bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5410: Simultaneously tackling NFκB and JNK pathways to sensitise breast cancer cell lines to conventional anticancer drugs
Authors: Yip* Nga C. , Fombon* Ivo S. , Liu Peng , Brown Sarah , Armesilla Angel L. , Cassidy James , Darling John L. , Wang Weiguang 
Published: February 2011

Abstract
Many anticancer drugs induce reactive oxygen species (ROS) in cancer cells. High ROS will activate JNK pathway and induce cancer cell apoptosis. Meanwhile, ROS also strongly induces NFκB activity which triggers expression of many antiapoptotic factors and inhibits ROS/JNK pathway therefore antagonises anticancer drug-induced programmed cell death. The fate of anticancer agent-treated cancer cells is highly determined by the cross-talk between NFκB and JNK pathways. In this study, we demonstrated that a clinically used anti-alcoholism drug, disulfiram (DS), simultaneously activated ROS-JNK pathway and inhibited NFκB. DS was cytotoxic to breast cancer cell lines in vitro. As a divalent metal ion chelator, the cytotoxic effect of DS on breast cancer cell lines was highly copper-dependent. In the medium containing physiological concentration of copper (Cu, 1µM) the IC50 concentrations of DS to breast cancer cell lines were 200 - 500nM. The chemosensitizing effect of DS on 3 anti-breast-cancer agents, gemecitabine (dFdC), doxorubicine (DOX) and paclitaxel (PAC), was determined in 3 breast cancer cell lines (MCF-7, MDA-MB-231 and T47D). In combination with DS/Cu, the cytotoxicity of dFdC, DOX and PAC was significantly enhanced (Table 1. DOX: 8 - 11-fold; dFdC: 1.2 - 4-fold; PAC: 4 - 10-fold). DS also reversed dFdC resistance in acquired dFdC resistant cell lines. CI-isobologram analysis demonstrated synergistic effect between DS and anticancer drugs. Flow cytometric analysis showed DS enhanced anticancer drug-induced apoptosis. DS enhanced anticancer drug-induced ROS activity. The phosphorylated c-Jun and JNK protein in breast cancer cell lines was significantly induced by exposure of cancer cells to DS/Cu complex. Transfection of NFκB p50 and p65 induced dFdC resistance in MCF7 cells. DS inhibited drug-induced IκBα degradation and NFκB activation. Our data suggested that DS may be developed as a chemosensitizer for BC chemotherapy.
*Equal contributionTable 1.DS/Cu sensitised cytotoxicity of anticancer drugs to breast cancer cell linesTreatmentsDrug: DS/CuMCF7MDA-MB-231T47DDOX (nM) 440.5 (16.2)178.5 (11.9)160.0 (5.5)DOX + DS/Cu1:540.3 (9.3)22.0 (2.0)21.5 (3.1)dFdC (nM) 22.1 (3.4)12.3 (2.2)35.0 (4.3)dFdC + DS/Cu1:104.9 (0.5)11.3 (1.2)12.4 (0.7)PAC (nM) 4.3 (1.4)9.3 (0.7)2.6 (0.3)PAC + DS/Cu1:62.50.4 (0.1)0.6 (0.02)0.7 (0.1)
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5410.
