bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1774: The effects of diarylthiourea analogs on triple negative breast cancer cell growth
Authors: Nambi Deborah , Louie Maggie C. , Liu Shengquan 
Published: August 2015

Abstract
Breast cancer is the most common cancer occurring in women and the second leading cause of cancer death in women after lung cancer. Breast cancer is often classified at the molecular level in terms of whether the cancer expresses the estrogen receptor, progesterone receptor and human epidermal growth factor 2 receptor. Hormone receptor positive breast cancer accounts for 75-80% of all breast cancer and the remaining 20-25% accounts for the most aggressive types of cancer which are negative for all three receptors– known as triple negative breast cancer (TNBC). The current treatment used to manage TNBC is chemotherapy. Although chemotherapy has been effective in improving patients’ prognosis, a significant number of patients either relapse or develop resistance to these drugs. There is a significant interest in developing new therapeutic drugs aimed at improving outcomes in TNBC patients. Many studies have shown that flexible heteroarotinoids (Flex-Het) are a promising new class of drugs due to their ability to regulate growth, differentiation and apoptosis in a variety of cancer cells without activating the nuclear retinoic acid receptors. Previous studies have shown ShetA2 as the leading Flex-Het anti-cancer drug with the greatest efficacy in treating various types of cancer cells (Liu et al. 2004, Benbrook et al. 2005, and Liu et al. 2007). Some of the limitations of the ShetA2 are its high lipophilicity, toxic side effects and the low yields associated with the laborious synthesis. Therefore, efforts have been made to develop 2nd generation diarylthiourea compounds that retain anti-cancer activity, but with minimal side effects. The objective of this study was to examine the effects of two 2nd generation drugs SL1-18 and SL1-09 on various TNBC cell lines including MDA-MB-453, MDA-MB-231 and MDA-MB-468. Our preliminary data shows that exposure to micromolar levels of the diarylthiourea compounds effectively inhibited cancer cell growth in all three TNBC cell lines; however additional studies are necessary to understand the molecular mechanism of how SL1-18 and SL1-09 work to block cell growth and whether these anti-cancer drugs are promising therapeutic leads for the treatment of triple negative breast cancer.
Citation Format: Deborah Nambi, Maggie C. Louie, Shengquan Liu. The effects of diarylthiourea analogs on triple negative breast cancer cell growth. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1774. doi:10.1158/1538-7445.AM2015-1774
Abstract 1781: G1 phase melanoma cells escape proteasome inhibitor cytotoxicity
Authors: Daignault Sheena M. , Hill David S. , Beaumont Kimberley A. , Anfosso Andrea , Lovat Penny E. , Weninger Wolfgang , Haass Nikolas K. 
Published: August 2015

