bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2063: Synergistic anticancer activity of Sorafenib in combination with HS-173, a novel PI3K inhibitor against pancreatic cancer cells.
Authors: Yun Sun-Mi , Jung Kyung Hee , Lee Hyunseung , Park Byung Hee , Yan Hong Hua , Hong Soon-Sun 
Published: August 2014

Abstract
The K-RAS mutation, resulting in activation of the Raf/MEK/ERK pathway, has been implicated in pancreatic cancer development. And the PI3K/Akt pathway is highly activated in pancreatic cancer and considered to be a cancer hallmark. The principal objective of this study was to assess the synergic effect between Sorafenib (a Raf inhibitor) and HS-173 (a novel PI3K inhibitor) along with the underlying mechanism to gain insight into novel therapeutic strategies for treating pancreatic cancer. We first investigated the cytotoxic effect of co-treatment with Sorafenib and HS-173 using the Calcusyn program. Combined treatment with the two drugs synergistically inhibited the viability of Panc-1 cells (combination index &lt; 1). Concomitantly, co-treatment with Sorafenib and HS-173 induced G2/M arrest and increased apoptosis with the loss of mitochondria potential. Apoptosis resulting from co-treatment with Sorafenib and HS-173 was accompanied by increased levels of cleaved caspase-3 and PARP as well as greater numbers of TUNEL-positive apoptotic cells compared to treatment with either drug alone. Furthermore, combined treatment with these drugs decreased the expression HIF-1α and VEGF, two factors that play an important role in angiogenesis. The anti-angiogenic effect of simultaneous treatment with Sorafenib and HS-173 was confirmed by observing the suppressed tube formation of VEGF-induced human umbilical vein endothelial cells and inhibition of blood vessel formation in a Matrigel plug assay in mice. Taken together, our study demonstrated that combined treatment with Sorafenib and HS-173 has a synergistic anticancer effect on pancreatic cancer cells, indicating that simultaneously targeting the Raf/MEK and PI3K/Akt pathways can induce a synergistic inhibitory effect on pancreatic cancers in which both pathways are activated. Based on the observations from our study, we suggest that the combined administration of these two drugs may be considered to be a new therapeutic regimen for treating pancreatic cancer.
Citation Format: Sun-Mi Yun, Kyung Hee Jung, Hyunseung Lee, Byung Hee Park, Hong Hua Yan, Soon-Sun Hong. Synergistic anticancer activity of Sorafenib in combination with HS-173, a novel PI3K inhibitor against pancreatic cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2063. doi:10.1158/1538-7445.AM2013-2063
Abstract 2064: SF3B1 inhibitors sensitize head and neck squamous cell carcinoma to Bcl-xL inhibition by regulating Mcl-1 alternative splicing.
Authors: Gao Yang 
Published: August 2014

Abstract
This study explored the application of the alternative splicing of Bcl-2 family protein Mcl-1 in combination chemotherapy for head and neck squamous cell carcinoma (HNSCC) cell lines: meayamycin B (SF3b inhibitor) switched the pre-mRNA alternative splicing of Mcl-1 from anti-apoptotic to pro-apoptotic; the combination of meayamycin B with ABT-737 (Bcl-xL inhibitor) rapidly stimulated apoptosis in a panel of HNSCC cells, overcoming the HPV-16-mediated Mcl-1 over-expression.
Western blotting and semi-quantitative RT-PCR as well as qPCR afforded evaluation of the expression of Mcl-1 splicing variants at mRNA and protein levels. Apoptosis status was monitored by using caspase 3/7 activity assays and Annexin V/7-AAD staining. siRNA was used to specifically knock down HPV-16 E6 gene.
Meayamycin B exhibited 0.1-10 nM ED50 values in HNSCC cell lines that are mostly resistant to ABT-737. In HPV-16 positive HNSCC, E6 oncogene affords moderate resistance to meayamycin B. The combination of meayamycin B and ABT-737 synergistically induced apoptosis in HNSCC cell lines regardless of HPV status. These data demonstrate the potential of meayamycin B, both as a single agent and in combination with Bcl-xL inhibitors, for both research and targeted molecular therapeutic purposes for HNSCC.
Citation Format: Yang Gao. SF3B1 inhibitors sensitize head and neck squamous cell carcinoma to Bcl-xL inhibition by regulating Mcl-1 alternative splicing. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2064. doi:10.1158/1538-7445.AM2013-2064
Abstract 2085: The antileukemic drug nilotinib inhibits the invasive activity and the metastatic potential of colorectal cancer cells by targeting the receptor tyrosine kinase DDR1.
Authors: Tosti Priscillia , Leroy Cédric , Simon Valérie , Robert Bruno , Pierre Josiane , Sirvent Audrey , Roche Serge 
Published: August 2014