Abstract 5415: Histone deacetylase inhibitors and 15-deoxy-Δ12,14-prostaglandin J2 synergistically induce apoptosis
Authors: Koyama Makoto , Izutani Yasuyuki , Goda Ahmed E. , Matsui Taka-aki , Horinaka Mano , Tomosugi Mitsuhiro , Fujiwara Jun , Nakamura Yoshitaka , Wakada Miki , Yogosawa Shingo , Sowa Yoshihiro , Sakai Toshiyuki 
Published: February 2011

Abstract
The histone deacetylase inhibitors (HDIs) valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA, vorinostat) are used clinically for the treatment of epilepsy and cutaneous T-cell lymphoma, respectively. HDIs have been shown to be more effectively utilized in combination with other agents despite the promising anti-tumor effect of HDIs alone. Therefore, additional mechanism-based therapeutic strategies for use of HDIs in combination with other agents should be investigated to overcome resistance to HDIs or to increase the efficacy of HDIs. The natural endogenous ligand of peroxisome proliferator-activated receptor γ (PPARγ) 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is a member of cyclopentenone prostaglandins and known to be a potent anti-neoplastic agent. Thus, we examined whether VPA or SAHA in combination with 15d-PGJ2 could show synergistic anti-tumor activitiy in colon cancer DLD-1 cells. Cell viability was determined using a Cell Counting Kit-8 assay. Apoptosis and reactive oxygen species (ROS) generation were determined using flow cytometry analysis. Western blotting and real-time RT-PCR analysis were carried out to investigate the expressions of apoptosis-related molecules. Small interfering RNA or transient transfection with plasmids was used for gene silencing, gene overexpression or luciferase assays. Mice bearing DLD-1 xenograft were divided into 4 groups (n=5) and injected everyday (i.p.) with diluent, VPA (100 mg/kg), 15d-PGJ2 (5 mg/kg) or a combination for 25 days. Cotreatment with VPA or SAHA at clinically achievable concentrations and 15d-PGJ2 synergistically induced cell death and drastically caused caspase-dependent apoptosis in DLD-1 cells. The apoptosis induced by VPA/15d-PGJ2 cotreatment was due to alterations of apoptosis-related genes such as an antiapoptotic Bcl-2 family member Bcl-XL, X-chromosome-linked inhibitor of apoptosis (XIAP), C/EBP homologous protein (CHOP) and death receptor 5 (DR5) via ROS generation, subsequent endoplasmic reticulum stress and/or histone deacetylase inhibition. Moreover, VPA/15d-PGJ2 cotreatment induced ROS-dependent apoptosis in other malignant tumor cells and was more effective than a VPA or 15d-PGJ2 monotherapy in vivo. These results suggest that cotreatment with the clinically relevant HDIs and 15d-PGJ2 may warrant clinical investigation as a rational combination therapy against a broad spectrum of malignant tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5415.
Abstract 5420: Multi-targeted approach for inhibiting pancreatic tumor growth in vivo consistent with in vitro results
Authors: Ali Shadan , Banerjee Sanjeev , Schaffert Jacqueline M. , El-Rayes Bassel F. , Philip Philip A. , Sarkar Fazlul H. 
Published: February 2011

Abstract
Inactivation of survival pathways such as NF-κB, cyclooxygenase (COX-2) or epidermal growth factor receptor (EGFR) signaling individually may not be sufficient for the treatment of advanced pancreatic cancer (PC). Since these pathways are well known in the pathogenesis and aggressiveness of PC, we hypothesized that a multitargeted approach for the inhibition of NF-κB, COX-2 and EGFR may therefore be useful to improve the outcome of anti-EGFR therapies and will also potentiate the anti-tumor effects of gemcitabine. In this study, we determined the cell viability in seven PC cell lines with 3,3′-diindolylmethane (B-DIM), erlotinib or gemcitabine alone or in combination using MTT assay. Significant inhibition in cell viability and induction in apoptosis was observed in PC cells expressing high levels of COX-2, EGFR, and NF-κB proteins. A significant down-regulation in the expression of COX-2, NF-κB and EGFR in BxPC-3, COLO-357 and HPAC cells was observed, suggesting that multi-targeting of EGFR, NF-κB and COX-2 is more effective than targeting either signaling pathway separately. Most importantly, our in vivo results using animal model showed that B-DIM in combination with erlotinib and gemcitabine was significantly more effective than individual agents and these results were consistent with in vitro findings. Based on our pre-clinical in vitro and in vivo results, we conclude that this multi-targeted combination could be developed for the treatment of PC patients whose tumors express high levels of COX-2, EGFR and NF-κB.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5420.
