bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1903: Antiproliferative effect of cannabinoid receptor agonists on rectal cancer lines
Authors: Gómez Alette Ortega , Luna-Merlos Pedro , Hernández Victor Manuel García , García Abelardo Meneses , Vega Horacio Astudillo- de la , López Eric Alejandro García , Angel Abel Santamaría Del , García Erika Betzabé Ruiz 
Published: August 2018

Abstract
Rectal cancer is considered a major health issue in several countries that present advanced and metastatic stages and a limited response to standard treatments. Though the antineoplasic activity of cannabinoids has been documented in several studies, scarce information is available about the effect of these agents in cell lines of rectal cancer. In this work, we explored the antiproliferative effects of cannabinoid receptor agonists in rectal tumor cells. The effects of the three agonists anandamide, methanandamide and CP55940 were evaluated in the SW837 rectal tumor cell line. The three agents tested showed time and concentration dependent effects on cell viability, induction of cell death and morphological changes. The three agonists were effective to induce late apoptosis and necrosis and internucleosomal DNA fragmentation. In addition, we evaluated for the first time the patterns of CB1 and CB2 cannabinoid receptor expression in SW837. Though some differences in their effects were found, our data support the concept that these agents mostly share common antiproliferative/cell death mechanisms. Our results also confirm the antineoplasic potential of cannabinoids receptor agonists against rectal cancer, and suggest the design of cannabinoid based coadjutant therapies at the clinical level.
Citation Format: Alette Ortega Gómez, Pedro Luna-Merlos, Victor Manuel García Hernández, Abelardo Meneses García, Horacio Astudillo- de la Vega, Eric Alejandro García López, Abel Santamaría Del Angel, Erika Betzabé Ruiz García. Antiproliferative effect of cannabinoid receptor agonists on rectal cancer lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1903.
Abstract 1912: A microbial glucuronidase target implicated in intestinal reactivation of tyrosine kinase inhibitors
Authors: Wallace Bret David , Hymes Jeffrey , Redinbo Matthew , Peterson Ward 
Published: August 2018

Abstract
Many drugs are inactivated by liver UGT enzymes and reactivated by enteric bacterial β-glucuronidases (GUS), an axis of drug metabolism that contributes to gut toxicities of anti-neoplastic agents, NSAIDs, and potentially other drug classes. For example, toxic reactivation of irinotecan by E. coli GUS is the causative event leading to intense, delayed diarrhea. Receptor tyrosine kinase (RTK)-targeted cancer drugs that undergo this UGT-GUS axis of metabolism are also associated with a high incidence of diarrhea. However, glucuronides of RTK inhibitors (RTKi) are not substrates of E. coli GUS. We recently reported that the human gut microbiome expresses nearly 300 distinct GUS enzymes (GUSome). The objective of this work is to identify the GUS enzyme(s) capable of metabolizing the glucuronide of the RTKi, sorafenib, that may contribute to sorafenib-induced diarrhea.
We used UGT1A9 supersomes to make sorafenib-glucuronide (S-G) from commercially purchased sorafenib. S-G was screened against a library of 15 purified GUSome enzymes to identify the specific GUS orthologs that can cleave S-G, which was determined by monitoring sorafenib absorbance at 280 nm. Similar approaches were used to identify GUS enzymes that can cleave other RTKi's.
Of the GUS enzymes evaluated for cleavage of S-G, only the GUS enzyme from an uncultured Eubacterium species was active. The structurally similar regorafenib-glucuronide and two glucuronides of other RTKi's (axitinib and imatinib) are also substrates of Eubacterium GUS. All four RTKi's are associated with diarrhea in at least 40-60% of patients. In contrast to E. coli GUS, very little is known about Eubacterium GUS.
We have identified a set of RTKi-glucuronides as the first substrates of Eubacterium GUS, which may contribute to diarrhea associated with targeted anti-cancer drugs.
Citation Format: Bret David Wallace, Jeffrey Hymes, Matthew Redinbo, Ward Peterson. A microbial glucuronidase target implicated in intestinal reactivation of tyrosine kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1912.
