bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5491: Interrogating the mechanism of Wnt pathway inhibition by niclosamide
Authors: Mook Robert A. , Zhao Shengli , Chen Wei 
Published: May 2015

Abstract
The Wnt signaling pathway regulates genes critical for normal development and is dysregulated in many cancers. Indeed, more than 80% of all sporadic and hereditary colorectal cancers (CRCs) show hyperactivation of the Wnt/β-catenin pathway due to mutations in adenomatous polyposis coli (APC) or β-catenin genes. As a result, drugs that modulate the Wnt pathway are highly sought-after as the basis of a new generation of innovative therapeutic agents to treat CRC. Unfortunately, the ability to target this pathway with small molecule inhibitors has hampered drug discovery such that no approved drugs specifically targeting the pathway have been identified. To address this gap, we constructed a chemical genetics high-throughput screen that evaluated internalization of the Frizzled receptor in order to identify modulators of the Wnt/Frizzled/LRP5/6 signaling pathway. Using this assay we discovered the small molecule drug niclosamide, a FDA-approved anthelmintic agent, decreased β-catenin levels and inhibited Wnt/β-catenin signaling, findings since confirmed by others. To support efforts to evaluate niclosamide in clinical studies of colorectal cancer with aberrant Wnt signaling, we studied the translocation of Frizzled1-GFP induced by niclosamide and the kinetics of inhibition of Wnt signaling in cell culture. We found that niclosamide induces the co-localization of Frizzled1-GFP and lysosome markers indicating the translocation of Frizzled1-GFP to the lysosome. Kinetic studies indicated that β-catenin levels are reduced significantly within three hours and that both the levels of β-catenin and β-catenin gene transcription remained significant decreased 12 hours after the compound was removed. These data suggest a mechanistic hypothesis in which an extended duration of inhibition of Wnt signaling by niclosamide may result from the induced degradation of key proteins in the Wnt signaling pathway and that continuous exposure to niclosamide may not be necessary over the entire dosing period to maintain sufficient pathway inhibition. Overall, the findings support plans to investigate the use of niclosamide in clinical trials of CRC.
Citation Format: Robert A. Mook, Shengli Zhao, Wei Chen. Interrogating the mechanism of Wnt pathway inhibition by niclosamide. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5491. doi:10.1158/1538-7445.AM2014-5491
Abstract 5497: Targeting glioblastoma stem cells with withaferin A
Authors: Zhang Baoyu , Cuglievan Branko , Myrthil Nadia G. , Vanni Steven , Komotar Ricardo J. , Graham Regina M. 
Published: May 2015

Abstract
Introduction. Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer affecting 3 to 4 per 100,000 people annually in the United States. Despite aggressive therapy including surgical resection followed by both radiation and chemotherapy, overall survival remains dismal at approximately 14 months. Recent studies have determined that GBM's contain a small population of stem cells (GSCs), which promote tumor growth through unlimited self-renewal. Since GSCs are chemo- and radio-resistant and drive tumor regrowth following therapy, successful treatment depends on the elimination of these cells. Withaferin A (WA) is a bioactive compound derived from the plant Withonia somnifera which possesses anti-inflammatory and anti-cancer properties. Here we evaluated the effects of WA on patient derived GSCs.
Methods. With IRB approval, GSC lines were generated. GSCs were propagated in neurosphere media and examined for the stem cell markers CD133, nestin, musashi and BMi1 by immunocytochemistry and western blot analysis. Effect of WA on cell viability was determined using MTS assay. The effect of WA on cell survival and stress pathways was evaluated by western blot analysis.
Results. WA induced a significant decrease in cell viability at low micromolar concentrations. The IC50 for 3 patient derived GSC lines ranged between 0.96-1.78μM. WA induced ER stress and apoptosis in the GSCs as indicated by increased expression of ER stress markers grp78 and CHOP and increased levels of cleaved PARP. Furthermore, WA decreased survivin but increased phospho-ERK levels. However, inhibition of ERK activity with U0126 did not potentiate the effect of WA on cell death.
Conclusion. Ashwagandha has been used safely for medicinal purposes for centuries and pharmacokinetic studies in mice indicate that micromolar plasma concentrations of WA are obtainable. Our studies indicate that very low concentrations of WA induce ER stress and cell death in GSC lines. Targeting GSC with WA may increase patient survival by hindering GSC mediated tumor regrowth following surgery. Our data demonstrates the efficacy of WA and supports additional studies toward the use of WA as an adjuvant GBM therapy.
Citation Format: Baoyu Zhang, Branko Cuglievan, Nadia G. Myrthil, Steven Vanni, Ricardo J. Komotar, Regina M. Graham. Targeting glioblastoma stem cells with withaferin A. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5497. doi:10.1158/1538-7445.AM2014-5497
Abstract 5504: A potential source in oxidative cell death mediated by thymidylate synthase inhibitors: NADPH oxidase 2
Authors: Ozer Ufuk , Berger Franklin George , Barbour Karen Wood 
Published: May 2015