Abstract 5428: Histone deacetylase (HDAC) enzyme inhibition potentiates taxanes and doxorubicin activity in thyroid cancer cell lines
Authors: Owonikoko Taofeek K. , Zhang Guojing , Ramalingam Suresh S. , Khuri Fadlo R. , Sun Shi-Yong 
Published: February 2011

Abstract
Thyroid cancer is the fastest growing cancer in the US. Doxorubicin, the only approved medical therapy, has limited efficacy; therefore alternative treatment options are warranted. We previously showed increased cytotoxicity when HDAC inhibitor was combined with taxanes and carboplatin in lung cancer cell lines. We now studied the combination of HDAC inhibitor and cytotoxic agents in thyroid cancer cell lines. Exponentially growing cells (Cal 62, PTC1, and BCPAP) were treated by continuous exposure for 72 hrs to vehicle or increasing concentrations of doxorubicin, paclitaxel or docetaxel ± fixed concentration of LBH589. Surviving cell fraction was estimated by sulforhodamine B (SRB) colorimetric assay. IC50 concentration was determined by non-linear regression modeling of OD measurements. In a separate experiment, Western blot assay for markers of apoptosis (caspase and PARP cleavage), cell cycle regulation (p21, p27) and tubulin acetylation was performed using cell lysates from cells treated for 48 hrs with IC50 concentration of chemotherapy drugs ± LBH589. Similarly treated cells were analyzed for changes in cell cycle distribution using propidium iodide staining and flow cytometry. Doxorubicin, docetaxel and paclitaxel showed potent nanomolar activity with up to 80% reduction in the IC50 concentrations when combined with LBH589 (paclitaxel: 0% - 70%; docetaxel: 60% - 84%; doxorubicin: 2% - 65%). Flow cytometry showed qualitative evidence for increased cell death with a 1.5 to 6-fold increase in the subG1 apoptotic cell fraction with combined doxorubicin and LBH589 versus doxorubicin alone. The increased cytotoxicity correlated with increased PARP cleavage and increased p21 protein expression; p27 induction by doxorubicin was not augmented by co-treatment with LBH589. HDAC inhibition augments in vitro cytotoxicity of microtubule and DNA-damaging agents in thyroid cancer cell lines. This combination deserves further evaluation in this disease.DrugIC50 Concentrations in Thyroid Cancer Cell Lines (nM) BCPAPCAL 62PTC1 − L+L− L+L− L+L Paclitaxel3.60.641.310.538.6631.365Docetaxel6.9852.1450.710.282.252.25Doxorubicin34.2512.142278.6778.7188.542LBH569 16.84 11.94 22.71Flow Cytometry Analysis Following Propidium Iodide Staining BCPAPCAL 62PTC1TreatmentVDoxDox + LVDoxDox + LVDoxDox + L%Sub G145.5456.362.286.825.6766.775.456.914.21V: Vehicle;Dox: Doxorubicin;L: LBH589Full details of Western blot assay and complete flow analysis to be presented at the meeting.Acknowledgement: Taofeek Owonikoko, Suresh Ramalingam, Fadlo Khuri and Shi-Yong Sun are all supported by the Georgia Cancer Coalition as Distinguished Cancer Scholars.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5428.
