bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2174: Inhibition of CDK8 kinase with SEL120-34A allows for a personalized approach in AML
Authors: Rzymski Tomasz , Mikula Michal , Zylkiewicz Eliza , Dreas Agnieszka , Wiklik Katarzyna , Golas Aniela , Wojcik Katarzyna , Masiejczyk Magdalena , Dudzicz Iga , Kucwaj Katarzyna , Statkiewicz Malgorzata , Goryca Krzysztof , Grochowska Aleksandra , Cabaj Aleksandra , Ostrowski Jerzy , Kukliniska Urszula , Brzozka Krzysztof 
Published: July 2017

Abstract
Inhibition of oncogenic transcriptional programs is recognized to be a promising therapeutic strategy. SEL120-34A is a novel inhibitor of Cyclin- dependent kinase 8 (CDK8), which regulates transcription by associating with the Mediator complex. SEL120-34A interacts with the ATP binding site of CDK8 in type I inhibitor fashion and forms several types of interactions, including halogen bonds with the protein’s hinge region and hydrophobic complementarities within its front pocket. Although the compound was only modestly active in solid tumor cell lines, it repressed phosphorylation of STAT5 Ser726 and could differentially inhibit viability of AML and ALL cell lines in vitro and in vivo, along with other type I CDK8 inhibitors. Transcriptomic analysis identified major transcriptional programs altered in responder cell lines, which strongly indicated that apart from repression of survival pathways, CDK8 inhibitors could induce differentiation in cell lines with leukemia stem cells characteristics. Further studies on a large panels of responder and non-responder cell lines identified robust biomarkers which could be used with high confidence for stratification and personalized approach in CDK8-dependent AML cases. Favorable pharmacokinetics, confirmed safety and in vivo efficacy in leukemia models provide the rationale for further clinical development of SEL120-34A.
Citation Format: Tomasz Rzymski, Michal Mikula, Eliza Zylkiewicz, Agnieszka Dreas, Katarzyna Wiklik, Aniela Golas, Katarzyna Wojcik, Magdalena Masiejczyk, Iga Dudzicz, Katarzyna Kucwaj, Malgorzata Statkiewicz, Krzysztof Goryca, Aleksandra Grochowska, Aleksandra Cabaj, Jerzy Ostrowski, Urszula Kukliniska, Krzysztof Brzozka. Inhibition of CDK8 kinase with SEL120-34A allows for a personalized approach in AML [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 2174. doi:10.1158/1538-7445.AM2017-2174
Abstract 2180: Triphenylmethanol conjugates of leuprorelin asanti-cancer prodrugs
Authors: Ahmadibeni Yousef , Karim Kaleh , Boadi William 
Published: July 2017

Abstract
Leuprorelin (LEP) is a synthetic analogue of gonadotropin-releasing hormone (GnRH), first was approved by the FDA for treatment of advanced prostate cancer and endometriosis in 1985. The initial effect of administration LEP is to stimulate the pituitary secretion of FSH and LH. After a prolonged stimulation (constant concentration of LEP in the blood) pituitary becomes insensitive to the action of GnRH. This reduces the level of gonadotropin in the blood, resulting in decreased levels of sex hormones to postcastration or menopausal levels. In addition to the usual side effects of this agonist analogs of LH-RH, other reported adverse effects include transient hypertension, dry mouth, excessive salivation, paraesthesia and increased dysuria. Improving the biological activity of LEP by increasing the cellular uptake and retention is a remedy to this end.
In this study, a prodrug strategy has been introduced to optimize the hydrophobicity of LEP by using an appropriate hydrophobic linker attached to tris(4-methoxyphenyl)methanol (TPM) derivatives with the expectation to improve the cellular uptake. In this regard, several LEP conjugates of TPM derivatives with optimized hydrophobicity were synthesized by the reaction of methoxy benzenes (e.g. anisole, 2-fluoroanisole, 2-methylanisole 1,2-dimethoxybenzene or methyl 2-methoxybenzoate and 1,3,5-trioxane, followed by the conjugation with LEP and dodecanedioic acid in the presence of HBTU/DIPEA/DIC in moderate yields.
Comparative antiproliferative assays between TPM-LEP conjugates and the corresponding non-covalent physical mixtures of the TPM derivatives and LEP were performed against human Caucasian prostate adenocarcinoma (PC3), human breast cancer cell line (BT549) and mouse pre-adipocytes (3T3-L1) cells and indicated moderare to high inhibition of the cell proliferation at a concentration of 5-100 µM after 24-72 h of incubation. These data suggest that TPM-LEP derivatives with optimized hydrophobicity can be used to improve the biological activity of LEP.
Citation Format: Yousef Ahmadibeni, Kaleh Karim, William Boadi. Triphenylmethanol conjugates of leuprorelin asanti-cancer prodrugs [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 2180. doi:10.1158/1538-7445.AM2017-2180
Abstract 2187: A pro-nanodrug with intratumoral reconstitution and intracellular delivery beyond therapy-resistance molecular pumps
Authors: Xu Rong , Ferrari Mauro , Shen Haifa 
Published: July 2017

