bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1993: IL-18 induces an anti-apoptotic effect through stabilizing COX-2 mRNA expression in leukemia
Authors: Chu Yu Yi , KO Chiung Yuan , Wang Ju Ming 
Published: July 2016

Abstract
Leukemia is a cancer of bone marrow or blood cells. The acute myeloid leukemia (AML) is a common subtype occurred in adults to result in death. Forcing malignant cells to undergo differentiation instead of killing cancer cells is one of AML therapeutic strategy. However, the AML patients with poor outcome due to drug resistance is still a challenge. In this study, the abundances of the pro-inflammatory cytokine IL-18 and its receptor (IL-18R) were found to be correlated with the occurrence of drug resistance in AML patients. Importantly, we found that IL-18 induced an anti-apoptotic effect on U937 and THP-1 cells. Cyclooxygenase 2 (COX-2) has been suggested to have an anti-apoptotic role in chemo-resistant cancer cells. IL-18 increased COX-2 expression through post-transcriptional regulation in differentiated U937 cells. We found that two RNA binding proteins, HuR and IMP-3, stabilized COX-2 mRNA expression. In addition, IL-18 induced their interaction and facilitated this complex shuttle from nucleus to cytoplasm. Subsequently, HuR and IMP-3 bound to COX-2 mRNA 3’UTR. Two chemical inhibitors of JNK and ERK1/2 attenuated IL-18-enhanced COX-2 transcripts and the shuttle of HuR from nucleus to cytoplasm. These results suggested that IL-18 stabilized COX-2 mRNA through the JNK- and/or ERK1/2-regulated HuR nucleocytoplasmic shuttling and contributed to an anti-apoptotic effect in AML.
Citation Format: Yu Yi Chu, Chiung Yuan KO, Ju Ming Wang. IL-18 induces an anti-apoptotic effect through stabilizing COX-2 mRNA expression in leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1993.
Abstract 2023: SOX4 is essential for PTEN-mediated prostate tumorigenesis in vivo
Authors: Bilir Birdal , Osunkoya Adeboye O. , Wiles W. Guy , Sannigrahi Soma , Lefebvre Veronique , Metzger Daniel , Spyropoulos Demetri D. , Martin W. David , Moreno Carlos S. 
Published: July 2016

Abstract
Prostate cancer is the most common cancer and the second leading cause of cancer mortality in American men, underscoring the significance of unraveling the molecular mechanisms involved in the initiation and progression of the disease. The sex-determining region Y-box 4 (SOX4) gene is overexpressed in many types of human cancers, including prostate cancer, suggesting that SOX4 plays a fundamental role in tumorigenesis. In this study, we demonstrate that SOX4 is critical for PTEN-mediated prostate cancer progression in vivo. We show that homozygous deletion of Sox4 in the adult prostate epithelium strongly inhibits tumor progression initiated by homozygous loss of the Pten tumor suppressor, demonstrating the key role of SOX4 in the development of prostate cancer. Homozygous deletion of Sox4 also reduces the activation of AKT and β-catenin in Pten-null mice, resulting in inhibition of an invasive cancer phenotype. We also show that SOX4 expression is induced by loss of PTEN, and that PI3K-AKT-mTOR signaling activity is critical for SOX4 expression, suggesting a positive feedback loop between SOX4 protein and PI3K-AKT-mTOR activity. Our findings indicate that SOX4 is a critical component of the PTEN-PI3K-AKT pathway in prostate cancer, suggesting that SOX4 may be a promising molecular target for novel combinatorial therapies for both primary and advanced prostate cancers.
Citation Format: Birdal Bilir, Adeboye O. Osunkoya, W. Guy Wiles, Soma Sannigrahi, Veronique Lefebvre, Daniel Metzger, Demetri D. Spyropoulos, W. David Martin, Carlos S. Moreno. SOX4 is essential for PTEN-mediated prostate tumorigenesis in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2023.
Abstract 2048: Pharmacodynamic biomarker studies of TRC105 anti-endoglin (CD105) antibody revealed anti-angiogenic activity associated with CD105 depletion
Authors: Cao Liang , Karzai Fatima , Apolo Andrea , Madan Ravi , Yu Yunkai , Gulley James , Figg William , Dahut William 
Published: July 2016

