensitizers must target more than a single mechanism of resistance and must also selectively sensitize only tumor and not normal tissue. Nrf2 is a transcription factor that regulates a battery of cytoprotective genes, and is shown in multiple experimental systems to have a significant impact on sensitivity to cytotoxic treatments. Regulation of Nrf2 levels is largely post-translationally, as a result of its physical interaction with adapter protein Keap1, which targets it for proteosomal degradation. An increasing number of human tumors and cancer cell lines are found to have loss of function mutations in Keap1 that results in constitutively elevated Nrf2 and drug resistance. In such circumstances alternative pathways for Nrf2 degradation may predominate, including the PI3kinase pathway protein GSK-3β, which exports Nrf2 from the nucleus to the proteosome. When relatively common somatic mutations in the PI3kinase pathway result in phosphorylation of GSK-3β at Ser9, it is inactivated. However, the addition of a PI3kinase pathway inhibitors increases GSK-3β, depletes Nrf2 and significantly sensitizes these cells. We are further exploring mechanisms, and at the same time screening biobanks of various tumors to determine the incidence of somatic loss of function mutations in Keap1 and mutations in the Pi3K pathway that activate it. This would represent a molecular signature of tumors that would be highly selectively sensitized by this strategy.
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 820. doi:1538-7445.AM2012-820
Abstract 829: Down-regulation of insulin-like growth factor-binding protein 7 in cisplatin-resistant non-small cell lung cancer
Authors: Okamura Jun , Huang Yiping , Brait Mariana , Chang Xiaofei , Sidransky David , Kim Myoung S. 
Published: August 2012

Abstract
Cisplatin is an effective anticancer drug used to treat many types of cancer, including non-small cell lung carcinoma (NSCLCs), but development of resistance is the primary impediment in cancer treatment. Insulin-like growth factor-binding protein 7 (IGFBP7) is a secreted tumor suppressor that is inactivated in human lung cancer. IGFBP7 is known to alter sensitivity to interferon-based anticancer therapy, and here, we examined loss of IGFBP7 as a potential contributor to chemo-resistance to cisplatin. The transcriptional level of IGFBP7 was decreased in cisplatin-resistant human cancer cell lines and NSCLC xenografts. IGFBP7 knock-down increased cellular resistance to cisplatin and increased the level of mitogen-activated protein kinase phosphatases (MKP) 3 levels. The expression of MKP3 increased in a cisplatin-resistant NSCLC cell line and lung xenografts. MKP3 knock-down increased IGFBP7 level, indicating that MKP3 regulates IGFBP7. These findings suggest a novel molecular mechanism responsible for the tumor suppressive function of IGFBP7 in cisplatin-resistant human lung cancer and could lead to the development of IGFBP7 as a cisplatin-sensitizing agent.
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 829. doi:1538-7445.AM2012-829
Abstract 830: Insulin-like growth factor binding protein-2 and chemosensitivity in esophageal adenocarcinoma
Authors: Silvers Amy L. , Lin Lin , Beer David G. , Chang Andrew C. 
Published: August 2012