Abstract 1921: The sensitivity of ovarian cancer cells to the HDAC inhibitor belinostat is improved by inhibiting Bcl-xL or Mcl-1 anti-apoptotic proteins
Authors: Duboc Charlène , Abeilard Edwige , Voisin-Chiret Anne Sophie , Gauduchon Pascal , Poulain Laurent , Villedieu Marie 
Published: August 2018

Abstract
The identification of novel therapeutic strategies is an important urgent requirement for the clinical management of ovarian cancers, which remain the leading cause of death from gynecologic cancer. Our previous studies have shown that the anti-apoptotic proteins Bcl-xL and Mcl-1 cooperate to protect resistant ovarian cancer cells from apoptosis as their concomitant inhibition results in massive apoptotic cell death. Moreover, their BH3-only pro-apoptotic partners Bim and Puma are crucial actors in the induced cell death. This suggests that ovarian cancer cell apoptosis can be triggered by inhibiting Bcl-xL and Mcl-1 and/or by promoting their BH3-only partners, especially Bim and Puma. The expression of these Bcl-2 family proteins has been reported to be modulated by HDAC (histone deacetylases) inhibitors in various cancer models. The objective of the present study was to evaluate the efficacy of the FDA-approved pan-HDAC inhibitor belinostat (i) to reduce the [Bcl-xL and Mcl-1] / BH3-only proteins ratio and (ii) to trigger apoptosis in chemoresistant ovarian cancer cell lines, alone or in combination with other pharmacological molecules that modulate these Bcl-2 family proteins. HDAC inhibition by belinostat led to a G2/M blockade and consequently reduced cell proliferation. Moreover, belinostat used at high concentrations (from 1000 to 2000 nM) efficiently triggered apoptosis in chemoresistant ovarian cancer cells. This cytotoxic effect was associated with both an up-regulation of Bim and Puma protein expression and an inhibition of Bcl-xL protein expression. Used at sub-toxic concentrations, belinostat also up-regulated Bim and Puma proteins but failed to down-regulate Bcl-xL and Mcl-1 protein expression. We therefore investigated whether Bcl-xL or Mcl-1 inhibition could sensitize ovarian cancer cells to sub-toxic concentrations of belinostat. Interestingly, the combination of belinostat with the BH3-mimetic ABT-737, that inhibits Bcl-xL, induced massive apoptosis. Moreover, Mcl-1 direct or indirect inhibition was also very efficient to sensitize ovarian cancer cells to belinostat. These results suggest that belinostat, alone or in association with pharmacological molecules that inhibit Mcl-1 or Bcl-xL, represents a promising approach for the treatment of chemoresistant ovarian cancers.
Citation Format: Charlène Duboc, Edwige Abeilard, Anne Sophie Voisin-Chiret, Pascal Gauduchon, Laurent Poulain, Marie Villedieu. The sensitivity of ovarian cancer cells to the HDAC inhibitor belinostat is improved by inhibiting Bcl-xL or Mcl-1 anti-apoptotic proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1921.
Abstract 1974: Inhibition of the P-glycoprotein with a novel agent in overexpressing P-glycoprotein chemotherapy resistant colorectal cancer cells
Authors: Farrell Christopher L. , Mahan Rebecca , Blauvelt Catherine , Servais Taylor Kaye , Lane Jessica 
Published: August 2018

Abstract
Multidrug resistance (MDR) plays a key role in chemotherapy failure and poor patient outcome. One of the ways multidrug resistance occurs is through the efflux of chemotherapeutic agents using the P-glycoprotein transporter protein on the surface of the tumor cell. There are several medications that work through P-glycoprotein (Pgp), which can either induce or inhibit the activity of the transporter. The purpose of this study was to evaluate known P-glycoprotein inhibitors and their effects on chemotherapy resistance in Caco2 cells, a colorectal cancer cell line. The experiments consisted of feeding the colorectal cancer cells with commonly known drugs that are Pgp substrates such as vinblastine for 4-8 months to establish an overexpressing Pgp transporter. An untreated negative control was used to show that Pgp was not overly expressed. Once the treated cells were overexpressing Pgp, the cells were seeded into a 96 well plate with a matrix of increasing chemotherapy and bergamottin, a known P-glycoprotein inhibitor. A cell proliferation assay was performed according to manufacturer protocol, with a Presto-Blue Cell Proliferation Assay kit to assess the effects of the chemotherapy agent, vinblastine and the bergamottin. Absorbance was recorded at 595 nanometers. This assay was tested on several multidrug resistant colorectal cell with different substrates and normal P-glycoprotein expressing cancer cells. The overexpressing Pgp cell lines required higher doses of vinblastine to exhibit cell death compared to the negative cells. The positive cells treated with bergamottin only showed change in cell death with increasing bergamottin concentration. From these results, it was determined that the use of the novel P-glycoprotein inhibitor was able to reverse the chemotherapy induced multidrug resistance in the cells with high Pgp expression. Patients whose tumor cells develop MDR have a poor prognosis compared to patients whose cells are responsive to chemotherapy. Because the chemotherapy agents are ineffective in killing the all of the tumor cells including cells which have become metastatic, the overall survival rate for patients with MDR-positive tumors is markedly decreased. Identify these patients as potential candidates for the Pgp inhibitor could significant increase their chances of survival with this aggressive form of cancer.