Abstract
Utilising the fluorescent ubiquitination-based cell cycle indicator (FUCCI), which facilitates real-time cell cycle tracking, we have demonstrated in vitro and in vivo that melanomas are composed of differentially cycling tumour cells in a subcompartment-specific distribution. Further, we have shown that targeting the endoplasmic reticulum with fenretinide (synthetic retinoid) or bortezomib (26S proteasome inhibitor) induces cell cycle arrest and apoptosis of metastatic melanoma cells in vitro and in vivo.
This study aims to investigate the effect of ER stress-inducing agents on the dynamics of cell division and cell death of individual melanoma cells within the complex tumor microenvironment, and to develop combination strategies that increase the efficacy of ER stress-inducing agents for melanoma therapy.
FUCCI-melanoma cells were grown as 3D spheroids and implanted into a collagen matrix to mimic tumor architecture and microenvironment. Utilising the F-XBP1ΔDBD-venus reporter construct, which labels the cytoplasm in response to ER stress, we found that bortezomib induced ER stress, delayed cell cycle progression, and combination with fenretinide increased cell death in 2D and 3D culture. Flow cytometry and confocal microscopy indicated that treatment of FUCCI-melanoma cells with bortezomib induced G2 accumulation in 2D and 3D culture over the course of 24 h. In contrast, by 72 h the majority of cells were in G1 phase. Analysis of 2D and 3D real-time cell cycle imaging movies revealed that bortezomib induced both G1- and G2 arrest, but preferentially killed G2-phase cells. Consequently, pretreatment with temozolomide or fenretinide, leading to G2-arrest, sensitised melanoma cells to bortezomib cytotoxicity. In contrast, pretreatment with MEK inhibitors, leading to G1 arrest, inhibited bortezomib cytotoxicity in all melanoma cells, as did selective BRAF inhibitors in BRAF mutant melanoma cells.
Our data suggest that bortezomib combined with fenretinide or temozolamide is a strategy worth exploring for the treatment of BRAF-inhibitor insensitive or resistant melanoma. Importantly, melanoma cells arrested in G1 are protected from bortezomib cytotoxicity, which excludes MAPK pathway inhibitors as combination partners.
Citation Format: Sheena M. Daignault, David S. Hill, Kimberley A. Beaumont, Andrea Anfosso, Penny E. Lovat, Wolfgang Weninger, Nikolas K. Haass. G1 phase melanoma cells escape proteasome inhibitor cytotoxicity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1781. doi:10.1158/1538-7445.AM2015-1781
Abstract 1786: Role of Euphorbia tirucalli terpenes cocktail extracts in the regulation of molecular cell death: implications in gynecological cancer progression
Authors: Choene Mpho , Motadi Lesetja 
Published: August 2015

Abstract
Gynaecological cancers are increasingly becoming the cause of death in females in developing countries. This type of cancers, especially cervical cancer is in the increase due to co-infection with HIV. Many of these people are solely dependent on traditional remedies, as conventional treatment might be expensive or inaccessible to them. In this study we characterised butanolic, hexane and methanolic extracts of Euphorbia tirucalli using both TLC and LC-MS spectroscopy. Following extract analysis, we looked at the effects of the extracts in regulating cell death in breast (MDA-MB 231), ovarian (RMG-1) and cervical (SiHa) cancer cell lines. The cells were treated with varying concentrations of the cocktailed extracts for up to 48 hours. A real time cell analyzer (xCELLigence) was used to monitor cell growth and to determine IC50. MTT assay was used to assess cell viability 24 hours post treatment with extracts. To determine if the extracts had an effect on cell cycle arrest, cell cycle distribution was determined by staining treated cancer cells with propidium iodide and the percentages of G0/G1, S, G2/M cell populations were analysed using flow cytometry. To determine the type of cell death induced, flow cytometry using annexin V was employed. At IC50, molecular analysis was performed to evaluate the effect cocktailed extracts had on apoptotic and cell cycle genes. Cocktailed extracts were found to inhibit cell proliferation in a concentration and cell type dependent manner. Cells were also found to have been arrested at G0/G1 and in some cases apoptosis induced. In general most pro-apoptotic genes like Bax and caspase-8 were upregulated this included the cell cycle gene p21 which was found to be significantly up-regulated in cells treated with extracts. These results suggest that the 3 cocktailed extracts might induce apoptosis or arrest cells at G0/G1 with the molecular mechanism that suggest activation of caspase-8 and Bax.
Note: This abstract was not presented at the meeting.
Citation Format: Mpho Choene, Lesetja Motadi. Role of Euphorbia tirucalli terpenes cocktail extracts in the regulation of molecular cell death: implications in gynecological cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1786. doi:10.1158/1538-7445.AM2015-1786
Abstract 1789: Drug repurposing: Sulfasalazine sensitizes gliomas to gamma knife surgery by blocking cystine uptake through System XC−, leading to gluthatione depletion
Authors: Sleire Linda , Skeie Bente Sandvei , Netland Inger Anne , Førde Hilde Elise , Dodoo Ernest , Selheim Frode , Leiss Lina , Wang Jian , Heggdal Jan , Pedersen Paal-Henning , Enger Per Øyvind 
Published: August 2015

