bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4894: Identification of small molecules for the prevention and treatment of colon cancer
Authors: Pal Deeksha , Baby Becca Von , Chandrasekaran Balaji , Sharma Arun , Damodaran Chendil 
Published: July 2017

Abstract
Metastatic colon cancer or colorectal cancer (CRC) is associated with poor survival rate which is less than 5% due to chemo resistance. We previously showed that overexpression of AKT and Notch1 are key players for progression of metastasis of colon cancer cells. Withaferin-A (WA) is a potent herbal molecule that inhibited CRC growth by down regulating AKT and Notch1 signaling in both in vitro and in vivo colon cancer models. We found that WA binds to AKT with a predicted binding affinity of -10.6 kcal/mol and inhibited its activation. So, we designed and developed several analogs of WA, that exhibits a stronger AKT binding (binding energy higher than -10 kcal/mole) and more potent than the parental WA. UL16 is one such compound which inhibited the growth of colon cancer cells (HCT-116 and SW-620: IC50-300nM) at nanomolar concentration. Western blot analysis revealed that UL16 inhibits AKT/NF-κβ/ Bcl2- signaling axis in colon cancer cells. In addition, UL16 concurrently inhibited Notch1 signaling pathway in colon cancer cells. Then we systematically investigated the anti-migratory and anti-invasive effect of UL16by cell migration and invasion assays. Inhibition of both migration and invasion of colon cancer cells corresponds with downregulation of mesenchymal markers of Snail, Slug and β-catenin expression. We also examined the in vivo efficacy of UL16 in ApcMin/+ mouse model. Treatment of ApcMin/+ with UL16 (0.5 mg/kg/IP/twice a week) over 12 weeks significantly reduced the number of intestinal polyps (distal 84%; Middle 63% and Proximal 2%) as compared vehicle treated mice. In addition, we also observed 50% reduction in number of colon tumors in UL16 treated mice. Our ongoing immunohistochemistry studies may confirm the in vitro mechanistic results. In conclusion, our studies suggest that UL16 inhibits both AKT and Notch1 signaling and suppresses intestinal polyp formation in ApcMin/+ mice. Hence UL16could be a viable therapeutic agent for treating patients with metastatic colon cancer.
Citation Format: Deeksha Pal, Becca Von Baby, Balaji Chandrasekaran, Arun Sharma, Chendil Damodaran. Identification of small molecules for the prevention and treatment of colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4894. doi:10.1158/1538-7445.AM2017-4894
Abstract 4899: The small molecule cathepsin L and K inhibitor KGP-94 impairs the metastatic phenotype of osteosarcoma cells
Authors: Fasanya Henrietta , Siemann Dietmar 
Published: July 2017

Abstract
Osteosarcoma (OS) is the most common primary malignant bone cancer and primarily affects adolescents between the ages 10-20 years old. Today, OS remains the second leading cause of cancer-related death for patients in this age group. With current therapy, the 5-year survival for patients with clinically metastatic disease has remained unchanged at 20% since the early 1970s. There is a significant need for novel therapies that will increase overall survival for patients with metastatic OS.
Proteases secreted within the tumor microenvironment enable primary tumor development and potentiate the ability of OS cells to metastasize. Typically, cysteine proteases under normal physiologic conditions function primarily within the lysosome to facilitate protein cell turnover. During tumorigenesis, Cathepsin L (CTSL) is secreted into the tumor environment by the tumor. CTSL secretion potentiates metastasis through its regulation of cell motility, extracellular matrix degradation, angiogenesis, and bone remodeling. Cathepsin K (CTSK) is overexpressed in OS and is secreted during bone remodeling by osteoclast to degrade the bone matrix. The bone environment is hypoxic which induces proteomic changes that enable OS cells to survive in a nutrient deprived environment and increase CTSL/CTSK secretion by the tumor cells.