Citation Format: Christopher L. Farrell, Rebecca Mahan, Catherine Blauvelt, Taylor Kaye Servais, Jessica Lane. Inhibition of the P-glycoprotein with a novel agent in overexpressing P-glycoprotein chemotherapy resistant colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1974.
Abstract 1979: HQP1351, a novel multikinase inhibitor in clinical development, overcomes drug resistance for the treatment of gastrointestinal stromal tumors in preclinical models
Authors: Wang Guangfeng , Qiu Haibo , Min Ping , Wu Miaoyi , Dang Shuo , Yang Chunyang , Zhang Fei , Zhuang Wei , Zhou Zhiwei , Fang Douglas D. , Yang Dajun , Zhai Yifan 
Published: August 2018

Abstract
Gastrointestinal stromal tumors (GIST) harbor driver mutations of signal transduction kinases such as KIT. Besides surgical resection for primary localized tumors, imatinib remains the first-line treatment for advanced and metastatic GISTs. Imatinib targets a few kinases including KIT that often carries the primary driver mutations commonly located on exon 11 and exon 9. Unfortunately, a large proportion of the patients ultimately develop progressive disease owing to the secondary resistance mutations in KIT gene. We have developed an orally bioavailable multikinase inhibitor HQP1351, which is currently in clinical trials for the treatment of T315I mutant CML. Here, we demonstrated that HQP1351 inhibited both wild type and mutant (i.e., KITL576P, KITV559D, and KITV559D/T670I) KIT in biochemical assays. Using a panel of imatinib-resistant and sensitive GIST cancer cell lines derived from patient samples, we showed that HQP1351 exhibited more potent anti-proliferative activities than ponatinib (range of IC50 values: 0.027-0.133 µM vs. 0.021-0.730 µM), the latter of which is currently in clinical development in GIST to overcome the resistance to imatinib (NCT03171389). In addition, the treatment of GIST cancer cells with HQP1351 in vitro led to more profound inhibition of pharmacodynamic markers, including p-c-KIT, p-AKT, p-ERK1/2, and p-AKT, in comparison with ponatinib. Correspondingly, in multiple xenograft tumor models derived from these GIST cancer cell lines carrying the secondary mutations of KIT, HQP1351 exhibited superior antitumor activities to ponatinib. Collectively, considering that HQP1351 has already been in clinical trials, the above results suggest that therapeutic application of HQP1351 in imatinib-resistant GIST patients deserves further investigation in human.
Citation Format: Guangfeng Wang, Haibo Qiu, Ping Min, Miaoyi Wu, Shuo Dang, Chunyang Yang, Fei Zhang, Wei Zhuang, Zhiwei Zhou, Douglas D. Fang, Dajun Yang, Yifan Zhai. HQP1351, a novel multikinase inhibitor in clinical development, overcomes drug resistance for the treatment of gastrointestinal stromal tumors in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1979.
