bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1864: Verticillin A causes DNA damage and apoptosis in high grade serous ovarian cancer
Authors: Salvi Amrita , Austin Julia , Lantvit Daniel , Burdette Joanna 
Published: August 2019

Abstract
High grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy affecting women worldwide and the fifth most common cause of cancer related deaths among U.S. women. New targeted therapies are needed to prevent HGSOC progression and metastasis related lethality from the disease. The goal of this study was to test the novel natural compound, Verticillin A, for its anticancer properties and mode of action in HGSOC cells. Verticillin A is an epipolythiodioxopiperazine (ETP) alkaloid that is isolated from several terrestrial and marine filamentous fungi and has been shown to be cytotoxic in several cancer cell lines including OVCAR8, OVCAR4 and Kuramochi. Our data indicated that Verticillin A treatment caused cytotoxicity in HGSOC cell lines in a dose-dependent manner.
Furthermore, treatment with Verticillin A in HGSOC cell line OVCAR8 and OVCAR4 enhanced apoptosis, which was demonstrated by PARP cleavage and Annexin V/ Propidium iodide staining. To determine whether Verticillin A caused in vivo tumor growth inhibition, OVCAR8-RFP cells were xenografted in mice to form tumors and the mice were treated with Verticillin A. Encapsulated nanoparticles of Verticillin A decreased tumor growth in vivo and had low cytotoxicity compared to the naked drug. RNA-Seq analysis was performed with OVCAR8 cells treated with Verticillin A and the data found an upregulation of apoptosis signaling pathway and oxidative stress response and downregulation of cancer stemness signaling pathways. A proteomic histone profiling performed in OVCAR8 cells indicated that Verticillin A caused epigenetic modifications with global changes in histone methylation and acetylation marks. Thus, our study identifies Verticillin A as a novel epigenetic modifier in ovarian cancer cells and indicates therapeutic potential for treatment of HGSOC.
Note: This abstract was not presented at the meeting.
Citation Format: Amrita Salvi, Julia Austin, Daniel Lantvit, Joanna Burdette. Verticillin A causes DNA damage and apoptosis in high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1864.
Abstract 1868: B-125, a novel berberine derivative, acts as a better retinoid X receptor a agonist with stronger anti-tumor activity in colon cancer
Authors: Xu Beibei , Hu Tian hui , Xiong jing 
Published: August 2019

Abstract
Our previous study showed that Berberine binds to RXRα to suppress colon cancer growth (Ruan et. al., Oncogene 2017, 36: 6906). To achieve better RXRα binding activity, stronger anti-tumor effect and higher bioavailability, 21 novel berberine derivatives were designed based on the binding information of berberine to RXRα. Among them B-125 performs the best solubility, RXRE luciferase activity and tumor suppressing ability. NMR and fluorescent titration results show that B-125 retain the similar binding ability to RXRα compared with Berberine. CD study suggests that B-125 has stronger allosteric effect on RXRα than berberine. The bioavailability of B-125 is 25 times higher than berberine. In KM12C colon cancer cells, B-125 performs stronger RXRα dependent inhibitory effects than berberine. In vivo results showed that B-125 inhibits the growth of colon cancer xenograft in nude mice, and the effect is stronger than that of berberine. All the above results indicate that B-125 is a better anti-cancer drug than berberine with better RXRα modulation ability, higher bioavailability and stronger tumor suppressing effect. The study promotes B-125 as a potential novel RXRα based anti-cancer drug in the treatment of colon cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Beibei Xu, Tian hui Hu, jing Xiong. B-125, a novel berberine derivative, acts as a better retinoid X receptor a agonist with stronger anti-tumor activity in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1868.
Abstract 1869: Mechanistic evaluation of ergosterol peroxide onin vitrobreast cancer models
Authors: Santiago Camille L. , Rivas Fatima , Ling Taotao , Suarez-Arroyo Ivette J. , Ortiz Gabriela , Lacourt Mercedes Y. , Valentin Anibal , Lang Walter H. , Martínez-Montemayor Michelle M. 
Published: August 2019