Abstract
The overall long-term survival for patients with esophageal adenocarcinoma (EAC) remains poor. Despite improved understanding of the progression from Barrett's esophagus to dysplasia to adenocarcinoma, patients commonly present with advanced stage disease and demonstrate resistance to conventional therapy, with response rates below 40%. Understanding the molecular mechanisms of resistance is crucial for predicting and overcoming this resistance. Twenty EAC tissues obtained from patients subsequently treated with chemotherapy were examined using Affymetrix oligonucleotide microarrays. Genes differentially expressed in disease-free patients compared to patients with recurrent disease were identified. One such gene, insulin-like growth factor binding protein-2 (IGFBP-2), is a member of the IGF signaling pathway, which has been shown to play pivotal roles in cell growth, differentiation, survival, transformation, and metastasis. Increased IGFBP-2 expression has been reported in many advanced tumor types and has been previously linked to chemoresistance, making it a promising potential target in EAC. Mean IGFBP-2 levels were significantly higher in patients with recurrent disease and increased expression was associated with worse outcome independent of stage. Of three EAC cell lines examined (Flo-1, OE33, OE19), Flo-1 cells showed the highest IGFBP-2 expression at both the mRNA and protein levels. To examine the role of IGFBP-2 in chemoresistance, Flo-1 cells were pre-treated with siRNA to IGFBP-2 followed by chemotherapy in the presence or absence of serum and analyzed using WST-1 cell proliferation assays. Knocking down IGFBP-2 sensitized Flo-1 cells to cisplatin in the presence of serum and increased proliferation in serum-free conditions, suggesting that IGFBP-2 may be anti-proliferative in this EAC cell line. In addition, treatment of Flo-1 cells with both acute and chronic doses of cisplatin decreased expression of IGFBP-2. Stable transfection of IGFBP-2 into low-level IGFBP-2-expressing OE33 and OE19 cells did not alter cellular proliferation/chemosensitivity, migration, or epithelial-mesenchymal transition as determined by WST-1, wound healing, and Western analyses, respectively, possibly due to amplification of the ErbB2 gene in these cell lines. Although preliminary data suggest that IGFBP-2 may mediate chemoresistance in EAC, its effects may be masked by more potent genetic alterations. Further analysis of the IGF signaling pathway is warranted to determine its significance in the chemoresistance of EAC.
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 830. doi:1538-7445.AM2012-830
Abstract 837: Copper efflux transporter-mediated resistance to cisplatin
Authors: Mathews Ryan A. , Safaei Roohangiz , Howell Stephen B. 
Published: August 2012

Abstract
The copper (Cu) efflux transporters ATP7A and ATP7B individually mediate resistance to the Pt-containing chemotherapeutic agents and have been identified as a primary pathway for the sequestration and/or export of these drugs. While the structure and transport function of ATP7A and ATP7B have been well studied, the mechanism by which they mediate resistance to the Pt drugs remains unknown. The experimental system consisted of the human fibroblast cell line Me32a, which does not express either ATP7A or ATP7B, and sublines previously produced by transfection that express either ATP7A (MeMNK) or ATP7B (MeWND). The MeMNK sub-line was 2.2-fold resistant to cisplatin whereas the MeWND cells had a 1.8-fold increase in IC50. The MeMNK and MeWND cell lines also contained a small population of cells that survived lethal dosages of DDP (10 - 20%). The MeMNK and MeWND cells were also 1.6- and 1.9-fold, respectively, resistant to the specific vacuolar proton pump (V-ATPase) inhibitor bafilomycin (Baf). Further investigation revealed that cells expressing ATP7A or ATP7B also had increased expression of V-ATPase subunits A, D and H at the mRNA level that corresponded to 8.6 - 14-fold increases at the protein level indicating that ATP7A and ATP7B perturb the proton transport system that accounts for progressive acidification of vesicles in the secretory pathway. MeMNK and MeWND cells were found to be 34- and 22-fold resistant to brefeldin A (BFA) which reversibly disrupts transport of proteins in the vesicle secretory pathway and specifically targets the ADP-ribosylation factor-1 (Arf1). This led us to investigate the Arf family of proteins and we found that the levels of Arf1, Arf3 and Arf4 were markedly reduced in cells expressing ATP7A and ATP7B at the RNA level; the reduction in Arf1 appears to account for the resistance to BFA and indicates the that function of Arf1 has been taken over by some other protein. Furthermore, we found large perturbations in the level of proteins that constitute the regulatory machinery of the vesicle secretory pathway including guanine nucleotide exchange factors (GEFs) and coat protein complexes in the MeMNK and MeWND cells. These findings indicate that ATP7A and ATP7B both produce quite large perturbations in the expression of proteins whose function is essential to the formation and trafficking of vesicles in the secretory pathway. As ATP7A and ATP7B have previously been shown to be capable of sequestering cisplatin into the microvesicular fraction of the MeMNK and MeWND cells, we conclude that these changes are linked to the ability of these Cu transporters to mediate cisplatin resistance.
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 837. doi:1538-7445.AM2012-837
Abstract 839: Chemotherapeutic sensitization of drug-resistant lung cancer cells by doxorubicin and leptomycin B
Authors: Lu Chuanwen 
Published: August 2012