The goal of these studies was to determine if CTSL/CTSK inhibition via KPG-94 (3-bromophenyl-3-hydroxyphenyl-ketone thiosemicarbazone) could decrease the metastatic phenotype of human osteosarcoma cells under normoxic and hypoxic conditions. The Hu09 cell line has been characterized as an osteoblastic cell line with the potential to grow orthotopically in vivo. Hu09 and its metastatic sublines Hu09-L6 and Hu09-M112 have been characterized to low and high metastatic capacity, respectively. Treatment with KGP-94 at 10 and 25 uM effectively decreases cell motility and invasion of Hu09 and its metastatic sublines under normoxic and hypoxic conditions.
Our results demonstrate that dual CTSL/CTSK inhibition is effective at decreasing two signature methods of measuring metastasis: 1) cell motility and 2) invasiveness. Targeting CTSL/CTSK may provide a novel therapeutic approach for patients with metastatic OS.
Citation Format: Henrietta Fasanya, Dietmar Siemann. The small molecule cathepsin L and K inhibitor KGP-94 impairs the metastatic phenotype of osteosarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4899. doi:10.1158/1538-7445.AM2017-4899
Abstract 4901: Urokinase-derived peptide UP-7 effectively inhibits metastatic growth of breast cancer through suppression of FAK activation
Authors: Joe Young Ae , Kim Hyun-Kyung , Naidansuren Purevjargal , Lee Seung Woo , Kim Rae-Kwon , Lee Su-Jae , Lee Suk Keun , Hong Yong-Kil 
Published: July 2017

Abstract
The recombinant kringle domain of urokinase-type plasminogen activator (UK1) has been shown to inhibit angiogenesis in vitro and in vivo and suppress brain tumor in vivo. To avoid limitations in application due to mass production of recombinant proteins, we dissected UK1 sequences to seven peptides based on structure and amino acid characteristics, and examined the anti-angiogenic activities for the constructed peptides. UP-7 peptide derived from ß-sheets region of UK1 was the most potent inhibitor of the proliferation and migration of endothelial cells (ECs) in vitro, and it also inhibited in vivo angiogenesis in the mouse matrigel plug assay. Such anti-angiogenic activities were not exerted by the scrambled peptide. At molecular level, UP-7 inhibited the VEGF or bFGF-induced phosphorylation of FAK and ERK1/2 and suppressed formation of stress fibers and focal adhesions. It also inhibited the attachment and spreading of ECs onto immobilized fibronectin. In a lung cancer animal model xenografted with UP-7-non-sensitive NCI H460, systemic treatment of UP-7 effectively suppressed tumor growth through inhibition of angiogenesis. Interestingly, breast cancer cells such as MDA-MB231 were sensitive to UP-7 in proliferation differently from other cancer cells. It inhibited the migration and invasion of LM-2-MDA-MD231 and suppressed the phosphorylation of FAK. Accordingly, UP-7 potently inhibited lung metastatic growth of LM2-MDA-MB-231 in experimental metastasis model. Taken together, these results suggest that novel UK1-derived peptide, UP-7 can be effectively used for treatment of the metastatic growth of breast cancer. (NRF-2012R1A1A2007175, NRF-2012R1A5A2051476)
Citation Format: Young Ae Joe, Hyun-Kyung Kim, Purevjargal Naidansuren, Seung Woo Lee, Rae-Kwon Kim, Su-Jae Lee, Suk Keun Lee, Yong-Kil Hong. Urokinase-derived peptide UP-7 effectively inhibits metastatic growth of breast cancer through suppression of FAK activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4901. doi:10.1158/1538-7445.AM2017-4901
Abstract 4903: Cationic polymer inhibits pancreatic cancer invasion in vitro and metastasis in vivo
Authors: Naqvi Ibtehaj A. , Gunaratne Ruwan , McDade Jessica , Rouse Douglas , Yeh Jen Jen , Pisetsky David , Lee Jaewoo , White Rebekah , Sullenger Bruce 
Published: July 2017

Abstract