Abstract
Ganoderma lucidum extract (GLE), an extensively studied mushroom for its anti-cancer and anti-inflammatory properties, has been shown to possess physiologically active compounds such as polysaccharides, triterpenoids and sterols. In our previous studies, we reported that commercially available GLE whole mushroom extract selectively inhibits cancer cell viability, induces apoptosis, reduces invasion, and regulates key signaling molecules in various cell models of breast cancer. Hence, we sought to elucidate the compounds responsible for the observed anti-cancer activity. Among the isolated compounds from GLE, we identified a steroidal compound, Ergosterol Peroxide (EP), which has shown antiproliferative activity against cancer. EP is a member of natural endoperoxides, featuring the peroxy- warhead that can lead to hydroxyperoxy radicals or be activated and react as nucleophile, leading to significant biological cytotoxicity against various cancer models (e.g. ovarian, liver, colon). We hypothesized that EP would promote cell death mechanisms in the aggressive breast cancer phenotype. Thus, in this study, we evaluated EP’s anti-cancer potential using immunoblotting, colony formation, cell motility, cell cycle and reactive oxygen species (ROS) production assays against human breast cancer SUM-149, MCF-7, MDA-MB-231 cellular models. We show that EP displays anti-proliferative effects through cell arrest in G1 phase, and apoptosis induction via caspase 3/7 activation. EP induced ROS and decreased the migratory and invasive phenotype of these cancer cells. Moreover, it inhibited the expression of total AKT1, AKT2, BCL-2, BCL-XL, Cyclin D1 and c-Myc. Our combined results indicate that EP from GLE is a promising molecular scaffold for further exploration as an anti-cancer agent,particularly in aggressive breast cancer models.
Citation Format: Camille L. Santiago, Fatima Rivas, Taotao Ling, Ivette J. Suarez-Arroyo, Gabriela Ortiz, Mercedes Y. Lacourt, Anibal Valentin, Walter H. Lang, Michelle M. Martínez-Montemayor. Mechanistic evaluation of ergosterol peroxide onin vitrobreast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1869.
Abstract 1872: Oleuropein reduces Prdx1 expression, cell proliferation and viability in K562 human leukemia cells
Authors: Fulco Natalie , Fagan Sophia , Phelan Shelley A. 
Published: August 2019

Abstract
Oleuropein is one of the two main phenolic compounds derived from olive leaves. Numerous studies have found that the polyphenols contained in olive leaves possess strong antioxidant properties, and increase apoptosis in many types of cancer cells, suggesting its possible efficacy as an anti-cancer treatments. The purpose of our study was to examine the effects of oleuropein extract on cell growth and viability of the K562 human leukemia cell line, and to investigate possible molecular mechanisms of action. Oleuropein of 98% purity was used for our studies. We first demonstrated that K562 cells treated with 200 and 400 μg/ml oleuropein exhibited a significant reduction in cell growth and viability after four days as compared to ethanol-treated controls. Cells treated with 200μg/ml oleuropein showed decreased cell proliferation and viability after two days, and exhibited approximately 90% reduction in cell density and viability after four days of treatment. A concentration of 400 μg/ml oleuropein resulted in 100% toxicity by day four. We also examined the effects of oleuropein on cellular cytotoxicity using an LDH release assay and found a two-fold elevation in LDH release within 24 hours of treatment with 200 μg/mL oleuropein. To begin to explore a mechanisms of action, we used western blotting to examine known antioxidant and signaling pathways for possible regulation by oleuropein in these cells. We examined expression of the Peroxiredoxin (Prdx) family of proteins, a group of thiol-specific antioxidants found to be elevated in many types of cancer. We found that 200 ug/ml oleuropein reduced Prdx1 expression by about 50% after eight and twenty-four hours, while having no significant effect on expression levels of Prdx-2, -3, -4, and -6. We are currently investigating the mechanism of cell death induced by oleuropein, as well as the role of Prdx1 in oleuropein-induced toxicity. Together with previously reported cancer-cell specific effects, this research provides a promising new avenue for the use of natural products as anti-cancer agents.
Citation Format: Natalie Fulco, Sophia Fagan, Shelley A. Phelan. Oleuropein reduces Prdx1 expression, cell proliferation and viability in K562 human leukemia cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1872.
Abstract 1877: The role played by SLUG, an epithelial-mesenchymal transition factor, in invasion and therapeutic resistance of malignant glioma
Authors: Lee Kyung-Hwa , Oh Se-Jeong , Ahn Eun-Jung , Jung Shin , Lee Jae-Hyuk , Kim Kyung-Keun , Kim Hangun , Moon Kyung-Sub 
Published: August 2019

