bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3548: Role of synuclein-gamma (SNCG) in paclitaxel resistance and mitogen activated protein kinase activation in uterine papillary serous carcinoma(UPSC)
Authors: Chapman-Davis Eloise , Patel Parin A. , Kim J. Julie , Buttin Barbara 
Published: February 2011

Abstract
Objectives: SNCG is a novel prognostic biomarker in UPSC. We have shown that its overexpression correlates with aggressive cellular properties and resistance to paclitaxel in a UPSC cell line (SPEC2) as well as poor prognosis in a pilot set of UPSC patients. The goal of this study was to determine the mechanism of SNCG-associated taxane resistance by evaluating the effect of SNCG on the mitotic checkpoint and its propensity to modulate extracellular signal-regulated protein kinase 1/2 (ERK 1/2) signaling pathways.
Methods: A stably transfected SPEC2 cell line was created using shSNCG versus shControl oligonucleotides. Similarly, Ishikawa cells were transiently transfected with an SNCG expression vector versus empty vector. Differences in cell proliferation were measured using a cell viability assay and BrdU incorporation assay after treatment with paclitaxel. Cell cycle analysis was used to study the effect of SNCG on the mitotic checkpoint. Differences in expression of the checkpoint kinase BubR1 due to SNCG were studied using real time PCR, Western blot, 26S ubiquitin-proteasome inhibition, and siRNA to BubR1. ERK and phospho-ERK levels were measured in SPEC2 cells with and without SNCG expression by Western blot. SPEC2 cells were treated with paclitaxel with and without the MEK inhibitor UO126 and apoptosis was measured using cleaved PARP analysis.
Results: SNCG overexpression lead to acquired, reversible paclitaxel resistance in endometrial cancer cell lines. SNCG was noted to interfere with mitotic checkpoint function by causing degradation of the critical checkpoint protein BubR1 thereby allowing cells to escape paclitaxel-induced mitotic arrest. SPEC2 cells exhibited sustained activation of ERK which was attenuated by silencing SNCG. When SPEC2 cells were exposed to paclitaxel combined with the MEK inhibitor UO126, decreased cell viability and increased apoptosis was noted compared to either agent alone. SNCG knockdown further enhanced paclitaxel and UO126 sensitivity. Cell cycle analysis revealed that silencing SNCG in SPEC2 cells and adding UO126 acted synergistically in overcoming paclitaxel resistance.
Conclusions: SNCG overexpression in UPSC leads to taxane resistance by interacting with the mitotic checkpoint kinase BubR1 causing its degradation. SNCG is also associated with sustained ERK activation. Targeting SNCG in conjunction with MEK inhibition may represent a novel therapeutic strategy to overcome taxane resistance in these cells.
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 3548.
Abstract 3549: miR-451 links CRC stem-like cells with chemoresistance
Authors: Bitarte Nerea , Boni Valentina , Zarate Ruth , Gonzalez-Huarriz Marisol , Lopez Ines , Rodriguez Javier , Bandres Eva , Garcia-Foncillas Jesus 
Published: February 2011