Abstract
Tumor metastases to distant organs pose a serious challenge to cancer treatment. The metastatic tumor lesions are less accessible to cancer drugs and the malignant cells often quickly develop therapy resistance. To address both biological and drug transport concerns in cancer treatment, we have developed a novel composite pro-nanodrug to provide sustained intra-tumoral assembly of nanotherapeutics, and tested its anti-cancer efficacy in murine models of breast cancer metastases to the lung and liver. Specifically, large payloads of polymeric doxorubicin (pDox) pro-drug were packaged as single molecules into a porous silicon microparticles that can be enriched in tumor tissue in the forms of vascular and cellular depots. Once inside the tumor, the pDox molecules self-assemble into nanoparticles that are released into the tissue where they are effectively internalized by tumor cells. The nanoparticulate prodrug is transported through the vesicular system, and doxorubicin is cleaved from the polymer and released in the immediate proximity of the nucleus beyond the reach of the drug efflux pumps. In vivo efficacy studies demonstrated that the pro-nanodrug was effective in treating metastatic tumors with or without expression of the multi-drug resistant genes.
Citation Format: Rong Xu, Mauro Ferrari, Haifa Shen. A pro-nanodrug with intratumoral reconstitution and intracellular delivery beyond therapy-resistance molecular pumps [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 2187. doi:10.1158/1538-7445.AM2017-2187
Abstract 2211: Characterization of monoclonal antibodies specific for HPV-positive head and neck cancer
Authors: Liu Hsuan-Chen , Parikh Falguni , Kraus Thomas , Moran Thomas , Sikora Andrew 
Published: July 2017

Abstract
HPV-driven head and neck squamous cell carcinoma (HNSCC) are among the fastest growing cancers. Although, HPV-HNSCC patients have an overall favorable prognosis, a significant number of patients relapse post-treatment, and currently there is no specific therapeutic approach targeting the unique biology of HPV-driven HNSCC. Our ongoing efforts to target HPV-HNSCC focus on the identification of cell surface antigens that are upregulated by HPV infection. We have developed an "antigen-agnostic" approach for generating HPV-HNSCC-targeting monoclonal antibodies for cancer diagnosis and treatment that does not rely on prior identification of target antigens. We used HPV-HNSCC membrane fractions to immunize recipient mice and generated HPV-specific hybridomas. We then screened five thousand hybridoma colonies by flow cytometry to test the specificity of binding to HPV-positive cancer cell lines (2HNSCC and 2 Cervical Cancer) and HPV-negative cancer cell lines (4 HNSCC and 1 CC). After primary screening, we narrowed down to forty-four clones; among these hybridoma clones, 6D8 and 6B3 bound preferentially to HPV-positive cancer cell lines. The binding targets of 6D8 and 6B3 were identified by immunoprecipitation and mass spectrometry; their targets are integrin alpha6 (ITGA6) and tissue factor (F3) respectively. Future work will validate the biological function of these mAbs in in vitro and in vivo models, and continue identifying more binding target of mAbs. We propose mAbs specifically targeting membrane-expressed antigens on HPV-related cancer cells as a potential approach for early diagnosis and targeted therapy.
Citation Format: Hsuan-Chen Liu, Falguni Parikh, Thomas Kraus, Thomas Moran, Andrew Sikora. Characterization of monoclonal antibodies specific for HPV-positive head and neck 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 2211. doi:10.1158/1538-7445.AM2017-2211
Abstract 2212: Protein engineering of the decapping enzyme NudT16 enhances its ability to hydrolyze protein-conjugated ADP-ribose for post-translational site identification via mass spectrometry
Authors: Thirawatananond Puchong , McPherson Robert L. , Malhi Jasmine K. , Leung Anthony K. , Gabelli Sandra B. 
Published: July 2017