Abstract
Purpose: In malignant gliomas, invasive phenotype and cancer stemness promoting resurgence of residual tumor cells, render treatment very difficult. Hence, identification of epithelial-mesenchymal transition (EMT) factors associated with invasion and stemness of glioma cells is critical.
Methods: To address the issue, we investigated several EMT factors in hypermotile U87MG and U251 cells, mouse xenograft model, and human glioma samples. Of several EMT markers, SLUG expression was notably increased at the invasive fronts of gliomas, both in mouse tumor xenografts and human glioma samples. The biological role played by SLUG was investigated using a colony-forming assay after chemotherapy and irradiation, and by employing a neurosphere culture assay. The effect of SLUG on glioma progression was examined in our patient cohort and samples, and compared to large public data from the REMBRANDT and TCGA.
Results: Genetic upregulation of SLUG was associated with increased levels of stemness factors and enhanced resistance to radiation and temozolomide. In our cohort, patients exhibiting lower-level SLUG expression evidenced longer progression-free survival (P=0.042). Also, in the REMBRANDT dataset, a group in which SLUG was downregulated exhibited a significant survival benefit (P&lt;0.001). Although paired gliblastoma multiforme (GBM) samples from our patients did not showed significant increase of SLUG expression, increased mRNA levels of SLUG was found in recurred GBM from TCGA (P=0.052), and in TMZ-treated glioma cells and mouse xenograft.
Conclusion: SLUG may contribute to glioma progression by controlling invasion at infiltrating margins, associated with increased stemness and therapeutic resistance.
Citation Format: Kyung-Hwa Lee, Se-Jeong Oh, Eun-Jung Ahn, Shin Jung, Jae-Hyuk Lee, Kyung-Keun Kim, Hangun Kim, Kyung-Sub Moon. The role played by SLUG, an epithelial-mesenchymal transition factor, in invasion and therapeutic resistance of malignant glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1877.
Abstract 1882: Molecular context dictates the effects of eribulin on key EMT regulators: Snail and Slug
Authors: Kaul Roma , Risinger April L. , Mooberry Susan L. 
Published: August 2019

Abstract
Microtubule targeting agents (MTAs) are a mainstay in the treatment of breast cancer and a growing body of evidence demonstrates that they have non-mitotic effects that contribute to their anticancer actions. Even after decades of clinical use, there is much to be learned about the mechanisms of action these drugs, and differences among them, for optimal utility. MTAs rapidly alter microtubule dynamics, often within minutes, leading to significant changes in oncogenic cellular signaling. We evaluated the early effects of eribulin on key oncogenic signaling pathways following a 2 h incubation using clinically relevant concentrations and compared the effects to those initiated by other MTAs. These studies led to the identification of novel mechanisms by which MTAs disrupt oncogenic signaling and contribute to the reversal of epithelial to mesenchymal transition (EMT), including unanticipated differences among drugs. The TGF-β-mediated expression of the Snail transcription factor is a key driver pathway of EMT in breast cancer. The effects of eribulin and other MTAs on TGF-β-induced, Smad-dependent expression of Snail were evaluated. Our results show that eribulin and vinorelbine inhibit the ability of TGF-β to promote the transcriptional induction of Snail by impeding the nuclear transport of Smad2/3 proteins in 4 triple-negative breast cancer cell lines. The effects of microtubule destabilizers contrasted with those of paclitaxel, which had no effect on the expression of Snail. This study begins to explain how microtubule disruption might contribute to the eribulin-mediated EMT reversal. Slug is another member of the Snail family of transcription factors that plays a central role in breast cancer EMT. Although Snail and Slug are often grouped together due to functional similarities, it is now understood that they regulate non-overlapping sets of genes. In contrast to our findings with Snail, eribulin and vinorelbine, but not paclitaxel or ixabepilone, induced Slug over-expression in a subset of breast cancer cell lines. We have identified molecular contexts where eribulin and vinorelbine induced Slug expression, resulting in the identification of a potential biomarker for response to microtubule destabilization. This work highlights the multifaceted nature of MTA-mediated effects on EMT-associated signaling pathways in breast cancer cells. These studies are supported by Eisai Inc.
Citation Format: Roma Kaul, April L. Risinger, Susan L. Mooberry. Molecular context dictates the effects of eribulin on key EMT regulators: Snail and Slug [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1882.
Abstract 1884: Development of a novel VIM-RFP reporter line for colorectal cancer EMT study and drug discovery
Authors: Shu Weiguo , Douglas Diana , Kumari Sangeeta , Romero Luis , Rodriguez Luis G. , Zou Chaozhong , Newman Robert 
Published: August 2019