Abstract
Thymidylate synthase (TS) catalyzes the reductive transfer of a methyl group from N5,N10-methylenetetrahydrofolate (CH2-THF) to dUMP, forming dTMP and dihydrofolate (DHF). It is generally accepted that inhibition of the enzyme leads to a deficiency of dTMP, followed by genome damage and programmed cell death. As such, TS has long been viewed as an important target of anti-neoplastic agents, such as 5-fluorouracil (5-FU) and raltitrexed (RTX), which lead to inhibition of the enzyme. Oxidative stress is well-recognized as having a central role in cellular response to a number of DNA damaging agents, and may be a proximate cause of therapy-induced cell death. Despite such recognition, little detail exists on the origin and regulation of reactive oxygen species (ROS) during TS-directed chemotherapy. We have undertaken a detailed examination of the origin, nature, and role of ROS in cell death mediated by TS inhibitors. We have previously identified NADPH oxidase (NOX) as the primary source of increased ROS following exposure to TS-directed agents, as indicated by the observation of decreased ROS production and apoptotic indices in presence of NOX inhibitors. We have found that in response to TS inhibitors, NOX enzyme activity increases in association with induction of the transcript for p67phox, which specifically regulates the NOX2 isoform. This result is also verified by silencing p67phox gene in HCT116 cells. Silencing p67phox gene inhibits drug-induced NOX activity and decreases drug-induced apoptotic indices. To substantiate and expand results obtained from HCT116, we used other colorectal cancer cells, including HCT15, SW480, DLD-1, LoVo, MOSER and LS180. We have determined that colon cancer cells exhibit diverse responses in both basal and drug-inducible levels of apoptosis, NOX activity and mRNA of NOX2 regulatory subunits, implicating the heterogeneity in colorectal cancer cells. Based on these results, we conclude that augmentation of NOX2 activity via induction of p67phox mRNA expression is the proximate cause of programmed cell death elicited by dTMP deficiency in HCT116 cells. Each colorectal cancer cells might have different mechanism to undergo ROS-mediated cell death.
Citation Format: Ufuk Ozer, Franklin George Berger, Karen Wood Barbour. A potential source in oxidative cell death mediated by thymidylate synthase inhibitors: NADPH oxidase 2. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5504. doi:10.1158/1538-7445.AM2014-5504
Abstract 5515: Combining FK228 and cisplatin synergistically induces cancer cell death and reduces clonogenic survival
Authors: Choudhary Shambhunath , Sood Shilpa , Pluchino Lenora A. , Wang Hwa-Chain R. 
Published: May 2015