Abstract 198: MUC13 promotes pancreatic tumor-stromal interactions by influencing tumor microenvironment
Authors: Khan Sheema S. , Doxtater Kyle , Kumari Sonam , Setua Saini , Sikander Mohammed , Malik Shabnam , Yallapu Murali , Behrman Stephen , Chauhan Subhash , Jaggi Meena 
Published: August 2018

Abstract
Objective: Pancreatic cancer (PanCa) is the third leading cause of cancer-related deaths in the U.S. MUC13, mucin, is aberrantly expressed in PanCa and its overexpression leads to tumorigenic and metastatic behavior of cancer cells. Herein, we investigate the role of MUC13 in tumor microenvironment (TME) that favors PanCa progression/metastasis and drug resistance.
Methods: MUC13 expressing (Panc-1) and knockdown PanCa cells (HPAF-II) and pancreatic stromal cells (PSCs), derived from freshly collected human pancreatic tissues, were utilized for the study. Using immunoblotting, ELISA, qPCR and RT-PCR techniques, we assessed the MUC13-induced alterations in the expression of important molecules that are involved in promotion of pancreatic tumor stromal interactions and drug resistance. Cytation 3 live cell imaging was performed for 3D tumor-stromal cell co-culture and invasion assays. Xenograft mice tumor tissues generated using ectopically expressing MUC13 and null cells were used for the study.
Results: Our results demonstrate that MUC13 activates SHH signaling pathway in PanCa cells via upregulation of SHH and its related important downstream targets such as CXCR-4, Gli-1, SMO, PTCH1/2, NFκB and p-AKT in PanCa cells using immunoblotting and PCR. We also observed increased expression of SHH, Gli-1, CXCR-4 and α-SMA in MUC13-expressing xenograft tumors using Immunohistochemistry. Ectopic MUC13-expressing PanCa cells grown in co-culture with PSCs showed enhanced secretion of IL-6 and CXCL-12 (ELISA), increase in invasion (Matrigel invasion assay) and migratory (Boyden chamber assay) potential of both the cultured PanCa as well as stromal cells. Additionally, ectopically MUC13-expressing cells were resistant to treatment with gemcitabine as depicted by proliferation assay and qPCR results showed enhanced expression of ribonucleoside-diphosphate reductase (RRM1/2) and miR-21, which are known to be involved in gemcitabine resistance. Overall, our results suggest that MUC13 modulates tumor-stromal crosstalk, promoting tumor growth, invasion and drug resistance in TME.
Conclusion: Our results suggest that MUC13 expression might influence signaling supportive of interactive TME, leading to increased tumor growth and drug resistance. These findings illustrate mechanisms by which MUC13 promotes tumorigenic TME and contributes to PanCa cell survival, metastasis and drug resistance.
Citation Format: Sheema S. Khan, Kyle Doxtater, Sonam Kumari, Saini Setua, Mohammed Sikander, Shabnam Malik, Murali Yallapu, Stephen Behrman, Subhash Chauhan, Meena Jaggi. MUC13 promotes pancreatic tumor-stromal interactions by influencing tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 198.