Abstract 5429: Inhibition of LSD1 and HDACs causes synergistic cell death in glioblastoma cells
Authors: Singh Melissa , Manton Christa , Tsai Wen-Wei , Barton Michelle , Chandra Joya 
Published: February 2011

Abstract
Glioblastoma multiforme is a particularly aggressive brain tumor and remains a clinically devastating disease. More than 90% of children diagnosed with glioblastoma die within 2 years making it among the leading causes of cancer related morbidity and mortality. Despite innovative therapies for the treatment of glioblastoma, there has not been a significant increase in patient survival over the past decade. Enzymes that control epigenetic alterations have become popular targets for cancer therapy due to their ability to control cellular processes that lead to oncogenesis. Several inhibitors of histone deacetylases (HDACi) have been developed and are in clinical use for cancer therapy. Histone methylation can be modulated by HDACi and here we propose to examine the effect of dually inhibiting deacetylases and demethylases. Specifically, we focused on LSD1, lysine specific demethylase 1, a demethylase known to be in complex with HDAC1/2 and implicated in several high risk cancers. We evaluated apoptosis induction upon knockdown of LSD1 in combination with HDACi in glioblastoma cell lines. Our results demonstrate a greater than two-fold increase in apoptosis in LSD1 knockdown cells treated with increasing doses (1-5 μM) of HDACi for 48 hours as compared to control as measured by DNA fragmentation by propidium iodide staining and analysis by flow cytometry. Furthermore, pretreatment of LSD1 knockdown cells with the general caspase inhibitor zVAD-fmk prior to treatment with vorinostat only partially protects against DNA fragmentation suggesting that cell death proceeds through both caspase-dependent and -independent mechanisms. Similar results were obtained by pharmacologically inhibiting LSD1 with the monoamine oxidase inhibitor tranylcypromine. Treatment of LN-18 cells with combinations of tranylcypromine (100-1000 μM) and vorinostat (1-5 μM) for 72 hours demonstrate that these two agents synergize to promote cell death with 1000 μM tranylcypromine and 5 μM vorinostat showing the most synergistic effect (CI 0.313). Surprisingly, the increase in apoptosis observed upon LSD1 inhibition, by knockdown and pharmacological inhibitors, and HDACi also correlates with an increase in intracellular superoxide as measured by hydroethidum staining and analysis by flow cytometry. These data suggest that reactive oxygen species may play a role in the apoptosis induced by the combination of LSD1 and HDAC inhibition. Further studies aimed at understanding the mechanism by which LSD1 and HDAC inhibition leads to enhanced tumor cell death will substantially increase our knowledge of how epigenetic modifiers interact to control cell survival and may suggest novel options for cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5429.
Abstract 5431: Histone deacetylase inhibitor (HDAC) panobinostat (LBH589) enhances the antiproliferative effect of a topoisomerase II (topo II) inhibitor in doxorubicin-resistant HL-60 cells, despite high MDR expression
Authors: Brady Anna K. , Advani Anjali S. , Grabowski Dale , Ganapathi Ram , Ganapathi Mahrukh K. 
Published: February 2011

Abstract
Acute myeloid leukemia (AML) is difficult to treat, particularly in the relapsed or refractory setting due to drug resistance. Topo II inhibitors are effectively used to treat AML, and histone deacetylase (HDAC) inhibitors have been used pre-clinically and clinically with some success. We previously reported that vorinostat (SAHA) was effective in combination with topo II inhibitors in AML cells (Proc. AACR, 2009, Abstract 4567). In the present study we evaluate LBH589, a novel class I/II HDAC inhibitor. Since resistance to HDAC inhibitors has not been well described, we hypothesized that LBH589 would be effective in combination with a topo II inhibitor in a doxorubicin-resistant AML cell line that expresses MDR and resistant by MDR-independent mechanism. A sensitive HL60 parent line (S) and the doxorubicin-resistant sub-line (R) were used. Early studies revealed that vorinostat (SAHA) had comparable anti-proliferative effects in S & R cells but the R cells were relatively more resistant to LBH589. This resistance was likely MDR-mediated. We then tested whether sub-lethal doses of SAHA or LBH589, used in combination with sub-lethal doses of etoposide (VP-16), would be effective. S and R cells were treated with VP-16 for 1 h, washed, and re-incubated with SAHA or LBH, or drug-free media, for a total of 144 hours. Cell viability and apoptosis were measured at 72 h and 144 h following treatment. At 72 h and at 144 h, the combination of VP-16 and LBH was significantly more effective (p&lt;0.01) in reducing proliferation in HL60/S and HL60/R cells, compared to either agent alone. At both 72 h and 144 h the combination of VP-16 and LBH also led to significantly (p&lt;0.05) greater apoptosis in both S & R cells. Western blotting for phospho-histone H2AX, a marker of DNA damage, showed increased DNA damage in the R cells treated with VP-16 and LBH589 compared to either drug alone. Overall, the effects of LBH589 in combination with VP-16 were significantly (p&lt;0.05) more effective than SAHA in the S & R cells. In summary, our results demonstrate that MDR may mediate resistance to LBH589. Further, in spite of MDR expression, LBH589 is a useful adjunct to VP-16 treatment and enhances the anti-proliferative effect of the topo II inhibitor via increased apoptosis, even in the doxorubicin-resistant cells. Thus, post-treatment with LBH589 in combination with a topo II inhibitor may be useful treatment strategy in relapsed / refractory AML.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5431.