Abstract
The purpose of this study was to investigate the effectiveness of FK228 (romidepsin) to increase cisplatin's ability to induce cell death and reduce clonogenic survival of human urinary bladder cancer cells. Human urinary bladder cancer is the fifth most common cancer in the United States, but long-term, disease-free survival in patients is still suboptimal. Therefore, it is crucial to develop effective chemotherapeutic regimens to decrease the morbidity and mortality of this cancer. FK228, a depsipeptide and histone deacetylase inhibitor, is approved by the U.S. Food and Drug Administration for treatment of T cell lymphoma. However, its therapeutic value in treatment of bladder cancer is yet to be determined. Cisplatin is a DNA-damaging agent for treating various human cancers, including bladder, brain, ovary, lung, and testis cancers. However, the efficacy of cisplatin is often dampened by cancer cell drug resistance, mostly associated with glutathione (GSH)-based detoxification. Our study revealed that FK228 combined with cisplatin synergistically induced cell death and reduced clonogenic survival of human urinary bladder cancer cells. The Erk-Nox pathway played an important role in mediating signals highly increased by this combined treatment to induce significantly-elevated levels of reactive oxygen species, leading to substantially-induced caspase activation and synergistically-increased death in cancer cells. Cisplatin was able to enhance the ability of FK228 to significantly reduce GSH, indicating a novel activity of combined FK228 and cisplatin in reducing drug resistance. The ability of combined FK228 and cisplatin to synergistically induce cell death and reduce clonogenic survival was also applicable to colon cancer cells. Hence, combined use of FK228 with cisplatin should be considered in development of therapeutic strategies to control urinary bladder cancer and other cancer development and recurrence.
Citation Format: Shambhunath Choudhary, Shilpa Sood, Lenora A. Pluchino, Hwa-Chain R. Wang. Combining FK228 and cisplatin synergistically induces cancer cell death and reduces clonogenic survival. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5515. doi:10.1158/1538-7445.AM2014-5515
Abstract 5520: A novel HDAC inhibitor, N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), induces apoptotic cell death through mitochondrial cytochrome c release in renal cell carcinoma
Authors: Han Kyung Seok , Park Ki Cheong , Jeon Jeong Yong , Kim Sang Yong , Song Dami , Han Woong Kyu , Hong Sung Joon 
Published: May 2015

Abstract
Introduction: N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA) is a novel HDAC inhibitor that shows better pharmacological properties than known HDAC inhibitors. We investigated a therapeutic role and its mechanisms of HNHA in renal cell carcinoma.
Methods: Renal cell carcinoma cell lines, Caki-1, A-498, 786-O and UMRC-3 cells were used for in vitro study. Crystal violet assay was used to assess cell growth. Apoptosis was evaluated by TUNEL assay and confirmed by expression of cleaved caspase-3 and caspase-7. Cytochrome c release was evaluated by mitochondria staining. For in vivo study, Caki-1 and A-498 cells were injected (1.0 x 107/mouse) into the dorsal sub-membrane of 6-week-old BALB/C nude mice. Two different drugs were injected at Lethal Dose 50: HNHA, 206 µg/mL and SAHA, 138 µg/mL.
Result: HNHA suppressed tumor proliferation in all panels of renal cell carcinoma cells. TUNEL assay and Western blots showed that remarkable apoptosis was induced by HNHA in Caki-1 and A-498 cells. HNHA induced apoptotic cell death by caspase activation and Bcl 2 suppression in renal cell carcinoma in vitro and in vivo. HNHA also caused cytochrome c release from mitochondria through Bax and Bak expression. A primary caspase activation was initiated by cytochrome c release from mitochondria, which is able to induce biochemical reactions, caspase activation and subsequent cell death.
Conclusion: HNHA induces more potent apoptotic cell death in renal cell carcinoma in vitro and in vivo than the previous HDAC inhibitors. HNHA-induced apoptosis is mediated by cytochrome c release from mitochondria through induction of Bax and Bak expression in renal cell carcinoma.
Citation Format: Kyung Seok Han, Ki Cheong Park, Jeong Yong Jeon, Sang Yong Kim, Dami Song, Woong Kyu Han, Sung Joon Hong. A novel HDAC inhibitor, N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), induces apoptotic cell death through mitochondrial cytochrome c release in renal cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5520. doi:10.1158/1538-7445.AM2014-5520
Abstract 5522: Anticancer activity of novel PI3K inhibitor BYL719 in head and neck cancer cell lines
Authors: Keam Bhumsuk , Ahn Yong-Oon , Kim Tae Min , Lee Se-Hoon , Kim Dong-Wan , Heo Dae Seog 
Published: May 2015