Abstract
Introduction: In recent years, an emerging role for microRNAs (miRNAs) in human cancer has been proposed. Our group has previously identified miR-451 as a potential tumor suppressor microRNA involved in cell cycle progression and radiation response. We hypothesized whether miRNAs may be involved in drug resistance mechanisms among cytotoxic agents commonly used in metastatic colorectal cancer (mCRC).
Experimental Design: miR-451 was overexpressed by ectopically synthetic pre-miR-451 transient transfection and by generating stable-miR-451 overexpressed cells through retroviral vectors. The role of miR-451 on chemosensitivity to 5-fluorouracil (5FU), oxaliplatin (LOHP) and SN38, an active metabolite of irinotecan, was characterized by MTS. We sought to determine links between miR-451 and cancer stem cells (CSCs) by colonspheres generation, soft-agar cell invasion and xenograft in vivo experiments. Down-stream targets involved in drug-resistance mechanisms were also identified.
Results: Overexpression of miR-451 significantly increased the sensitivity of CRC cell lines to SN38. The IC50 values were significantly lower in pre-miR-451-transfected cells, including DLD1, LoVo and RKO than in controls (950 nM versus 460 nM for DLD1; 10 nM versus 1.4 nM for LoVo and 20 nM versus 5.9 nM for RKO). No changes were detected for 5-FU and LOHP response. ATP-binding cassette transporter protein 1 (ABCB1) proved to be miR-451-target directly associated with SN38 sensitivity. Moreover, restoring miR-451 levels translated into a reduced tumorigenicity in a xenograft model and a decreased ability of CRC cells to growth under anchorage-independent conditions in soft agar.
These results suggest that miR-451 down-regulation in CRC cells may be involved in CSCs generation. Indeed, overexpression of miR-451 was able to reduce the number and size of CRC cells-derived colonspheres. The phenotype of formed colonspheres was confirmed evaluating overexpression of several putative CSCs markers (CD133, CD44, EpCam and CD166). We also found colonspheres to be more resistant to SN38 treatment and to express higher levels of ABCB1 than parental cells. Finally, miR-451 restoration levels reverted CSCs resistance to SN38 through ABCB1 down-regulation.
Conclusions: Our findings suggest that miR-451 is involved in SN38 resistance through suppression of ABCB1 and regulation of CRC stem-like cell phenotype. Therefore, miR-451 may represent a novel potential candidate target to circumvent drug resistance in CRC.
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 3549.
Abstract 355: CIP2A mediates effects of bortezomib on phospho-Akt and apoptosis in hepatocellular carcinoma cells
Authors: Chen Kuen-Feng , Liu Chun-Yu , Lin Yu-Chin , Yu Hui-Chuan , Liu Tsung-Hao , Hou Duen-Ren , Chen Pei-Jer , Cheng Ann-Lii 
Published: February 2011

Abstract
Previously, we reported that Akt inactivation determines the sensitivity of hepatocellular carcinoma (HCC) cells to bortezomib (Chen et al, Cancer Res 2008). Here, we report that cancerous inhibitor of protein phosphatase 2A (CIP2A), a cellular inhibitor of protein phosphatase 2A (PP2A), mediates the apoptotic effect of bortezomib in HCC. Silencing PP2A by small interference RNA (siRNA) abolishes bortezomib-induced down-regulation of phospho-Akt and apoptosis. Bortezomib increases PP2A activity in sensitive HCC cells, including Sk-Hep1, Hep3B and Huh-7 but not in resistant PLC5 cells. Bortezomib down-regulates CIP2A in a dose- and time-dependent manner in all sensitive HCC cells whereas no alterations in CIP2A were found in resistant PLC5 cells. Knockdown of CIP2A by siRNA restored bortezomib's effects on apoptosis and PP2A activity in PLC5 cells. Moreover, over-expression of CIP2A up-regulated phospho-Akt and protected Sk-Hep1 cells from bortezomib-induced apoptosis. Importantly, ectopic expression of CIP2A decreased Akt-related PP2A activity whereas silencing CIP2A increased this activity, indicating that CIP2A negatively regulates Akt-related PP2A activity in HCC cells, Furthermore, our in vivo data showed that bortezomib down-regulates CIP2A and up-regulates PP2A activity in Huh-7 tumors but not in PLC5 tumors. In conclusion, inhibition of CIP2A determines effects of bortezomib on apoptosis and PP2A-dependent Akt inactivation in HCC. CIP2A may be a biomarker for predicting clinical response of bortezomib in HCC treatment. Supported by NTUH98P03, NTUH98FTN21, NSC97-2314-B-002-182, NSC98-2314-B-002-067-MY3, and NSC98-3112-B-002-037.
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 355.
Abstract 3550: Role of TNFα in the cytotoxicity of docetaxel and in docetaxel resistance in MCF-7 cells
Authors: Sprowl Jason A. , Parissenti Amadeo 
Published: February 2011