Abstract
Tyrosine kinases (TK) are frequently deregulated in human cancer and they play important roles in tumor progression. Since then, they have become valuable therapeutic targets and several inhibitors are currently used in the clinic. For example, the BCR-ABL inhibitor nilotinib is currently used for the treatment of patients with chronic myeloid leukemia (CML). Here we show that this antileukemic drug also inhibits invasive properties of colorectal cancer (CRC) cells. Inhibition was observed at the same dose-range for growth inhibition of CML cells. Nilotinib also strongly reduced liver metastasis induced by injection of CRC cells in the spleen of nude mice. Since we could not detect Abl deregulation in CRC cells, we speculated the involvement of an alternative target to be identified. Interestingly, a previous chemical-proteomic approach identified DDR1 as a novel target of nilotinib (Rix et al, Blood, 2007). DDR1 is a poorly-characterized TK and a receptor for collagen, a major component of the extracellular matrix. Accordingly, we found that DDR1 catalytic activity regulates cell invasion and metastasis of CRC cells. In addition, we demonstrate that nilotinib pharmacological activity is mediated by the inhibition of DDR1 in CRC cells: expression of the nilotinib resistant DDR1/T701I mutant renders CRC cells resistant to nilotinib treatment. Finally, we found that DDR1 catalytic activity is significantly increased in metastatic nodules compared to the primary tumor and the healthy tissue of the same patient. Altogether, these data suggest that the targeting of DDR1 by nilotinib may be of therapeutic value in metastatic CRC.
Citation Format: Priscillia Tosti, Cédric Leroy, Valérie Simon, Bruno Robert, Josiane Pierre, Audrey Sirvent, Serge Roche. The antileukemic drug nilotinib inhibits the invasive activity and the metastatic potential of colorectal cancer cells by targeting the receptor tyrosine kinase DDR1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2085. doi:10.1158/1538-7445.AM2013-2085
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2088: NVP-BKM120 decreases cell survival and antagonizes resistance signals derived from protective tissue microenvironment by interfering with the Akt/FoxO3a/Bim axis in CLL cells.
Authors: Rosich Laia , Saborit-Vilarroya Ifigenia , Lopez-Guerra Monica , Xargay-Torrent Silvia , Montraveta Arnau , Aymerich Marta , Villamor Neus , Campo Elias , Perez-Galan Patricia , Roue Gael , Colomer Dolors 
Published: August 2014

Abstract
Phosphatidylinositol-3-kinase (PI3K) pathway is a key component of many cancers survival. Particularly, PI3K is constitutively activated in chronic lymphocytic leukemia (CLL) due to microenvironment signals, including stromal cell interaction, CXCR4 activation and B-cell receptor (BCR) triggering. Because of the importance of PI3K for CLL-microenvironment cross-talk and chemotherapy resistance, we investigated the activity of the NVP-BKM120, an orally available pan class I PI3K inhibitor.
Here, we show that NVP-BKM120 promoted mitochondrial apoptosis in primary CLL cells independently of common prognostic markers. At the molecular level, NVP-BKM120 blocked PI3K signalling, resulting in decreased phosphorylation of Akt and FoxO3a while downregulating Mcl-1 and inducing Bim. Importantly, selective knockdown of BIM rescued cells from NVP-BKM120-induced apoptosis. Moreover, NVP-BKM120 enhanced the activity of the BH3-mimetic ABT263 in CLL cells, leading to synergistic apoptosis induction. We also found that NVP-BKM120 inhibited BCR- and stromal-induced Akt activation as well as induced Bim in presence of BCR-derived and stromal survival signals. In stromal cocultures, NVP-BKM120 sensitized CLL cells towards bendamustine and fludarabine. Furthermore, NVP-BKM120 downregulated secretion of chemokines after BCR triggering and inhibited CLL cell chemotaxis and actin polymerization toward CXCL12.
Altogether, our data suggest that NVP-BKM120 displays a dual mechanism of action, directly decreasing cell survival and antagonizing survival and drug-resistance signals derived from protective tissue microenvironment.
Citation Format: Laia Rosich, Ifigenia Saborit-Vilarroya, Monica Lopez-Guerra, Silvia Xargay-Torrent, Arnau Montraveta, Marta Aymerich, Neus Villamor, Elias Campo, Patricia Perez-Galan, Gael Roue, Dolors Colomer. NVP-BKM120 decreases cell survival and antagonizes resistance signals derived from protective tissue microenvironment by interfering with the Akt/FoxO3a/Bim axis in CLL cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2088. doi:10.1158/1538-7445.AM2013-2088
Abstract 2103: XB05: a promising small molecule for cancer therapy.
Authors: Salipur Francesca R. , Reyes Elsa M. Reyes , Xu Bo , Smith Ned , Cai Jian , Hammond Gerald B. , Bates Paula J. 
Published: August 2014