Abstract
Introduction: Activating mutations of the PIK3CA gene occur frequently in head and neck squamous cell carcinoma. The purpose of this study was to explore the antiproliferative effect of BYL719, specific inhibitor for phosphatidylinositol 3-kinase (PI3K) p110α, in human head and neck cancer cell lines as a single agent or in combination with irreversible EGFR TKI.
Methods: Six head and neck cancer cell lines (SNU-1066, SNU-1041, SNU-1076, SCC25, Detroit562, and FaDu) were tested. The growth inhibitory effect was assessed using the modified tetrazolium bromide assay. The cell cycle at various concentrations of BYL719 was analyzed by flow cytometry, and analysis of downstream molecules was performed by western blot analysis. Mutational profiles of cell lines were screened by Cancer Cell Line Encyclopedia.
Results: PIK3CA mutant cell lines (SNU-1076 and Detroit562) were more sensitive to BYL719 than PIK3CA wild type cell lines (SNU-1066, SNU-1041, SCC25, and FaDu). PIK3CA wild type cell lines except SNU-1066 exhibited higher IC50 values for BYL719 (IC50 were 6.82, 1.10 μM in mutant cell lines and 1.13, 20.65, 19.67, 49.30 μM in wild type cell lines, respectively). BYL719 induced G0/1 arrest and resulted in apoptosis with dose dependant manner, in PIK3CA mutant cell lines. It reduced the level of p-mTOR, p-AKT, p-S6, suggesting its effectiveness in inhibition of translation and protein synthesis. BYL719 combined with dacomitinib also showed a synergistic inhibitory effect on PIK3CA mutant cell lines, while PIK3CA wild type cell lines showed no synergism.
Conclusion: BYL719 could be a promising treatment for head and neck cancer cells with PIK3CA mutation as a single agent or in combination with dacomitinib. The beneficial effects of BYL719 in in vitro studies for head and neck cancer warrant a further clinical investigation.
Citation Format: Bhumsuk Keam, Yong-Oon Ahn, Tae Min Kim, Se-Hoon Lee, Dong-Wan Kim, Dae Seog Heo. Anticancer activity of novel PI3K inhibitor BYL719 in head and neck cancer cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5522. doi:10.1158/1538-7445.AM2014-5522
Abstract 5525: Antitumor effect of Realgar in combination with chemotherapy drugs on human gastric cancer cells
Authors: Zhang Lian , Kim Sungkyoung , Ding Wenping , Zheng Leizhen , Zhang Li , Tong Yingying , Chen Siyu 
Published: May 2015

Abstract
Background: Realgar, a Chinese traditional medicine, of which the main component is arsenic sulfide (As4A4), has potentially anti-tumor property in various cancers. We aimed to study the antitumor effect of Realgar in combination with chemotherapy drugs on human gastric cancer cells. Methods: Human gastric cancer AGS cells were treated with Realgar in combination with Oxaliplatin, Irinotecan, Cisplatin, 5-FU and docetaxol with escalating dose level. Antitumor effect was measured by 24,48-hr growth inhibition by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cell morphology was observed under microscope. Results: Realgar in combination with chemotherapy drugs exhibited a dose-dependent and time-dependent cytotoxic effect on AGS cells. The combination of Realgar and Irinotecan or Cisplatin showed the most potent synergistic effect. Conclusions: Realgar combined with chemotherapy drugs such as Irinotecan or Cisplatin has potent antitumor effect on human gastric cancer cells. Further mechanistic and animal studies are being performed.
Citation Format: Lian Zhang, Sungkyoung Kim, Wenping Ding, Leizhen Zheng, Li Zhang, Yingying Tong, Siyu Chen. Antitumor effect of Realgar in combination with chemotherapy drugs on human gastric cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5525. doi:10.1158/1538-7445.AM2014-5525
Abstract 559: Patterns of Telomerase reverse transcriptase (TERT) promoter mutations in melanoma and bladder cancer
Authors: Kumar Rajiv , Heidenreich Barbara , Hosen Ismail , Rachakonda Sivaramakrishna , Hemminki Kari 
Published: May 2015