Abstract
During nonhomologous end joining of DNA follow double-stranded breaks, one common signaling response is the adenosine diphosphate ribosylation (ADP-ribosylation) of recruiter scaffold proteins. ADP-ribosylation is a post-translational modification (PTM) that occurs on aspartate, glutamate, lysine, arginine and cysteine on proteins and is mediated chiefly by polyadenosine ribose polymerases (PARP). Using NAD+ as its substrate, PARP transfers an ADP-ribose onto another protein, releasing a nicotinamide ring in the process; this modification presents as a mono-ADP-ribosylation (MARylation) or poly-ADP-ribosylation (PARylation). While site identification of MARylated protein can be achieved through tandem MS/MS and searching for peptides whose spectra have been shifted by 541.0611 Da, a similar approach for PARylated protein is confounded by the variable length and branching of its PTM. To this end, ADP-ribosylated protein is normally incubated with a snake venom phosphodiesterase (SVP) to leave a standardized phosphoribose tag of 212.0086 Da. It has been shown that a recombinantly-expressed Nudix protein NudT16 provides a cost-effective alternative to SVP to process ADP-ribosylated protein. NudT16 in the cell normally decaps small nucleolar RNA. Our studies here sought to utilize the x-ray crystallographic structure of NudT16 in complex with ADP-ribose in guiding rational design mutations to enhance binding of our desired ADP-ribose substrate and to widen the hydrolase’s active site to better accommodate a protein-conjugated ADP-ribose. Mutants have demonstrated improved catalytic efficiency for ADP-ribose hydrolysis. Radiolabeled immunoassays of PARylated protein concur with these kinetic experiments by showing a reduction of radiolabeled PARP. Rational design of a ADP-ribose-hydrolyzing NudT16 with comparable catalytic efficiency to SVP eases lead discovery of biological mechanisms that are mediated through ADP-ribosylation such as DNA repair.
Citation Format: Puchong Thirawatananond, Robert L. McPherson, Jasmine K. Malhi, Anthony K. Leung, Sandra B. Gabelli. Protein engineering of the decapping enzyme NudT16 enhances its ability to hydrolyze protein-conjugated ADP-ribose for post-translational site identification via mass spectrometry [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 2212. doi:10.1158/1538-7445.AM2017-2212
Abstract 2224: Increased 15-lipoxygenase-1 activity limits tumor development in the azoxymethane mouse model of colon cancer: impact of omega-3-acid ethyl esters
Authors: Zuo Xiangsheng , Colby Jennifer K. , Liu Fuyao , Gao Shen , Wu Ling , Jaoude Jonathan C. , Moussalli Micheline J. , Tan Lin , Yang Peiying , Shureiqi Imad 
Published: July 2017

Abstract
Pro-inflammatory signaling has been shown to promote colorectal tumorigenesis and is a target for the development of effective chemopreventive approaches. The specialized pro-resolving lipid mediators (SPMs, e.g. resolvins), bioactive metabolites of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), actively terminate inflammation and have been proposed to possibly contribute to the anti-tumorigenic effects of DHA and EPA. The enzyme 15-lipoxygenase-1 (ALOX15) is a key biosynthetic enzyme in generation of resolvins. However, 15-LOX-1 expression is commonly lost during human CRC tumorigenesis starting in premalignant stages via transcriptional mechanisms independent of substrate availability. The impact of ALOX15 on DHA and EPA’s effects on tumorigenesis remain unknown. Mice with intestinal epithelium-specific expression of human ALOX15 (15-LOX-1-gut mice) and wild-type FVB controls were injected with azoxymethane (AOM, 7.5mg/kg) once weekly for 6w and followed for 20w. Mice were fed diet with 1% omega-3-acid ethyl esters (O3AEE, a pharmaceutical grade fish oil preparation of EPA and DHA ethyl esters) or control diet starting 3w before initiation with AOM. Colonic tumors developed in 10 of the 13 (77%) wild type (WT) mice fed control diet, 5 of the 10 (50%) WT mice fed O3AEE diet, 5 of the 12 (42%) 15-LOX-1-gut mice fed control diet, and 3 of the 10 (30%) 15-LOX-1-gut mice fed control diet. Lipid mediator levels were measured by liquid chromatography/ tandem mass spectrometry (LC-MS/MS). The SPMs resolvin E1 and D2 (RvE1, RvD2) as well as the pathway intermediates 18-HEPE and 17-HDHE were increased in ALOX15-gut mice on O3AEE (see Table; data are shown as ng/mg protein; mean ± SEM). Our results demonstrate that ALOX15 activity is important to DHA and EPA formation of resolvins and inhibition of colonic tumorigenesis. Supported by grants CPRIT RP150195 and NIH RO1 R01CA195686
SPMs in O3AEE or control diet fed miceWTWT15-LOX-1-gut15-LOX-1-gutControl dietO3AEE dietControl dietO3AEE diet18-HEPE00.46 + 0.500.82 + 0.3117-HDHE0.21 + 0.090.2 + 0.74.2 + 0.4113.35 + 3.1RvE10001.98 + 0.77RvD200.024 + 0.0240.17 + 0.0220.3 + 0.077
Citation Format: Xiangsheng Zuo, Jennifer K. Colby, Fuyao Liu, Shen Gao, Ling Wu, Jonathan C. Jaoude, Micheline J. Moussalli, Lin Tan, Peiying Yang, Imad Shureiqi. Increased 15-lipoxygenase-1 activity limits tumor development in the azoxymethane mouse model of colon cancer: impact of omega-3-acid ethyl esters [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 2224. doi:10.1158/1538-7445.AM2017-2224
Abstract 2228: Altering rictor with diosmetin reduces tumor progression in orthotopic prostate cancer model
Authors: Pakradooni Rebecca , Khalifa Ahmad , Patel Riddhi , Shukla Sanjeev 
Published: July 2017