Abstract
Introduction: CD105 is involved in normal vascular development. It is over expressed on the surface of proliferating vascular endothelial cells and is implicated in tumor angiogenesis. In hypoxic conditions, CD105 is upregulated through induction of hypoxia-inducible factor 1-α. TRC105 is a chimeric IgG1 antibody specific for CD105 and the agent for this phase I trial.
Methods: 20 patients with metastatic prostate cancer were treated with TRC105 at six dose levels in a phase I trial. Blood samples were analyzed for CD105 antigen depletion, VEGF as a marker for systemic hypoxia, and PSA.
Results: Maximum tolerated dose of 20 mg/kg every two weeks was reached. Significant plasma CD105 reduction was observed at high dose levels. The reduction of CD105 was associated with induction of plasma VEGF. Ten patients had stable disease, and the reduction of CD105 is associated with PSA stabilization.
Conclusion: A significant induction of VEGF was associated with CD105 reduction at three high dose levels, suggesting the anti-angiogenic activity of TRC105. Exploratory analysis showed a tentative correlation between the reduced CD105 and a decreased PSA velocity, suggestive of potential antitumor activity of TRC105 in metastatic prostate cancer.
Citation Format: Liang Cao, Fatima Karzai, Andrea Apolo, Ravi Madan, Yunkai Yu, James Gulley, William Figg, William Dahut. Pharmacodynamic biomarker studies of TRC105 anti-endoglin (CD105) antibody revealed anti-angiogenic activity associated with CD105 depletion. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2048.
Abstract 2147: Overcoming mTOR resistance mutations with a new generation mTOR inhibitor
Authors: Rodrik-Outmezguine Vanessa S. , Okaniwa Masanori , Yao Zhan , Novotny Chris , McWhirter Claire , Banaji Arpitha , Won Helen , Wong Wai , Berger Mike , de Stanchina Elisa , Barratt Derek G. , Cosulich Sabina , Klinowska Teresa , Rosen Neal , Shokat Kevan M. 
Published: July 2016

Abstract
First generation mTOR inhibitors (rapalogs) have modest activity in some tumors. We sought to delineate the likely resistance mechanisms to existing mTOR inhibitors as a guide for next generation therapies. We identified FRB domain and kinase domain mutations as causing acquired-resistance to rapamycin and mTOR kinase inhibitor respectively.
Resistance to rapamycin was due to loss of binding of the FKBP12-rapamycin complex to the FRB domain of mTOR mutant protein. Resistance to the mTOR kinase inhibitor was not due to a gatekeeper mutation but rather to an increase in the intrinsic kinase activity of the mTOR kinase domain mutant. These and similar mutations have also been identified in tumors from untreated patients. These findings suggest that these mutations are gain of function mutants but also that tumors with these activating mutations will be intrinsically resistant to second generation mTOR kinase inhibitors.
We have designed a new class of mTOR inhibitor, RapaLink-1, that takes advantage of the juxtaposition of two drug binding pockets to create a bivalent interaction. This compound potently inhibits mTOR activation in cells with mTOR wild-type and overcomes resistance to existing first and second generation inhibitors. Moreover, intermittent dosing of RapaLink-1 effectively suppresses mTOR-dependent tumor growth in vivo. Thus, such third generation mTOR inhibitors could be useful for treating tumors with activating mutations of mTOR and for tumors with acquired-resistance to current mTOR inhibitors.[N.R. and K.S. contributed equally to this work.]
Citation Format: Vanessa S. Rodrik-Outmezguine, Masanori Okaniwa, Zhan Yao, Chris Novotny, Claire McWhirter, Arpitha Banaji, Helen Won, Wai Wong, Mike Berger, Elisa de Stanchina, Derek G. Barratt, Sabina Cosulich, Teresa Klinowska, Neal Rosen, Kevan M. Shokat. Overcoming mTOR resistance mutations with a new generation mTOR inhibitor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2147.
Abstract 2177: Rutin enhances the antiproliferative effect of 5-FU and oxaliplatin in colon cancer cells
Authors: Nasiri Farnoud , Kismali Gorkem , Alpay Merve , Kosova Funda , Cakir Dilek Ulker , Sel Tevhide 
Published: July 2016