Pancreatic cancer has the poorest prognosis of all major cancers with a 5-year survival of less than 5%. Cell-free DNA (cfDNA) has been well-validated as a biomarker that correlates with tumor burden. More recently, a role for cfDNA in facilitating tumor progression has also been identified. The latter occurs through activation of nucleic acid sensing receptors such as toll-like receptors (TLRs) in both tumor cells and the host environment, which can upregulate pro-metastatic signaling pathways. In addition, tumor-derived extracellular vesicles such as microparticles and exosomes have also been implicated in promoting metastasis by activating pro-invasive pathways in tumor cells and pre-conditioning secondary sites for metastatic establishment. Our laboratory has previously shown that cationic polymers can scavenge negatively charged nucleic acids like cfDNA and abrogate aberrant inflammation in disease models of autoimmunity and infection. Herein, we investigated the ability of the cationic polymer, PAMAM-G3, to bind and inhibit cfDNA as well as anionic tumor-derived extracellular vesicles using in vitro models of pancreatic cancer cell line invasion. We also evaluated the effect of PAMAM-G3 treatment in a bioluminescent syngeneic murine model of pancreatic cancer metastasis. PAMAM-G3 significantly inhibited in vitro invasion of pancreatic cancer cell lines in response to both cfDNA and tumor-derived extracellular vesicles. Moreover, biweekly intraperitoneal treatment with PAMAM-G3 (20 mg/kg) starting 48 hours after pancreatic tumor cell implantation led to a significant reduction in liver metastasis without affecting primary tumor growth. Thus, cationic polymers such as PAMAM-G3 may represent a novel class of therapeutics to combat pancreatic cancer metastasis.
Citation Format: Ibtehaj A. Naqvi, Ruwan Gunaratne, Jessica McDade, Douglas Rouse, Jen Jen Yeh, David Pisetsky, Jaewoo Lee, Rebekah White, Bruce Sullenger. Cationic polymer inhibits pancreatic cancer invasion in vitro and metastasis in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4903. doi:10.1158/1538-7445.AM2017-4903
Abstract 4906: Sphingolipid regulates pro-inflammatory cytokines to subdue the neoplastic lesions in hepatocellular carcinoma
Authors: Chatterjee Nabanita , Saha Krishna Das 
Published: July 2017

Abstract
Hepatocellular carcinoma (HCC), is the most leading cause of cancer-related death in all over the world (seems to more than 80% of death cases). It is frequently linked with continuous hepatocytes death, inflammatory cell infiltration, and compensatory liver regeneration with higher angiogenic rate. Considering the different signalling process during this tumorogenesis with the involvement of new ‘lead’ identification of different sources, desire to be less toxic and higher bioavailability. The use of live, attenuated or genetically compensated microbes or its cellular component(s) or metabolites has begun to emerge as a potential new approach in medicinal research to deliver bioactive entities. Thus, advancing our knowledge of such microbes-mediated therapy may suggest new avenues for therapeutic intervention in many fatal diseases. Lipid (LSPL-1) isolated from Leishmania donovani could induce apoptosis in human HepG2 (Hepatocellular carcinoma cell, human) cells, as characterized by phosphatydylserine serine exposure, DNA fragmentation, alteration of BaX/Bcl2 ratio with loss of mitochondrial membrane potential and cytochrome C release, activation of series of caspases and cleaved PARP. LSPL-1 also modulates the various transcription factors like NF-kb65, p53 through regulation of cell proliferation exerted the death cause. Moreover this study also focused that the LSPL-1 effectively suppressed diethylnitrosamine (DEN) induced liver inflammation and hyperplasia in murine also decline in lipid peroxidation and increase in enzymic antioxidants (SOD, CAT, GPx, GR and GST) status with improvement of their survival rate. It reduced the elevated level of cytokines including tumor necrosis factors, interleukins, interferon (alpha and gamma), and transforming growth factors in hepatocytes from liver fibrosis bearing mice. As evident from immunochemical analysis, inflamed hepatocytes and liver tissue may up regulated the various growth factors including EGF, HGF, endothline-1 regulation with promoting angiogenic activity via modulation of CD34, VEGF, HIF-1α expression and alteration of these changes were balanced by LSPL-1. So taken together, these finding indicated that, LSPL-1 may induce apoptosis and in hyper proliferating cancer cells via altering cytokines level with tumour growth regulation in carcinogen exposed rodent system.
Note: This abstract was not presented at the meeting.