Abstract
Taxanes such as paclitaxel and docetaxel are widely used in cancer chemotherapy regimens due to their ability to stabilize microtubules and to arrest cell division in mitosis (Chazard, 1994). While the events leading to mitotic arrest are well understood, the mechanism by which the drug induces cytotoxicity is unclear. Paclitaxel has previously been shown to promote secretion of TNFα in macrophages; however this has not been observed in other cell lines (Bogdan, 1992). TNFα induces cell death in many cell lines through interaction with its receptor TNFR1 (Hsu, 1996). TNFα also binds to a second receptor, TNFR2, which does not possess a death domain. TNFR2 does however retain the ability to induce expression of NFκB-dependent survival genes.
Our laboratory group recently selected MCF-7 cells for survival in increasing concentrations (doses) of paclitaxel or docetaxel (MCF-7TAX and MCF-7TXT, respectively). Resistance was only achieved at or above selection dose 9 (3.33nM docetaxel) (Hembruff et al., 2008). MCF-7 cells were also “selected” in the absence of these drugs to control for changes simply associated with extended cell propagation. The ABC transporter inhibitor cyclosporin A either had no effect on docetaxel sensitivity at selection dose 9, or partially restored sensitivity at selection dose 12 (Hembruff, 2008). These observations suggest there are likely additional mechanisms of docetaxel resistance at selection doses 9 through 12.
Interestingly, we observed that docetaxel concentrations between 1.11nM and 3.33nM induced a &gt;100-fold increase in TNFα secretion from MCF-7 cells, which likely contributes to cytotoxicity. Consistent with this view, a neutralizing TNFR1 antibody decreased cytotoxicity of docetaxel in MCF-7 cells. We also discovered that MCF-7TXT and MCF-7TAX cells at or above selection dose 9 were resistant to TNFα-induced cell death. Moreover, MCF-7TXT cells displayed downregulation of TNFR1 upon the acquisition of resistance to taxanes. Increased levels of TNFα were observed within the media of MCF-7TXT cells selected to dose levels 9 and 10, but not dose levels 11 or 12. We further provide evidence that the increased levels of TNFα in the medium of MCF-7TXT cells contributes to increased cell survivability through a TNFR2-dependent activation of NFκB and its resulting increase in the expression of cell survival genes.
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 3550.
Abstract 3556: New curcumin analogues are cytotoxic towards estrogen receptor negative human breast cancer cell lines
Authors: Yadav Babasaheb D. , Taurin Sebastien , Larsen Lesley , Rosengren Rhonda J. 
Published: February 2011

Abstract
There is an urgent need for the development of a safe and efficacious drug therapy for the treatment of estrogen receptor negative breast cancers due to their high malignant nature and poor prognosis. In this study, a series of new heterocyclic monoketo curcumin analogues were synthesized and screened for anticancer activity. Among twenty eight analogues screened in estrogen receptor negative human breast cancer cell-lines MDA-MB-231 (ER-/HER2-), MDA-MB-468 (ER-/HER2-) and SKBr3(ER-/HER2+), the two most potent compounds were designated as RL-71 and RL-66. Cytotoxicity was assessed by sulforhodamine B (SRB) assay. Furthermore, the compounds were studied for their ability to modulate cell cycle progression and induce apoptosis. The mechanism of these drugs was also examined by determining protein expression by Western blot analysis. The results showed that RL-71 and RL-66 had sub micromolar EC50 values in all the cell lines and the cytotoxicity was concentration and time dependent. Mechanistic analyses demonstrated that RL-71 at 1µM and RL-66 at 2µM increased the proportion of MDA-MB-231 cells in G2/M-phase by 162.02 ± 1.53% and 134.12 ± 2.17% over control (P&lt;0.001) respectively. In addition, the treatment with RL-71 (1µM) and RL-66 (2µM) increased the proportion of apoptotic MDA-MB-231 cells by 10-fold and 4-fold over control (p&lt;0.001), respectively. Similar results were also produced in SKBr3 and MDA-MB-468 cells. Furthermore, Western blot analysis confirmed the effect of drugs on different cancer related genes involved in cell proliferation and apoptosis. Thus, these data suggest that the novel curcumin analogues RL-71 and RL-66 are potent antitumor drugs and have significant potential for further drug development for estrogen receptor negative breast cancer.
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 3556.
Abstract 3560: Evaluation of RNA-stress granules formation as an indicator of response to Darinaparsin in cancer cell lines
Authors: Kolobova Elena , Larocca M. Cecilia , Goldenring James R. 
Published: February 2011