Abstract
Epithelial-to-Mesenchymal Transition (EMT) describes a dynamic and reversible process by which cells lose their epithelial characteristics and acquire mesenchymal properties. Accumulating evidence indicates that EMT displays an array of intermediate states, a phenotype referred to as “partial MET”. EMT is executed in response to signaling pathway molecules and microRNAs (miRNAs) that induce the expression of specific EMT associated transcription factors (EMT-TFs), including Zeb1/2, Snail1/2, and Twist. There is an ever-growing body of research and clinical evidence indicating that EMT plays an important role in cancer cell dissemination and distal metastasis. Therefore, targeting EMT is considered a novel opportunity in anti-cancer treatment and drug development.
Vimentin, a hallmark of mesenchymal cells, is of increasing interest as a novel anti-cancer therapeutic drug target. In colorectal cancer (CRC) patients, increased expression of the vimentin protein predicts a poor prognosis. Here, we developed a novel CRC HCT-116 VIM-RFP reporter line using CRISPR/Cas9 technology. In this cell line, the RFP reporter was incorporated into the endogenous vimentin gene just before the stop codon at the last exon, enabling real-time monitoring of EMT states in live cells. The VIM-RFP knock-in allele was confirmed at genomic, transcriptional, and translational levels. Bio-functional evaluation data revealed that miRNA-200 inhibitor treatment induced the increased expression of VIM-RFP, and decreased expression of E-cadherin, a hallmark of epithelial cells. The expression of EMT-TFs ZEB-1 and ZEB-2 was also upregulated upon induction. In addition, we showed that induced VIM-RFP cells displayed increased migration capacity. These data suggested that miRNA-200 inhibitor induced VIM-RFP cells have undergone EMT. Azacitidine, a clinically approved demethylating agent, has been extensively evaluated in a number of clinical trials as a treatment for CRC patients. Studies reported that azacitidine can induce MET in a number of cancer cell lines. We showed that azacitidine treatment of VIM-RFP cells can effectively induce RFP expression, suggesting a potential application of this VIM-RFP reporter line as a platform for drug evaluation and compound screening. Taken together, the HCT-116 Vim-RFP EMT reporter line could be a valuable tool for dissecting the molecular mechanisms underlying EMT and for evaluating or screening compounds targeting EMT in CRC.
Citation Format: Weiguo Shu, Diana Douglas, Sangeeta Kumari, Luis Romero, Luis G. Rodriguez, Chaozhong Zou, Robert Newman. Development of a novel VIM-RFP reporter line for colorectal cancer EMT study and drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1884.
Abstract 19: Design and synthesis of biaryl indolyl benzamides as HDAC1-selective inhibitors via a fragment-based lead generation approach
Authors: Negmeldin Ahmed T. , Pflum Mary Kay H. 
Published: August 2019