Citation Format: Nabanita Chatterjee, Krishna Das Saha. Sphingolipid regulates pro-inflammatory cytokines to subdue the neoplastic lesions in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4906. doi:10.1158/1538-7445.AM2017-4906
Abstract 4915: Alcohol-induced reprogramming of tumor plasticity is mediated via suppression of CCN5 signaling in breast cancer cells
Authors: Haque Inamul , Subramanian Arvind , Gupta Vijayalaxmi , Sarkar Sandipto , Banerjee Snigdha , Banerjee Sushanta K. 
Published: July 2017

Abstract
Background and Objective: The epidemiological and experimental studies suggest that alcohol consumption is associated with increased risk for breast cancer development and metastasis. However, the mechanisms of alcohol-induced breast cancer progression and metastasis remain unknown. In this study, we examined the roles of CCN5, a tumor suppressor gene in alcohol induced breast cancer cell migration/invasion, epithelial to mesenchymal transition (EMT) and stemness.
Methods: Estrogen receptor-positive (ER+) human breast cancer cell line MCF-7 and immortalized normal human epithelial breast cell line MCF-12A were treated with ethanol at various concentrations in the presence and absence of human recombinant human CCN5 protein (hrCCN5) . Invasive/migratory ability of treated and untreated cells was measured by Boyden chamber assays. The mRNA and protein expression level of CCN5 was determined by real-time qRT-PCR and Western blot. EMT and stemness markers were evaluated by Western blot. Single-cell suspensions from pre-treated cells were re-suspended at a density of 500 cells/ml mammocult media in ultralow attachment dishes. Number as well as the size of the mammosphere in specified experimental set-up was monitored and recorded alternate day for 8-10 days.
Results: The studies demonstrated that alcohol promotes significantly the invasive/migratory ability and EMT phenotypes of breast cancer cells through the suppression of CCN5. Interestingly, hrCCN5 protein treatment suppresses the effect of alcohol and reprograms MET (mesenchymal to epithelial transition). In addition, alcohol-induced mammosphere formation efficiency is also suppressed by hrCCN5 protein-treatment.
Conclusions: Our findings suggest that the CCN5 signaling plays a preventive role in alcohol-induced reprogramming of tumor plasticity in breast cancer cells.
Citation Format: Inamul Haque, Arvind Subramanian, Vijayalaxmi Gupta, Sandipto Sarkar, Snigdha Banerjee, Sushanta K. Banerjee. Alcohol-induced reprogramming of tumor plasticity is mediated via suppression of CCN5 signaling in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4915. doi:10.1158/1538-7445.AM2017-4915
Abstract 4916: E3 ubiquitin ligase Cbl-b prevents tumor metastasis by maintaining the epithelial phenotype in multiple drug-resistant gastric and breast cancer cells
Authors: Xu Ling , Qu Xiujuan , Zhang Ye , Che Xiaofang , Guo Tianshu , Cai Ying , Li Aodi , Li Danni , Li Ce , Wen Ti , Fan Yibo , Hou Kezuo , Ma Yanju , Hu Xuejun , Liu Yunpeng 
Published: July 2017

Abstract
Background: Multiple drug resistance (MDR) and metastasis are two major unfavorable factors causing failure of cancer treatment. However, the relationship between MDR and metastasis is not characterized. Additionally, the role of the E3 ubiquitin ligase Cbl-b in metastasis of MDR gastric and breast cancer is little known.
Methods: The effect of Cbl-b on tumor invasion and metastasis was analyzed in P-gp-positive gastric adenocarcinoma tissues. Transfections of Cbl-b WT and epidermal growth factor receptor (EGFR) WT plasmid were used to assess Cbl-b and EGFR involvement in epithelial-mesenchymal transition (EMT) and tumor metastasis.