Abstract
Glioblastomas (GBMs) are lethal cancers and inherently resistant to radiotherapy. Established treatments including surgery, radio- and chemotherapy have a limited efficacy, and the median survival is approximately 14.6 months. Thus, treatment resistance represents a major challenge in the clinical management of these patients, and new therapies are urgently needed.
We hypothesized that the Xc−-inhibitor sulfasalazine (SAS) could potentiate the efficacy of radiotherapy against gliomas. Expression of the catalytic subunit of system Xc−, xCT, was found in a panel of 30 human GBM biopsies. Sections from normal brain tissue displayed only weak immunopositivity, thus our findings therefore suggest that xCT expression is common to most GBMs, which together with its low expression in normal brain tissue could provide a therapeutic window. SAS treatment dramatically reduced cysteine-uptake and glutathione (GSH) levels in glioma cells in vitro and markedly increased the levels of reactive oxygen species (ROS). Furthermore, SAS and radiation synergistically increased DNA double-strand breaks and increased glioma cell death, whereas adding the antioxidant N-acetyl-L-cysteine (NAC) reversed cell death. Moreover, SAS and gamma knife radiosurgery (GKRS) synergistically prolonged survival in nude rats harboring human GBM xenografts, compared to controls or either treatment alone. In conclusion, SAS effectively blocks cystine uptake in glioma cells in vitro, leading to GSH depletion and increased ROS levels, DNA damage and cell death. Moreover, it potentiates the anti-tumor efficacy of GKRS in rats with human GBM xenografts, providing a survival benefit. Thus, SAS may have a role as a radiosensitizer to enhance the efficacy of current radiotherapies for glioma patients. We are currently preparing a clinical trial for patients with GBM recurrences combining pre-treatment with SAS and GKRS.
Citation Format: Linda Sleire, Bente Sandvei Skeie, Inger Anne Netland, Hilde Elise Førde, Ernest Dodoo, Frode Selheim, Lina Leiss, Jian Wang, Jan Heggdal, Paal-Henning Pedersen, Per Øyvind Enger. Drug repurposing: Sulfasalazine sensitizes gliomas to gamma knife surgery by blocking cystine uptake through System XC−, leading to gluthatione depletion. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1789. doi:10.1158/1538-7445.AM2015-1789
Abstract 181: miR-134 targets programmed cell death 7 (PDCD7) gene to modulate the pathogenesis of head and neck carcinoma
Authors: Peng Shih-Yuan , Chang Kuo-Wei , Lin Shu-Chun , Tu Hsi-Feng 
Published: August 2015

Abstract
Head and neck squamous cell carcinoma (HNSCC) is one of the prevalent malignancies in the world. microRNAs (miRNAs) are involved in the neoplastic process of various malignancies including HNSCC to mediate post-transcriptional down-regulation of target genes. This study shows that miR-134 enhances the proliferation, migration and invasion of HNSCC cells. In silico modules predict that programmed cell death 7 (PDCD7) gene could be one of the targets of miR-134. In stable HNSCC cell subclones, ectopic miR-134 expression decreased PDCD7 expression; while the ectopic miR-134Zip expression increased PDCD7 expression. Reporter assays confirmed the binding of miR-134 to the wild type 3′UTR of PDCD7, which decreased reporter activity. The targeting of miR-134 to the 3′UTR of PDCD7 was abolished by the mutations in targeted sequences. Moreover, miR-134Zip expression increased the activity of wild type reporter. Down-regulation of PDCD7 was identified in around 70% of HNSCC tumors, which was significantly opposite to miR-134 expression. A trend of reverse expression between miR-134 and PDCD7 was also present in HNSCC cell lines. PDCD7 was up-regulated following the apoptosis induced by cis-platin. Ectopic PDCD7 expression decreased the proliferation and migration of HNSCC cells, but it was unable to affect apoptosis or drug resistance status. Moreover, miR-134 associated oncogenicity was attenuated by PDCD7 expression. Taking together, this study concludes that the oncogenic potential of miR-134 in head and neck carcinoma is able to be mediated by targeting PDCD7.
Citation Format: Shih-Yuan Peng, Kuo-Wei Chang, Shu-Chun Lin, Hsi-Feng Tu. miR-134 targets programmed cell death 7 (PDCD7) gene to modulate the pathogenesis of head and neck carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 181. doi:10.1158/1538-7445.AM2015-181
Abstract 1825: Carbonylation and degradation of cardiac myosin binding protein C serves as an indicator of doxorubicin-induced cardiotoxicity
Authors: Aryal Baikuntha P. , Jeong Jinsook , Rao V. Ashutosh 
Published: August 2015