Abstract
Darinaparsin (ZIO101) is a novel organic arsenic compound demonstrating clinical efficacy and a favorable safety profile in hematological cancers and solid tumors. Its mechanism of action includes disruption of mitochondrial functions and induction of apoptosis. We studied the ability of darinaparsin to induce RNA stress granules, a critical survival adaptation mechanism for cells under stress. Darinaparsin caused a stress granule response similar to sodium arsenite, but at lower concentrations. Treatment of cells with darinaparsin induced the formation of granules containing a number of proteins specifically associated with stress granules, including G3BP (the Ras-GAP SH3 domain binding protein), CCAR1 (Cell Cycle and Apoptosis Regulatory Protein-1), caprin-1 (Cytoplasmic Activation/Proliferation-associated protein1) and AKAP350A (AKAP9). However, darinaparsin led to development of a greater number of smaller granules compared to sodium arsenite-induced stress.
We evaluated the effect of 0.5 mM arsenite or 0.05 mM darinaparsin on poorly differentiated uterine sarcoma (MES-SA) and the multiple drug resistant cell line MES-SA/Dx5 that was established from MES-SA cells. MES-SA/Dx5 cells express high levels of mdr-1 mRNA and P-glycoprotein. Both sodium arsenite and darinaparsin led to stress granule formation in both cell lines. However, MES-SA/Dx5 cells were extremely sensitive to darinaparsin treatment and exhibited a prominent loss of cell contact. The amount of cleaved PARP (a marker of apoptosis) determined at 48h and 72h after darinaparsin treatment was consistent with the immunofluorescence findings in that cleaved PARP was significantly elevated in MES-SA/Dx5 cells compared to MES-SA cells. This indicates enhanced cytotoxic effects of darinaparsin on this otherwise chemotherapeutic resistant cell line.
We also evaluated the effect of darinaparsin and sodium arsenite on different leukemia cell lines including Jurkat (T-cell lymphoblastic leukemia derived), Oci and THP1 (acute myeloid leukemia derived). THP1 cells express wild type nucleophosmin (NPM), while Oci cells are heterozygous for its mutant form NPMc+. Interestingly, we found that Jurkat cells did not developed stress granules in response to darinaparsin treatment and this cell line showed accelerated toxicity compared with THP1 and Oci cells, which did form stress granules. These studies demonstrate that darinaparsin has a different spectrum of activity than sodium arsenite and can elicit differential toxicity on specific classes of tumor cells.
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 3560.
Abstract 3562: Characterization of a novel small molecule inhibitor with potent anticancer activity
Authors: Chun Gina , Lee Young Bok , Kim Deog Joong , Cho Won-Jea , Lee Sang Kook , Chung Hwa-Jin , Ahn Chang-Ho 
Published: February 2011

Abstract
A series of isoquinolineamine small molecule derivatives were synthesized and screened as potential anticancer agents. Among them, we identified one isoquinolineamine analogue with potential anticancer activity. This compound inhibited the proliferation of a variety of cancer cells derived from many human solid tumors with IC50 values ranging from 14 nM to 71 nM. The compound also was more effective against gemcitabine and cisplatin-resistant cancer cell lines when compared to the original cytotoxic cancer drugs. In mice bearing tumor xenografts, treatment with the compound significantly inhibited the growth of tumors, enhanced tumor regression, and also prevented the growth of tumors in a paclitaxel-resistant xenograft model. This compound is well tolerated and had no effects on body weight compared to control animals. Mechanistic studies showed that cancer cells treated with this compound resulted in the elevation of cytochrome c in the cytosol, the decrease of Bcl-2 and the activation of Caspase 9. Further studies showed inhibition of the expression of several signaling molecules important for cell proliferation (p-Erk, p-p38 and p-Akt) and also decreased protein levels of p-GSK3α/β and β-catenin. Therefore, our result suggests that this compound could be a promising antitumor agent.
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 3562.
Abstract 3564: Anti-breast cancer activity of NIM811, a nonimmunosuppressive cyclosporine A analogue
Authors: Zeng Xianke , Harrington Katie , Clevenger Charles 
Published: February 2011