Abstract
XB05 is synthetic small molecule which was serendipitously discovered to have potent anticancer properties. XB05 displays selectivity for malignant cells over non-malignant cells. Human myeloid leukemia cells (U937) and human lung cancer cells (A549) treated with XB05 show an increase in oxidative stress, DNA damage and a mixed apoptotic and necrotic mechanism of cell death. We conducted a COMPARE analysis to search for correlations between XB05 response and gene expression using publicly available microarray studies of the National Cancer Institute 60 cell line panel. This analysis uncovered a correlation between cell death in response to XB05 and expression of the transcription factor, SOX9. We find that SOX9 is differentially expressed across a panel of human lung cancer cell lines. MTT proliferation and clonogenic cell survival assays suggest that SOX9 expression positively correlates with the sensitivity of lung cancer cells to XB05. Furthermore, we show that siRNA knockdown of SOX9 recapitulates the phenotype of XB05-induced cell death, and that SOX9 may be downregulated at the protein level by XB05 treatment. Overall, these data demonstrate potent activity of XB05 against human cancer cells via a novel mechanism of action, and a potential role for SOX9 as a biomarker for selection and monitoring of therapy with XB05.
Citation Format: Francesca R. Salipur, Elsa M. Reyes Reyes, Bo Xu, Ned Smith, Jian Cai, Gerald B. Hammond, Paula J. Bates. XB05: a promising small molecule for cancer therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2103. doi:10.1158/1538-7445.AM2013-2103
Abstract 211: Control of integrin expression and signaling by claudin-3 and claudin-4 in ovarian cancer.
Authors: Lin Xinjian , Shang Xiying , Manorek Gerald , Howell Stephen 
Published: August 2014

Abstract
Changes in cell-cell and cell-matrix adhesion are central to ovarian cancer metastasis. We have previously demonstrated that the two major tight junction proteins claudin-3 (CLDN3) and claudin-4 (CLDN4) function to restrain in vivo growth and metastatic potential of ovarian cancer cells by sustaining expression of E-cadherin and limiting β-catenin signaling. Here we report that CLDN3 and CLDN4 control integrin αvβ3 expression and signaling through which they regulate cell-matrix adhesion and anchorage-dependent growth. Knockdown of CLDN3 or CLDN4 in human ovarian carcinoma cells reduced their ability to adhere to fibronectin whereas increased expression of CLDN3 or CLDN4 enhanced adherence to the extracellular matrix protein. A flow cytometric analysis revealed that CLDN3 and CLDN4 knockdown reduced αvβ3 complex formation at the cell surface by a factor of 1.7- and 12.4-fold, respectively, relative to the parental 2008 cells. Deconvoluting microscopic analysis of immunocytochemically stained cells confirmed the reduction in αvβ3 expression in the CLDN3KD and CLDN4KD cells. Measurement of β3 mRNA levels by qRT-PCR demonstrated a 55 ± 11.0% reduction in the CLDN3KD cells and a 51 ± 13.7% decrease in the CLDN4KD cells while the αv mRNA level was not affected. Interestingly, ablation of αvβ3 increased CLDN3 and CLDN4 expression at both the mRNA and protein level. Anchorage-independent growth was markedly reduced in both CLDN3KD and CLDN4KD cells with respect to the number and the size distribution of the colonies that formed in soft agar. Moreover, loss of either CLDN3 or CLDN4 resulted in activation of focal adhesion kinase (FAK) as the phosphorylation of Tyr-397 residue within FAK, which reflects FAK activity, was significantly increased in the CLDN3 and CLDN4 knockdown cells. Taken together, these results indicate a novel role for CLDN3 and CLDN4 in regulating integrin αvβ3 expression and signaling that control cell-matrix adhesion and aggressiveness of the ovarian carcinoma cells.
Citation Format: Xinjian Lin, Xiying Shang, Gerald Manorek, Stephen Howell. Control of integrin expression and signaling by claudin-3 and claudin-4 in ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 211. doi:10.1158/1538-7445.AM2013-211
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2110: Realgar exerts cytotoxic killing of gastric cancer cells through Bax apoptotic pathway.
Authors: Chen Siyu , Tian Wei , Ding Wenping , Zheng Leizhen , Li Xiaoping , Zhang Li , Gu Jianchun , Tao shuangfen , Kim Sungkyoung , Gu Wenhua 
Published: August 2014