Abstract
The development of novel targeted therapies has become an important research focus for lung cancer treatment. Our previous study has shown leptomycin B (LMB) significantly inhibited proliferation of lung cancer cells; however, p53 wild type lung cancer cells were resistant to LMB. Therefore, the objective of this study was to develop and evaluate a novel therapeutic strategy to sensitize LMB-resistant lung cancer cells by combining LMB and doxorubicin (DOX). Among the different treatment regimens, pre-treatment with DOX (pre-DOX) and subsequent treatment with LMB to A549 cells significantly decreased the 50% inhibitory concentration (IC50) as compared to that of LMB alone (4.4 nM vs. 10.6 nM, P &lt; 0.05). Analysis of cell cycle and apoptosis by flow cytometry further confirmed the cytotoxic data. To investigate molecular mechanisms for this drug combination effects, p53 pathways were analyzed by Western blot, and nuclear proteome was evaluated by two dimensional difference gel electrophoresis (2D-DIGE) and mass spectrometry (MS). In comparison with control groups, the levels of p53, phospho-p53 (ser15), and p21 proteins were significantly increased while phospho-p53 (Thr55) and survivin were significantly decreased after treatments of pre-DOX and LMB (P &lt; 0.05). The 2D-DIGE/MS analysis identified that sequestosome 1 (SQSTM1/p62) had a significant increase in pre-DOX and LMB-treated cells (P &lt; 0.05). In conclusion, our results suggest that drug-resistant lung cancer cells with p53 wild type could be sensitized to cell death by scheduled combination treatment of DOX and LMB through activating and restoring p53 as well as potentially other protein(s)/pathway(s).
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 839. doi:1538-7445.AM2012-839
Abstract 845: In vitro and in vivo pharmacology of SAR125844, a potent and selective intravenous MET kinase inhibitor undergoing Phase I clinical trial
Authors: Goulaouic Hélène , Kenigsberg Mireille , Delaisi Christine , Begassat Françoise , Do-Vale Véronique , Mestadier Jessica , Bonche Fabrice , Bénard Tsiala , Nicolas Jean-Paul , Calvet Loreley , Egile Coumaran , Nemecek Conception , Lengauer Christoph 
Published: August 2012

Abstract
SAR125844 is a potent MET kinase inhibitor for intravenous (IV) administration, with nanomolar activity against the wild-type enzyme (IC50 = 4.2 nM) and some kinase domain mutants, such as M1250T and Y1235D. It is highly selective for MET kinase in a panel of 275 kinases tested, with only 5 other protein kinases inhibited at IC50 values below 300 nM. In cellular assays, SAR125844 inhibits MET autophosphorylation at the nanomolar range (IC50 from 1.4 to 5.1 nM), translating into antiproliferative activity selectively in MET-driven cell lines such as MET-amplified cell lines, with IC50 values in the low nanomolar range and induction of apoptosis. SAR125844 induces a G1 block in the two MET-amplified tumor cell lines tested. Moreover, the compound is also able to inhibit HGF-induced cell migration in PC-3 prostate tumor cell line. In two MET-amplified human gastric tumor xenograft models tested, SNU-5 and Hs 746T, SAR125844 intravenous treatment leads to potent impact on the MET signaling pathway in a dose and time dependent manner, with potent inhibition of MET autophosphorylation, as well as a significant effect on downstream PI3K/AKT and RAS/MAPK pathways. As a single agent, this translates into a dose-dependent antitumor activity in these two xenograft models, with tumor stasis at the lowest active dose and tumor regression at the highly active doses. High loading single dose administration of SAR125844 using a nanosuspension formulation allowed a sustained P-MET inhibition in tumors up to 7 days. In all models, antitumor activity was achieved at well tolerated doses without significant effect on body weight. The observed correlation between P-MET inhibition in the tumor and antitumor activity in preclinical settings suggests that P-MET evaluation in tumor biopsies could be a direct pharmacodynamic biomarker of SAR125844 activity in patients. In order to investigate whether a non-invasive biomarker could also be used as pharmacodynamic read-out, we measured shed-MET (soluble extracellular domain of the MET receptor) in the plasma of tumor-bearing mice and showed that its level correlates with tumor burden in 2 MET-amplified xenograft models.
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 845. doi:1538-7445.AM2012-845