Abstract
Histone deacetylase (HDAC) proteins are epigenetic regulatory enzymes that deacetylate protein substrates, leading to subsequent changes in cell function. HDAC proteins are implicated in cancers and several HDAC inhibitors have been approved by the FDA as anti-cancer drugs. Unfortunately, most of the FDA-approved drugs non-selectively inhibit most of the HDAC isoforms, which may lead to side effects in the clinic and limit their use on the bench top. Isoform-selective HDAC inhibitors may decrease or eliminate the side effects associated with non-selective inhibitors treatment. In addition, isoform-selective HDAC inhibitors can be used as molecular tools to study HDAC-related cancer biology. In this work, several biaryl indolyl benzamide compounds were designed and synthesized based on a fragment-based lead generation approach as potential HDAC1-selective inhibitors. The design was based on combining two different fragments from known HDAC1/2 and HDAC1/3 selective inhibitors. These fragments can discriminate against both HDAC2 and HDAC3 and possibly impart selectivity towards HDAC1. Docking studies were performed to validate the design of the inhibitors and to understand the binding of different isoform-selective inhibitors to HDAC1, HDAC2, and HDAC3. Potency and isoform selectivity of the new compounds were assessed via in vitro screening with different HDAC isoforms. All analogs showed modest selectivity for HDAC1 over HDAC2. Bnz-3 was identified as the best compound in terms of potency and selectivity. In particular, Bnz-3 displayed roughly 10- to 100-fold higher potency than the other compounds, with an IC50 value of 548 nM with HDAC1. In terms of selectivity, Bnz-3 showed about 10.6-fold selectivity for HDAC1 over HDAC2, with almost no inhibition of either HDAC3 or HDAC6. The new biaryl indolyl benzamide HDAC inhibitors represent potential lead compounds that can help to further develop more selective HDAC1 inhibitors.
Citation Format: Ahmed T. Negmeldin, Mary Kay H. Pflum. Design and synthesis of biaryl indolyl benzamides as HDAC1-selective inhibitors via a fragment-based lead generation approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 19.
Abstract 1919: Molecularly annotation of mouse avatar models derived from patients with colorectal cancer liver metastasis
Authors: Wang Jingyuan , Liu Wei , Gao Jing , Xing Baocai , Shen Lin 
Published: August 2019

Abstract
Background: Liver is the most common metastatic site in advanced colorectal cancer. Most patients with colorectal cancer liver metastasis (CRLM) do not benefit from current treatment. Patient-derived xenograft (PDX) with defined molecular signatures are attractive models for preclinical studies.
Methods: Successfully established PDXs were evaluated to elucidate their fidelity of patients’ biologic characteristics (pathologic, genetic and protein properties, together with chemosensitivity). The genomic variations of PDXs were analyzed by next-generation sequencing to explore the underlying molecular mechanism of metastasis and potential therapeutic targets.
Results: CRLM (N=73) showed a significantly higher successful PDX establishment rate than primary specimens (N=26; 76.7% vs. 57.7%). CRLM PDXs recapitulated the pathologic, genetic and protein properties of parental tumors, as well as chemosensitivity. Frequent altered genes in PDXs showed high consistency compared to patients’ genomic alterations and were enriched in MAPK, ErbB, cell cycle, focal adhesion pathways for CRLM PDXs, whereas primary tumor-derived PDXs only exhibited genomic variations involving ErbB and cell cycle. The genetic alterations showed high concordance between paired PDXs from primary and metastatic tissues, except for recurrent gene mutations (ARID1A, CDK8, ETV1, STAT5B and WNK3) and common copy number gains in chromosomes 20q (e.g., AURKA/TPX2). Several potential drug targets such as KRAS, HER2, and FGFR2 were validated using corresponding inhibitors. Additionally, PDX models could also be used in screening efficient regimens for patients with no druggable alterations.
Conclusion: This study has successfully established and validated a large panel of molecularly annotated platforms from patients with CRLM for preclinical studies.
Note: This abstract was not presented at the meeting.
Citation Format: Jingyuan Wang, Wei Liu, Jing Gao, Baocai Xing, Lin Shen. Molecularly annotation of mouse avatar models derived from patients with colorectal cancer liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1919.