Abstract
We previously reported a disease segregating causal germline mutation in a melanoma family and recurrent somatic mutations in metastasized tumours from unrelated patients within the core promoter region of the telomerase reverse transcriptase (TERT) gene1. Both the germline mutation at -57 bp from ATG start site and somatic mutations at -124 bp, -124/-125 bp, -138/-139 bp and -146 bp from ATG result in de novo creation of Ets/TCF transcription factor binding motifs that lead to the increased gene expression. Subsequent studies have shown that TERT promoter mutations are not only confined to melanoma and are rather recurrent in different cancer types that include bladder cancer, glioma, hepatocellular carcinoma and others. In this study we show the difference in pattern of the TERT promoter mutations between melanoma and bladder cancer. While in melanoma the -146 C&gt;T mutation is the most frequent detected somatic base change in the TERT promoter, the -124 C&gt;T mutation is overwhelmingly the most common mutation in bladder cancer. In melanoma CC&gt;TT tandem mutations at -124/-125 bp and -138/-139 bp positions from ATG constitute about 10 percent of the detected TERT promoter mutations whereas in bladder cancer we did not detect any tandem mutations. The differences in the mutational pattern reflect etiological differences between the cancer types. In conclusion, the pattern of mutations in the TERT promoter differ between the cancer types even though all common mutations within the TERT promoter result in de novo creation of a common CCGGAA/T motif for Ets/TCF transcription factors.
1Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, Kadel S, Moll I, Nagore E, Hemminki K, Schadendorf D, Kumar R. TERT promoter mutations in familial and sporadic melanoma. Science. 2013;22:339:959-961.
Citation Format: Rajiv Kumar, Barbara Heidenreich, Ismail Hosen, Sivaramakrishna Rachakonda, Kari Hemminki. Patterns of Telomerase reverse transcriptase (TERT) promoter mutations in melanoma and bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 559. doi:10.1158/1538-7445.AM2014-559
Abstract 5597: Targeted massively parallel sequencing for the diagnosis of hereditary neuroendocrine disorders
Authors: Dwight Trish , Richardson Anne Louise , Zhu Ying , Robinson Bruce G. , Benn Diana E. , Clifton-Bligh Roderick J. 
Published: May 2015

Abstract
Background: Genetic testing is a powerful tool for the diagnosis, management and treatment of inherited disease but these tests traditionally have been time-consuming, labour-intensive and costly. Significant improvements in sequencing technologies have the potential to overcome these limitations, through the simultaneous sequencing of multiple genes in multiple samples. Objective: The aim of this study was to develop a multi-gene panel, comprised of hereditary neuroendocrine associated genes, to enable parallel testing of known susceptibility genes; and to determine whether the sensitivity of massively parallel targeted sequencing is equivalent to Sanger sequencing, the current gold standard for diagnostic genetic testing.
Methods: We developed a custom gene panel, covering the coding regions of 8 known neuroendocrine suseptibility genes (MAX, SDHB, SDHC, SDHD, SDHAF2, RET, TMEM127 and VHL). In total, genomic DNA of 85 individuals with unique variants in five of the susceptibility genes (based on Sanger sequencing) was prepared using the TruSeq Custom Amplicon Assay (Illumina) and sequenced on an Illumina MiSeq™ platform.
Results: Overall, 95.1% of the target was sequenced adequately for variant calling (ie. reads with ≥Q30). Inadequate coverage of the target region was observed for VHL (exon 1), SDHC (exons 2 and 5) and SDHD (exon 4). Seventy-eight of the 85 known variants met the required minimum coverage threshold (7 fell within regions of inadequate coverage or depth of coverage was ≤40). Of these, one variant was undetected, giving an overall sensitivity of 98.7%.
Conclusions: Genetic testing using targeted capture followed by massively parallel sequencing, in conjunction with confirmation by Sanger sequencing, is a viable option to the current approach for diagnostic services.
Citation Format: Trish Dwight, Anne Louise Richardson, Ying Zhu, Bruce G. Robinson, Diana E. Benn, Roderick J. Clifton-Bligh. Targeted massively parallel sequencing for the diagnosis of hereditary neuroendocrine disorders. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5597. doi:10.1158/1538-7445.AM2014-5597