Abstract
Background: Rutin is a strong antioxidant molecule and it has advantageous over other flavonoids due to it is a nontoxic and nonoxidizable molecule. The concept of dual therapy of anti-cancer drugs with natural compounds has become a very promising approach in new strategy to treatment. The aim of this study was to evaluate the antiproliferative and apoptotic effects of rutin flavonoids and its efficacy in enhancing the anticancer effects of 5-FU (5-fluorouracil) and oxaliplatin against colon cancer cells.
Material and Methods: Caco-2 human colon cancer cells were treated with rutin and/or anticancer drugs (5-FU and oxaliplatin), cell viability and apoptotic parameters were examined. Cell viability was determined by MTT assay. Apoptotic markers (cleaved caspase 3, cleaved PARP and phosphor-Bad) were determined using specific enzyme-linked immunosorbent assay kits. Caspase-8 and caspase-9 were analyzed by colorimetric activity assay kit. DNA fragmentation was analyzed by agarose gel electrophoresis.
Results: The exposure Caco-2 human colon cancer cells to rutin, 5-FU and oxaliplatin resulted growth inhibition in a dose- and time-dependent manner. Cell viability assay shows that rutin inhibiting growth of Caco-2 cells at high concentrations (over 1000 μM). Combination with rutin markedly enhanced 5-FU and oxaliplatin growth inhibiting effects on Caco-2 cells. Results suggested that rutin had significant anticancer abilities; such rutin were capable of causing multifold decreases in the half maximal inhibitory concentration IC50 value of 5-FU and oxaliplatin. This flavonoid increased the levels of proteins associated with apoptotic cell death (phospho-Bad, cleaved caspase 3 and cleaved PARP) alone and combination. The activities of caspase 8 and caspase 9 were stimulated by the combination treatment of rutin and oxaliplatin then alone. DNA fragmentation was observed only on combination treatment.
Conclusions: Combined treatment with rutin and anticancer drugs (5-FU and/or oxaliplatin) is more effective than the individual treatments of drugs at inhibiting growth of Caco-2 cells. The use of lower 5-FU and oxaliplatin doses, with similar effects, could be also useful to reduce possible adverse effects of these drugs. However, further studies at molecular level are required to elucidate chemopreventive and chemotherapeutic effects of rutin on colon cancer.
Citation Format: Farnoud Nasiri, Gorkem Kismali, Merve Alpay, Funda Kosova, Dilek Ulker Cakir, Tevhide Sel. Rutin enhances the antiproliferative effect of 5-FU and oxaliplatin in colon cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2177.
Abstract 2473: Combined BET-bromodomain and CDK2 inhibition in MYC-driven medulloblastoma
Authors: Bolin Sara , Borgenvik Anna , Persson Camilla , Rosén Gabriela , Sundström Anders , Qi Jun , Bradner James E. , Weiss William A. , Cho Yoon-Jae , Weishaupt Holger , Swartling Fredrik J. 
Published: July 2016

Abstract
Misexpression of MYC genes (MYC and MYCN) occurs commonly in medulloblastoma (MB), the most frequent malignant childhood brain tumor. We previously showed that tumors are addicted to MYCN and that MYCN stabilization is required for MB development in mice (Swartling et al, Genes & Dev, 2010; Cancer Cell, 2012). Targeted MYCN suppression completely depleted MYCN-driven MB cells in vivo. Immediate transcriptional changes from such MYCN blockade were found by RNA-Seq and showed similarities to changes that occurred after CDK2 suppression or when inhibiting BET bromodomains. CDK2 and BET inhibitors both inhibited MYC protein expression and effectively induced cell cycle arrest or apoptosis. Compared with either agent alone a sustained combination treatment over 7-10 days displayed synergy and effectively abolished tumor cell proliferation in vitro. The combined treatment further reduced tumor growth in orthotopical MB transplants and significantly prolonged survival as compared to single agent therapy. Our data suggest that dual inhibition of CDK2 and BET Bromodomains could be a novel treatment approach in suppressing medulloblastoma by targeting MYC proteins.
Citation Format: Sara Bolin, Anna Borgenvik, Camilla Persson, Gabriela Rosén, Anders Sundström, Jun Qi, James E. Bradner, William A. Weiss, Yoon-Jae Cho, Holger Weishaupt, Fredrik J. Swartling. Combined BET-bromodomain and CDK2 inhibition in MYC-driven medulloblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2473.
Abstract 2481A: A novel chemically-modified curcumin (CMC 2.24) promotes chemosensitivity in neuroblastoma
Authors: Tauber David , Galinski Basia , Castellanos Raquel , Scaduto Joseph , Johnson Francis , Golub Lorne , Weiser Daniel A. 
Published: July 2016