Abstract 1984: Cell fate reprogramming of liver tumor-initiating stem-like cells via phosphorylated NUMB and TBC1D15
Authors: Machida Keigo , Siddique Hifzur R. , Zheng Mengmei , Winer Peleg , Kumar Dinesh Babu Uthaya , Rokan Ahmed , Sher Linda , Tahara Stanley M. , Elowitz Michael , Liang Chengyu , Tsukamoto Hidekazu 
Published: August 2018

Abstract
Tumor-initiating stem-like cells (TICs) are defective in their control of asymmetric division. Stem cells are maintained through asymmetric self-renewing divisions in which one daughter cell commits to a specific fate while the other retains the multipotent characteristics of its parent. The p53 interacting protein NUMB preserves this intrinsic cellular asymmetry and functions as a vital barrier against unchecked expansion as seen in TICs. How TICs overcome this control of asymmetric division to cause cancer is unknown. The hypothesis is that accentuated TLR4-NANOG-mediated NUMB phosphorylation and TBC1D15 upregulation promote self-renewal of TICs in liver oncogenesis caused by HCV and alcohol. Here, we determined the causal roles of NUMB phosphorylation and TBC1D15 oncoprotein in alcohol-induced liver tumorigenesis in HCV-Tg mice. Liver-specific TBC1D15 deficiency or non-phosphorylatable mutations of NUMB, reduce liver tumor incidence and tumor-associated NANOG+ TICs in HCV NS5A Tg mice fed alcohol Western diet. TICs lost asymmetric division capacity and overexpressed TBC1D15, which associated with NUMB to promote aPKCζ activity and NUMB phosphorylation. Thus, TIC self-renewal is dependent on TBC1D15 and NUMB phosphorylation. Similarly, aPKCζ-mediated NUMB phosphorylation and induced TBC1D15 are mutually required for self-renewal. Furthermore, TBC1D15 activated NOTCH via binding to NOTCH intracellular domain to trigger its proteolytic. TBC1D15 interacts with all NOTCH isoforms, activates NOTCH pathway, and induces Nanog and TIC self-renewal in a NOTCH-dependent manner. TBC1D15 cooperates with the NOTCH pathway to support TIC tumorigenic activity and an inhibitor of this interaction is potentially therapeutic. Candidate small molecule antagonists have been tested for their ability to block the interaction of TBC1D15-NOTCH/NICD. The originality of this findings lies within the discovery of the novel oncoprotein TBC1D15 and its unique oncogenic activities involving p53 degradation and cooperation with the NOTCH pathway in TICs and CD133+ Huh7 cells. These mechanistic findings have laid down the foundation for a new translational path for discovery of new therapeutic targets.
Citation Format: Keigo Machida, Hifzur R. Siddique, Mengmei Zheng, Peleg Winer, Dinesh Babu Uthaya Kumar, Ahmed Rokan, Linda Sher, Stanley M. Tahara, Michael Elowitz, Chengyu Liang, Hidekazu Tsukamoto. Cell fate reprogramming of liver tumor-initiating stem-like cells via phosphorylated NUMB and TBC1D15 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1984.
Abstract 1996: Nuclear factor (erythroid-derived 2)-like 2 promotes tumor-initiating cell lineage and drug resistance in hepatocellular carcinoma
Authors: Leung Hoi Wing , Lee Terence Kin Wah 
Published: August 2018

Abstract
Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. The long-term prognosis of HCC remains unsatisfactory due to high recurrence rates and chemoresistance. The efficacy of sorafenib, the only FDA-approved molecularly targeted drug in advanced hepatocellular carcinoma (HCC) is limited by acquired resistance. Increasing evidences showed that liver tumor-initiating cells (T-ICs) is the source of acquired resistance and metastasis. We have previously established sorafenib-resistant HCC cells both in vitro and PDTX models and demonstrated that these cells are endowed with enhanced T-IC properties. Interestingly, nuclear factor (erythroid-derived 2)-like 2 (NRF2) expression was elevated in these resistant cells. The transcription factor NRF2 has long been considered as a tumour suppressor, as it can regulate cellular antioxidant response to protect cells from oxidative stress, chemotherapeutic agents and radiotherapy. In HCC, NRF2 level was up-regulated, and its expression was correlated with tumor differentiation, metastasis, and tumor size, revealing its oncogenic role. By lentiviral based knockdown approach, we found that NRF2 repression suppressed liver T-IC properties including self-renewal, in vivo tumorigenicity, HCC invasiveness and expression of liver T-IC markers. In addition, we found that NRF2 repression not only sensitized HCC cells to sorafenib but also to other chemotherapeutic drugs including doxorubicin and fluorouracil. Mechanistically, the signaling cascade related to sonic hedgehog pathway was greatly suppressed in NRF2 knockdown HCC cells, when compared with control counterparts. Collectively, NRF2 was involved in drug resistance, invasion and migration, tumorigenicity and self-renewal via regulating T-IC properties at least in part through direct regulation of sonic hedgehog pathway in HCC. Targeting NRF2 mediated signaling cascade alone or in combination with other treatment modalities may be a new a potential therapeutic approach for treatment of HCC.
Citation Format: Hoi Wing Leung, Terence Kin Wah Lee. Nuclear factor (erythroid-derived 2)-like 2 promotes tumor-initiating cell lineage and drug resistance in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1996.