Abstract
Cyclophilin A (CypA) is a member of the immunophilin family of peptidyl prolyl isomerases (PPI) that catalyze the cis-trans interconversion of proline imide bonds of peptides. In this role, cyclophilins have been found to function as signaling switches, regulating the activity of receptors, kinases and transcription factors. The PPI activity of CypA is inhibited by the immunosuppressive drug cyclosporine A (CsA), and in turn the CypA-CsA complex inhibits calcineurin-mediated NFAT activation. Our laboratory has recently demonstrated that CypA is necessary for the prolactin (PRL)-induced activation of Jak2/Stat5 signaling and gene expression (Ca Res 68:7769, 2008). In addition, we have also shown that CsA inhibits the in vitro and in vivo growth and progression of both ER+ and ER- breast cancer cell lines. Here, we show that the non-immunosuppressive CsA analog NIM811 blocked PRL-stimulated activation of the Jak2/Stat5 pathway, and the kinases AKT and MAPK in T47D cells. NIM811 also inhibited ER+, ER-, and Her2+ breast cancer cell proliferation, survival and anchorage independent growth in a dose-dependent manner. NIM811 also blocked the PRL-induced association between Stat5 and cMyb, and at higher doses, triggered PARP cleavage. In summary, these results indicate that non-immunosuppressive cyclophilin inhibitor NIM811 has significant potential as a novel for breast cancer therapeutic.
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 3564.
Abstract 3565: Novel inhibitors of mPGES-1 exhibit anti-tumor activity in colorectal and lung cancers
Authors: Chang Hui-Hua , Song Zuohe , Tripp Tina , Wisner Lee , Gokhale Vijay , Hulme Chris , Meuillet Emmanuelle J. 
Published: February 2011

Abstract
Chronic inflammation is associated with 25% of all cancers. In the inflammation-cancer axis, prostaglandin E2 (PGE2) is one of the major players involved. Prostaglandin E synthase (PGES) is an enzyme downstream of the cyclooxygenases (COXs) in the PGE2 biosynthesis pathway. Among the three PGES isoforms, microsomal prostaglandin E synthase-1 (mPGES-1) is inducible by proinflammatory stimuli and constitutively expressed in colon, lung, and gastric cancers. The potential role for this enzyme in tumorigenesis has also been reported. Since inhibition of COXs may lead to some side effects due to the global reduction of other key prostaglandins, targeting downstream mPGES-1 might be a better therapeutic or chemopreventive strategy for cancers. In order to identify novel small molecule inhibitors of mPGES-1, we have screened in silico a small library of compounds. As a result, 14 lead compounds were identified by molecular docking simulations of the chemicals based on the crystal structure of mPGES-1. These compounds were tested for their ability to inhibit cell growth, induce apoptosis and decrease cytokine-stimulated PGE2 production in various colorectal and lung cancer cell lines. Using surface plasmon resonance (SPR) spectroscopy, we show the binding of the compounds PGE001 and PGE011 to human mPGES-1 recombinant protein with good affinity (KD at low micromolar range). These two compounds also showed the ability to reduce the IL-1beta-induced PGE2 production in HT29 and SW837 colon cancer cells and A549 lung cancer cell line with EC50 at low micromolar range. Furthermore, the compounds exhibit significant anti-tumor activity in the SW837 xenograft mouse model with T/C (relative size of treated and control tumors)=40.3% for compound PGE001 and T/C=68.7% for compound PGE011 (P&lt;0.05), when injected i.p. at 200 mg/kg for 5 and 10 days, respectively. When tested daily i.p. for 5 days at 100mg/kg in A549 lung cancer xenografts, the PGE001 showed anti-tumor activity with T/C=67% (P&lt;0.05). In summary, our data suggest that the identified compounds exert their anti-tumor activity through selective binding and inhibition of the enzyme mPGES-1 in the PGE2 synthesis pathway.
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 3565.