Abstract
Introduction
The chemically modified curcumin, CMC 2.24 (TRB-N0224, Traverse Biosciences Inc.), was designed to overcome the poor solubility, bioavailability, and biological potency of naturally occurring curcumin in an effort to achieve superior safety and efficacy in chronic inflammatory conditions and cancer. It has been demonstrated that CMC 2.24 can sensitize cancer cells that are otherwise refractory to chemotherapy. Patients with neuroblastoma, a highly lethal childhood cancer of the peripheral sympathetic nervous system, often have de novo chemotherapy resistance and therefore succumb rapidly to their disease. We hypothesize that chemoresistance in primary refractory neuroblastoma is mediated by anti-apoptotic mechanisms that can be overcome when conventional therapy is combined with CMC 2.24.
Experimental Procedures
A heterogeneous panel of neuroblastoma cell lines was cultured under routine conditions and subjected to varying concentrations of CMC 2.24 to establish IC50s. Subsequent studies were focused on NB-EBc1, a MYCN non-amplified cell line, and IMR-5, a MYCN amplified cell line. IC50s were also generated for cisplatin as a single agent, and then when administered in combination with CMC 2.24. Whole protein cell lysates were extracted at 24, 48, and 72 hours after treatment and cell viability was measured by MTT proliferation assays.
Results
Proliferation defects were observed in all neuroblastoma cell lines treated with CMC 2.24 as compared to vehicle (DMSO) control. Relatively cisplatin-resistant cell lines had diminished cell viability when CMC 2.24 was added in combination with cisplatin, suggesting a synergistic effect. Alterations in response to CMC 2.24 treatment occur in anti-apoptotic proteins survivin and BARD1, found to be upregulated in chemoresistant cell lines. Additional mechanistic evaluation is ongoing.
Conclusions
There is no known curative therapy for patients with primary refractory neuroblastoma. CMC 2.24 enhances chemosensitivity in a panel of neuroblastoma cell lines and may provide a new therapeutic approach that can overcome de novo chemotherapy resistance. Further mechanistic and in vivo studies are needed to facilitate clinical development of a promising novel anti-cancer agent.
Citation Format: David Tauber, Basia Galinski, Raquel Castellanos, Joseph Scaduto, Francis Johnson, Lorne Golub, Daniel A. Weiser. A novel chemically-modified curcumin (CMC 2.24) promotes chemosensitivity in neuroblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2481A.
Abstract 257: Evaluation of organic cation transporter 1 (OCT1, SLC22A1) as transporter for sorafenib
Authors: Neul Claudia , Baker Sharyn D. , Sparreboom Alex , Schaeffeler Elke , Laufer Stefan , Schwab Matthias , Nies Anne T. 
Published: July 2016