Abstract
Rapamycin insensitive companion of mTOR (Rictor) is an essential subunit of mTOR complex 2, maintains the integrity of the complex and functions as full activator of Akt. Rictor has been implicated to be involved in growth and progression of malignancies. Reports suggested that overexpression of Rictor in prostate cancer tissues, which may have potential role in prostate cancer progression. We demonstrated silencing Rictor in PC-3 cells decreased p- Akt (Ser-473) expression; conversely p-Akt (Thr-308) and p-PKCα (Ser-657) expression was increasing. Additionally to observe the molecular mechanism of Rictor regulation, we took HAP1 cells (derived from male chronic myelogenous leukemia (CML) cell line KBM-7) were edited and silenced by CRISPR/Cas9 with 2 and 10 base pair Rictor in a coding exon 5. HAP1 haploid human cell line contains a single copy of all chromosomes except for a heterozygous 30-megabase fragment of Chromosome 15; these cells are instrumental for genetic screening, as gene inactivation is greatly facilitated by the absence of a second gene copy. In these cells we observed p-Akt (Ser-473) expression was significantly less with more pronounced in 10 base pair than 2 base pair. Further to determine potential role of diosmetin (5, 7-Trihydroxy-4′-methoxyflavone; a natural flavonoid present in citrus plant, has anti-mutagenic properties) on Rictor silenced 2 base pair and 10 base pair HAP1 cells, we treated these cells in concentration response fashion, and observed decrease in p-Akt (Ser-473) expression than control cells. Next, we determine invivo potential of Rictor silencing, we used luciferase tag PC-3 cells silenced with Rictor gene orthotopically implanted in ventral prostate of mice. After 8 weeks of Rictor silenced cells implanted mice, we observed less luciferase activity in prostate and occasional metastasis than control luciferase PC-3 cells. Moreover, diosmetin fed mice in dose dependent fashion (20 and 50µg/animal/day) represented decrease in tumor luciferase activity with reduced tumor volume and no metastasis than control mice. We observed metastasis only in control and rapamycin (8 mg/kg body weight intraperitoneally every alternate day) treated mice in spine, lung and kidney. Taken together, our studies demonstrate that diosmetin fed animals resulted in growth inhibition and induction of apoptosis by altering Rictor signaling cascade. We are demonstrating that diosmetin modulates molecular targets viz., Rictor and Akt to alter cellular events and elicit anticancer effects in prostate cancer cells.
Citation Format: Rebecca Pakradooni, Ahmad Khalifa, Riddhi Patel, Sanjeev Shukla. Altering rictor with diosmetin reduces tumor progression in orthotopic prostate cancer model [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 2228. doi:10.1158/1538-7445.AM2017-2228
Abstract 2230: Luteolin selectively inhibits EZH2 and blocks H3K27 methylation in prostate cancer cells
Authors: Kanwal Rajnee , Yang Xiaoping , Shankar Eswar , Gupta Sanjay 
Published: July 2017