Results: MDR gastric and breast cancer cells possess a typical mesenchymal phenotype and an enhanced cell migration capacity. Additionally, Cbl-b is poorly expressed in MDR gastric and breast cancer cells. We performed immunohistochemical analysis on P-gp-positive gastric adenocarcinoma tissues and identified associations between Cbl-b expression and clinical pathological parameters. Gastric cancer patients with low Cbl-b expression were more likely to have tumor invasion (P=0.016) and lymph node metastasis (P=0.007). Moreover, over-expression of Cbl-b reduced cell migration in MDR cell cultures both in vitro and in vivo. Cbl-b over-expression also prevented EMT by inducing ubiquitination and degradation of EGFR, leading to inhibition of the EGFR- ERK/Akt-miR-200c-ZEB1 axis. However, further over-expression of EGFR on a background of Cbl-b over-expression restored both the mesenchymal phenotype and the cell migration capacity of MDR gastric and breast cancer cells.
Conclusions: These results suggest that Cbl-b is an important factor for maintenance of the epithelial phenotype and inhibition of cell migration in MDR gastric and breast cancer cells.
Note: This abstract was not presented at the meeting.
Citation Format: Ling Xu, Xiujuan Qu, Ye Zhang, Xiaofang Che, Tianshu Guo, Ying Cai, Aodi Li, Danni Li, Ce Li, Ti Wen, Yibo Fan, Kezuo Hou, Yanju Ma, Xuejun Hu, Yunpeng Liu. E3 ubiquitin ligase Cbl-b prevents tumor metastasis by maintaining the epithelial phenotype in multiple drug-resistant gastric and breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4916. doi:10.1158/1538-7445.AM2017-4916
Abstract 4920: Inflammation and estrogen receptor beta modulate bacterial diversity of the gut
Authors: Ibrahim Ahmed F. , Thomas Quentin , Saxena Ashish , Williams Cecilia 
Published: July 2017

Abstract
Background: Chronic inflammation is a risk factor of colorectal cancer (CRC), and the microbiota of the gut is important in both colitis and carcinogenesis. Estrogen receptor beta (ERβ) is the predominant nuclear receptor in the colon, and is downregulated in CRC. Here, we explore the role of colitis and ERβ signaling with respect to the microbiota diversity.
Methods: Intestinal ERβ-/- mice were generated using the Cre-loxP system. WT and knockout mice were treated with AOM/DSS inducing colitis (at 9 weeks) and CRC (at 16 weeks). After 9 and 16 weeks, stool pellets were collected from treated and untreated mice (n=39), and DNA was extracted. Library preparation and 16S rRNA-sequencing was performed using the illumina Miseq platform with specific primers targeting the V3-V4 regions, and QIIME software was used to analyze microbiota diversity. Sequencing results were validated by qPCR
Results: High-throughput 16S rRNA gene sequencing demonstrated that treatment induced significant differentiation of both alpha (p=0.01) and beta (p=0.01) microbiota diversity. Alpha diversity indicators implied a significant reduction of microbiota richness and evenness after treatment. qPCR confirmed that 9-weeks treatment increased OTUs affiliated with Bifidobacteria (p=0.03), Bacteroidetes (p=0.04), Lactobacilli (p=0.0014), Cyanobacteria (p=0.0023) and Gammaproteobacteria (p=0.05) in WT mice. After 16 weeks treatment, 16s rRNA sequencing show enrichment of Tenercutes, Proteobacteria and Cyanobacteria in all tumor-bearing mice (treated WT and ERβ-/-), while Verrucomicrobia increased in untreated mice (No tumors). Further treated ERβ-/- but not WT mice displayed significant reduction of Gammaproteobaceria (p=0.0083).
Conclusion: Our data demonstrate a clear effect of colitis-induced treatment on the microbiota, and that ERβ attenuates this response. Lactobacilli and Bifidobacteria has, for example, been shown to attenuate inflammatory response. We note an increase in Lactobacilli and Bifidobacteia after treatment in WT mice, but not in ERβ-/- mice. This can result in increased colitis in ERβ-/- mice and help explain the increased expression of pro-inflammatory cytokines we note in treated ERβ-/- mice.
Citation Format: Ahmed F. Ibrahim, Quentin Thomas, Ashish Saxena, Cecilia Williams. Inflammation and estrogen receptor beta modulate bacterial diversity of the gut [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4920. doi:10.1158/1538-7445.AM2017-4920