Abstract
Background:Arsenic compound has shown excellent activity in APL. Its anticancer activity in solid tumors is still being explored. We have tested realgar, arsenic sulfide (As4A4), in gastric cancer cells to understand its anticancer activity and mechanism.
Methods: The effects of the realgar on cell proliferation and apoptosis of AGS and MGC803 cell lines were determined using methyl thiazolyl tetrazolium (MTT) assay and Annexin V assay. Western blot analysis was used to detect the related pathways by measuring the expression levels of apoptotic proteins such as Bax, Bcl-2, c-myc, p53 and mdm2. Real-time PCR analysis was used to measure the mRNA levels of the related genes.
Results: Realgar significantly inhibited proliferation and induced apoptosis in gastric cancer cell lines AGS and MGC803 in a dose- and time-dependent manner, particularly in AGS cells. Realgar up-regulated the expression of p53 and p53 target genes MDM2 and Bax, down-regulated the expression of Bcl-2 and c-Myc in AGS cell lines, indicating that realgar could induce apoptosis via p53-bax pathway in AGS cell lines. However, similar dose of realgar up-regulated the expression of Bax, down-regulated the expression of Bcl-2 and c-Myc in MGC803 cell lines, with much less effect on the expression of p53.
Conclusion: Realgar has significant anti-cancer effect on gastric cancer cell lines through inhibiting cell proliferation and inducing apoptosis. Our findings suggest a potential therapeutic effect of realgar in gastric cancer and further study in this area is needed.
Citation Format: Siyu Chen, Wei Tian, Wenping Ding, Leizhen Zheng, Xiaoping Li, Li Zhang, Jianchun Gu, shuangfen Tao, Sungkyoung Kim, Wenhua Gu. Realgar exerts cytotoxic killing of gastric cancer cells through Bax apoptotic pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2110. doi:10.1158/1538-7445.AM2013-2110
Abstract 2115: A chemicogenetic interrogation of colorectal cancer identifies a shared chemical vulnerability in Wnt signaling and telomere length maintenance.
Authors: Kulak Ozlem , Holohan Brody , Wu Xiaofeng , Lum Lawrence 
Published: August 2014

Abstract
Despite the general acceptance that loss of the APC tumor suppressor is the predominant cancer-initiating event in colorectal cancer (CRC), a therapeutic strategy premised upon disabling deviant gene transcription associated with this phenomenon currently does not exist. Chemical antagonism of the poly-ADP ribosylase enzymes Tankyrase 1 and 2 (Tnks1&2) results in the destruction of the transcriptional co-activator β-catenin by promoting the stability of a β-catenin destruction complex. We have evaluated the consequences of disrupting β-catenin activity on the CRC signaling network using faithful reporters of the most frequently corrupted cellular processes (Wnt/β-catenin, p53, and Kras signaling), and a portfolio of Tnks inhibitors identified from a chemical library screen. In addition to inducing loss of β-catenin activity, the exposure of cells to Tnks inhibitors resulted in increased p53 activity. We demonstrated that this unexpected cellular response is due to loss of Tnks ability to regulate the shelterin complex that protects the telomeric sequences found at the ends of chromosomes. Long term culturing of cancerous cells with Tnks inhibitors resulted in telomere shortening and cellular senescence. Our findings reveal a single agent strategy for targeting two cellular processes that support the renewal of cancer initiating cells - Wnt signaling and telomere length maintenance.
Citation Format: Ozlem Kulak, Brody Holohan, Xiaofeng Wu, Lawrence Lum. A chemicogenetic interrogation of colorectal cancer identifies a shared chemical vulnerability in Wnt signaling and telomere length maintenance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2115. doi:10.1158/1538-7445.AM2013-2115
Abstract 212: Are there cell cycle-dependent variations in cadherin-mediated cell adhesion.
Authors: Cimpean Maria , Yu Yangjinqi , Laperle Brenna , Corey Edie , Thomas William A. 
Published: August 2014