Abstract 5433: Prolonged histone hyperacetylation with a novel class of HDAC1/2 selective inhibitors
Authors: Methot Joey L. , Chenard Melissa , Joshua Close , Jonathan Cruz , Dahlberg William , Fleming Judith , Hamblett Chris , Julie Hamill , Harrington Paul , Harsch Andreas , Heidebrecht Richard , Hughes Bethany , Jung Joon , Kenific Candia , Kral Astrid , Middleton Richard , Ozerova Nicole , Sloman David , Stanton Matthew , Szewczak Alexander , Wilson Kevin , Witter David , Secrist Paul , Miller Thomas 
Published: February 2011

Abstract
The histone deacetylase (HDAC) metalloenzymes are intricately involved in gene expression through epigenetic regulation of histone acetylation. They also regulate the acetylation status of numerous non-histone proteins such as transcription factors p53, STAT1 and NF-κB as well as α-tubulin, Hsp90 and Ku70. Of the eleven zinc-dependent HDAC enzymes identified, HDACs 1 and 2 appear to be most critical in oncogenesis and tumor maintenance. They are overexpressed in many human cancers and RNAi knockdown leads to increased apoptosis.
We recently disclosed a family of novel HDAC1/HDAC2-selective biaryl inhibitors. In this presentation, we will describe unique features of these biaryl inhibitors that contribute to improved preclinical efficacy and tolerability. Desirable HDAC inhibitor properties identified from preclinical experience with Zolinza™ include subtype selectivity toward HDAC1/HDAC2 and prolonged target inhibition. Compelling in vitro and in vivo data indicates that solid tumor cell lines are most sensitive to HDAC inhibition under continuous exposure rather than intermittent exposure. These biaryl inhibitors exhibit extended target engagement in vivo, and are well tolerated in nude mice. Unlike other known HDAC inhibitors, these compounds exhibit a delay in and prolongation of histone hyperacetylation in nude mice bearing HCT116 tumors, extending beyond plasma clearance of the drug.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5433.
Abstract 5434: Development and biological characterization of novel, potent and stable isoform-specific inhibitors of histone deacetylase-8 (HDAC8)
Authors: Balasubramanian Sriram , Sirisawad Mint , Verner Erik , Mani Chitra , Jejurkar Purvi , Buggy Joseph J. 
Published: February 2011

Abstract
Histone deacetylase (HDAC) inhibitors have shown promise for the treatment of hematological and solid tumors. The current clinical candidates all inhibit multiple isoforms of the 11-member zinc-dependent HDAC family. With a view to increasing disease specificity and decreasing toxicity, we have developed potent and selective inhibitors of one isoform, HDAC8. We have previously described one such molecule, PCI-34051, which inhibited HDAC8 with a Ki of 10 nM and greater than 200-fold selectivity over other HDAC isoforms. However, this compound displayed poor metabolic stability and was not suitable for in vivo testing in animal models. We have therefore developed a series of analogs to increase metabolic stability while maintaining potency and isoform selectivity. These compounds, which are based on different pharmacophores, have similar potency and selectivity to PCI-34051 but have increased cellular potency, inhibiting cell growth and inducing apoptosis with EC50 of ∼1-2 μM in Jurkat and Hut78 lymphoma cells. These compounds also showed increased metabolic stability in an in-vitro rat liver microsomal assay. Since increased HDAC8 expression has recently been shown to be correlated with poor survival in neuroblastoma, the biological activities of these novel HDAC8 inhibitors were tested in neuroblastoma cell lines. Interestingly, these compounds were found to inhibit cell growth and induce differentiation in neuroblastoma cells. However, incubation with higher concentrations of these compounds did induce caspase activation and apoptosis in these cells. In keeping with the HDAC8 selectivity, no tubulin or histone acetylation was observed at upto 25μM. The best of these inhibitors is currently being tested in mouse xenograft models of T-cell lymphoma as well as neuroblastoma and the results will be presented.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5434.