Abstract
The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex (PRC2) and is involved in chromatin remodeling and gene silencing through its methylation of histone H3 on lysine 27 (H3K27). Specifically, trimethylation of H3K27 is associated with gene silencing and plays critical role in cancer initiation and progression. Therefore, blocking EZH2 catalytic activity may present a valid preventive and/or therapeutic strategy for the treatment of cancers with EZH2 overexpression including prostate cancer. Our multistep approach of molecular modeling and direct binding has led to the identification of plant flavone luteolin (3’, 4’, 5, 7-tetrahydroxyflavone) as a specific inhibitor of EZH2 with preferential blocking of its catalytic site. Here we report luteolin, in micro molar range, inhibits EZH2 catalytic activity, demonstrates anti-proliferative and anti-invasive activities in functional cell based assays. Treatment of human prostate cancer DU145 and 22Rv1 cells, which possess high constitutive EZH2 expression, with 5-20 μM luteolin significantly inhibits EZH2 and SUZ12 protein expression in dose and time dependent manner, although luteolin treatment did not affect protein expression of EED and RbAp46/48 protein, other members of PRC2 complex. Treatment of both cell lines with luteolin also reduced H3K27me3 and H3K27me2 protein and its enzymatic activity in dose and time dependent manner without affecting total H3 protein. In addition, luteolin was also effective in suppressing in vitro methylation performed using recombinant PCR2 complex. These events led to increase in the expression of downstream tumor suppressor genes including E-cadherin, SLIT2 and TIMP3, respectively. Interestingly, treatment of cells with proteasome inhibitor, MG132 together with luteolin did not prevent EZH2 degradation indicating that proteasomal degradation might not contribute to EZH2 inhibition. Taken together, our study suggest that luteolin acts on the catalytic binding site of EZH2 to exhibit downregulation of histone H3 methylation and could be developed as a potential promising agent for the prevention and/or treatment of various human cancers including prostate cancer with EZH2 overexpression.
Citation Format: Rajnee Kanwal, Xiaoping Yang, Eswar Shankar, Sanjay Gupta. Luteolin selectively inhibits EZH2 and blocks H3K27 methylation in prostate 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 2230. doi:10.1158/1538-7445.AM2017-2230
Abstract 2246: Anti-proliferative activities of lipid fraction of extract from the skin of the catfish Arius Bilineatus, Valenciennes
Authors: Yang Peiying , Ding Jibin , Pan Yong , Jiang Yan , Afzal Mohammad , Paul Bincy M. , George Sosamma O. , Al-Hassan Jassim M. 
Published: July 2017

Abstract
The catfish (Arius bilineatus, Val.) secretes a gelatinous substance composed of biochemically active lipids and proteins from its skin upon stress or injury. Preparations from the skin have previously been shown to affect blood clotting and accelerates healing of non-healing diabetic foot ulcers in man. We have reported previously fish skin preparation (CSP) derived from the skin of the Catfish and it’s lipid fraction exerted anti-inflammatory activity in the in vitro cells and in vivo animal models. Here anti-proliferative effect of a lipid fraction of fish skin preparation (CSP-L) derived from the skin of the catfish and its plausible mechanism were investigated in human hepatocellular carcinoma (HCC) Hep3B and human pancreatic cancer Panc-1 cells. Cells were treated with CSP-L (0 to 100 μg/ml) for 72 hrs and cell proliferation was measured by the MTT assay. The results showed much stronger inhibition by CSP-L in Panc-1 cells than that of Hep3B cells with IC50 of 5.5 ± 1.4 μg/ml and 19.5 ± 7.7 μg/ml, respectively. Cell cycle analysis with PI staining suggested that CSP-L (25 - 100 μg/ml) led to G1 phase arrest in Hep3B cells whereas S phase arrest was observed in Panc-1 cells, suggesting the differential molecular mechanisms responsible for CSP-L induced cell growth suppression in Hep3B and Panc-1 cells. The alteration of cell cycle was concentration dependent. Additionally, CSP-L concentration dependently suppressed the invasion of Hep3B and Panc-1 cells. The molecular mechanism associated with CSP-L’s anti-proliferative effect was examined by Western blotting in both Hep3B and Panc-1 cells. Intriguingly, CSP-L (50 and 100 μg/ml) notably decreased protein levels of cyclin D, Stat3, pRB and pERk in Hep3 B cells in a concentration dependent manner. In contrast, only pRB and pERK protein expression were reduced in CSP-L treated Panc-1 cells. These again suggest that CSP-L inhibited the proliferation of Hep3B and Panc-1 cells by different molecular mechanisms. Collectively, our preliminary data suggest that CSP-L has a great potential to be developed as an anticancer or preventive agent for both HCC or pancreatic cancer and warrants further investigation. This study was support by a grant from Kuwait Foundation for the Advancement of Science No. KFAS 2013-120701A-D, and Kuwait University Research Grant No. SL03/14.
Citation Format: Peiying Yang, Jibin Ding, Yong Pan, Yan Jiang, Mohammad Afzal, Bincy M. Paul, Sosamma O. George, Jassim M. Al-Hassan. Anti-proliferative activities of lipid fraction of extract from the skin of the catfish Arius Bilineatus, Valenciennes [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 2246. doi:10.1158/1538-7445.AM2017-2246