Abstract
Cell adhesion makes possible the development of tissues and organs. It has thus been an important topic in biomedical research, cancer research in particular. One method used to quantify cell adhesion, the dual pipette assay, has shown persistent variability in the force required to separate adherent cells despite efforts to minimize variability through strict protocols and assay automation. We are using FUCCI (fluorescence ubiquitination cell cycle indicator) to determine if cell-cycle dependent changes might account for the observed variability in separation force. The FUCCI technique involves antiphase oscillating proteins that mark the cell-cycle transitions with corresponding fluorescent probes. Initial comparison of fluorescence distributions in aggregated and unaggregated FUCCI E cad cells showed no preferential accumulation in aggregates of cells in a particular stage of the cell cycle. Work continues to improve the resolution and reproducibility of the tests.
Citation Format: Maria Cimpean, Yangjinqi Yu, Brenna Laperle, Edie Corey, William A. Thomas. Are there cell cycle-dependent variations in cadherin-mediated cell adhesion. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 212. doi:10.1158/1538-7445.AM2013-212
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2120: Platinum-based cancer chemotherapeutics inhibit STAT signaling by blocking the SH2 domain.
Authors: Lesterhuis W. Joost , Hato Stanleyson V. , Figdor Carl G. , Takahashi Susumu , Punt Cornelis J.A. , Asai Akira , De Vries I. Jolanda M. 
Published: August 2014

Abstract
Platinum-based drugs form the corner stone of many treatment schedules in cancer. Their main mechanism of actions is the covalent binding to DNA, leading to the formation of platinum-DNA adducts and thereby inducing apoptosis. Recently, other so called off-target effects of these drugs have been described. These include the induction of immunogenic cell death and the downregulation of inhibitory molecule Programmed Death-Ligand 2 by inactivation of signaling molecule/transcription factor STAT6, a member of the Signal Transducer and Activator of Transcription (STAT) protein family. STAT proteins play crucial roles in the pathogenesis and progression of cancer and much research is being conducted to identify inhibitors of STAT signaling for use in cancer treatment.
Here, we investigated the potential of platinum-based chemotherapeutics to inhibit STAT signaling. We found that treatment of tumor cells of various origins with platinum drugs inhibit the activation of STAT proteins and leads to loss of cytokine-induced and constitutive STAT protein phosphorylation. Concurrently, a decrease of STAT protein nuclear accumulation was evident by confocal microscopy analysis. This resulted in a downregulation of STAT-regulated tumorigenic genes such as Bcl-xL, MCL-1, VEGF and survivin. Non-STAT target genes were not affected. Analysis of the known STAT inactivation pathways showed that these were not activated nor enhanced by treatment with platinum drugs. Finally, using a biochemical alphascreen-based assay, we demonstrated that platinum compounds directly interact with STAT proteins and inhibit binding to the SH2 domain.
These findings provide novel insight into the mechanism of action of platinum drugs and show for the first time that these clinically used compounds directly affect important cellular signaling pathways. These results indicate that part of the efficacy of these drugs may be derived from their inhibition of STAT signaling and they provide important leads for the development of novel innovative treatment schedules in cancer that exploit the STAT-inhibiting effect of platinum drugs, for example by potentiating targeted therapies or immunotherapy.
Citation Format: W. Joost Lesterhuis, Stanleyson V. Hato, Carl G. Figdor, Susumu Takahashi, Cornelis J.A. Punt, Akira Asai, I. Jolanda M. De Vries. Platinum-based cancer chemotherapeutics inhibit STAT signaling by blocking the SH2 domain. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2120. doi:10.1158/1538-7445.AM2013-2120