Abstract
The multikinase inhibitor sorafenib is approved for the treatment of advanced clear-cell renal and hepatocellular carcinomas, yet, patients’ survival is prolonged for only several months (Wilhelm et al., Mol Cancer Ther 2008). The understanding of this poor efficacy remains incomplete. One reason for treatment failure may be the high interindividual variability in pharmacokinetics of the orally-given sorafenib. Membrane transporters may contribute to pharmacokinetics of sorafenib and its metabolites as recently reported for the hepatic solute carrier (SLC) organic anion transporter family member 1B1 (OATP1B1) and OATP1B3 (Zimmerman et al, Clin Cancer Res 2013). In contrast, the role of organic cation transporter 1 (OCT1), which is also a major hepatic uptake transporter (Nies et al, Handb Exp Pharmacol 2011), for cellular uptake of sorafenib is controversial (Hu et al, Clin Cancer Res 2009; Swift et al, Drug Metab Dispos 2013; Herraez et al, Hepatology 2013). We therefore sought to comprehensively elucidate the impact of OCT1 on cellular sorafenib uptake by using a combination of different in vitro cell culture models and in vivo approaches involving experiments with Oct1 knockout (-/-) mice. Firstly, we analyzed cellular accumulation of radiolabeled sorafenib by the mammalian cell line HEK293 stably expressing OCT1. Despite overexpression of a functional OCT1 transporter, cellular uptake of neither sorafenib nor its active metabolite sorafenib N-oxide was increased. Next, we studied sorafenib and sorafenib N-oxide pharmacokinetics in mice with a homozygous genetic deletion of the Oct1 transporter. The deficiency of Oct1 had no influence on plasma and hepatic sorafenib and sorafenib N-oxide concentrations. Finally, we investigated sorafenib transport into the human hepatocellular carcinoma cell lines HepG2 and HuH7. Although neither OCT1 mRNA nor protein was detected, a considerable cellular accumulation of sorafenib was observed in both cell lines. Expression profiling of a panel of 55 relevant SLC drug uptake transporters identified several potential novel candidates mediating sorafenib accumulation.
We conclude from these findings that cellular uptake of sorafenib and sorafenib N-oxide is independent of OCT1 and that other, as yet unidentified, transport mechanisms are responsible for cellular sorafenib uptake.
Supported by the Robert Bosch Foundation, Stuttgart, Germany and the ICEPHA Grant Tübingen-Stuttgart, Germany.
Citation Format: Claudia Neul, Sharyn D. Baker, Alex Sparreboom, Elke Schaeffeler, Stefan Laufer, Matthias Schwab, Anne T. Nies. Evaluation of organic cation transporter 1 (OCT1, SLC22A1) as transporter for sorafenib. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 257.
Abstract 2611: Effects of chalcones, nicotinamide, and resveratrol on PPAR gamma activation in oral cancer cells
Authors: Diaz Jennifer , Wuertz Beverly , Galbraith Art , Ondrey Frank G. 
Published: July 2016

Abstract
Several classes of natural products have cancer prevention potential and PPAR gamma is an intriguing chemoprevention target as a nuclear receptor that controls multiple growth and differentiation processes. We have previously tested many classes of natural products in A/J mice and have found that the following chemoprevention compounds had no significant dietary toxicities: inositol, eucalyptol, chalcones, nicotinamides, and resveratrol. We tested these compounds for their capacity to activate PPAR gamma reporter genes in CA-9-22 oral cancer cells. In several repeated experiments we found that Inositol hexaphosphate did not activate PPAR gamma reporter genes at high concentrations of 1-4 mM. We found that eucalyptol, trans-Chalcone, 4 methoxy chalcone, Nicotinic Acid, and Nicotinamide had the capacity for statistically significant activation of PPAR gamma reporter genes in oral cancer cells from 20-60% at concentrations of 1-100 uM. We found that resveratrol was the most potent agent and could activate PPAR gamma reporter genes 2 fold. As a reference, this was about half the activity of the prototypic PPAR gamma activator pioglitazone. We performed additional experiments with resveratrol and found that it could activate the PPAR gamma dependent squamous differentiation gene Involucrin in oral cancer cells and BEAS 2B cells. Additionally, resveratrol significantly decreased BEAS 2 B proliferation from 48-96 hours at concentrations of 10 uM. From this data we conclude that resveratrol has the capacity to activate PPAR gamma in vitro and resveratrol and its derivatives may also function as PPAR gamma activators as an additional mechanism of action. We also conclude that inositol, eucalyptol, chalcones, and nicotinamides do not activate PPAR gamma.
Citation Format: Jennifer Diaz, Beverly Wuertz, Art Galbraith, Frank G. Ondrey. Effects of chalcones, nicotinamide, and resveratrol on PPAR gamma activation in oral cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2611.