Abstract
Dose-dependent oxidative stress by the anthracycline doxorubicin (Dox) and other chemotherapeutic agents causes irreversible cardiac damage, restricting their clinical effectiveness. We hypothesize that irreversible protein oxidation caused by oxidative stress could be correlated with physiological functional impairment. We focused our study on protein carbonylation as an indicator of severe oxidative damage. We identified a specific cardiac protein that showed selective carbonylation under Dox-induced cardiotoxic conditions in a spontaneously hypertensive rat (SHR) model and this protein was confirmed to be a 140 kDa cardiac myosin binding protein C (MyBPC) using mass spectrometry. We further analyzed and confirmed the carbonylation and degradation of this protein using HL-1 cardiomyocytes under Dox-induced oxidative stress, and a purified recombinant rat cardiac MyBPC under metal-catalyzed oxidative stress conditions. Using HL-1 cells we demonstrated that carbonylated MyBPC undergoes proteasome-mediated degradation under Dox-induced oxidative stress. Using immunoprecipitation, co-sedimentation, and actin-binding assays we confirmed the functional impairment of MyBPC as a consequence of carbonylation. Carbonylation of recombinant MyBPC showed significant impairment in its actin binding properties with a dissociation constant of 7.35±1.9 μM compared to 2.7±0.6 μM for native MyBPC. Overall, our findings indicate that MyBPC carbonylation serves as a critical determinant of cardiotoxicity. We are currently investigating the interaction of MyBPC with divalent metal ions and sites of carbonylation under oxidative stress conditions.
Citation Format: Baikuntha P. Aryal, Jinsook Jeong, V. Ashutosh Rao. Carbonylation and degradation of cardiac myosin binding protein C serves as an indicator of doxorubicin-induced cardiotoxicity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1825. doi:10.1158/1538-7445.AM2015-1825
Abstract 1847: AR-V7 regulation during epithelial plasticity
Authors: Ware Kathryn E. , Schaeffer Daneen , Zhang Tian , Garcia-Blanco Mariano A. , Armstrong Andrew J. 
Published: August 2015

Abstract
Background: The androgen receptor (AR) is a key gene involved in prostate cancer (PC) biology, including disease development, response to initial hormonal therapies, and subsequent resistance to hormonal therapies. AR variants lacking the ligand-binding domain, such as AR-V7, have been observed and enriched in metastatic castration resistant prostate cancer. These variants contribute to resistance mechanisms against agents that target hormonal regulation of the AR, including anti-androgens, such as enzalutamide. In addition to AR variants, epithelial plasticity, including an epithelial-to-mesenchymal transition (EMT), has been implicated in PC metastatic dissemination during castration-resistance. In response to androgen deprivation therapy, PC xenografts have been found to display an acute and reversible up-regulation of both EMT phenotypic markers and AR variants.
Methods: To explore the mechanism by which an EMT program may regulate AR variant expression and metastatic disease, we used pre- and post- EMT cells to compare AR expression, migration, invasion and enzalutamide resistance. To induce EMT, we stably transfected LNCaP95 PC cells with a plasmid encoding inducible Snail, a master regulator of EMT. In addition, LNCAP95 cells were serially passaged under increasing enzalutamide conditions and we assessed biomarkers of EMT and invasion/growth in resistant cells.
Results: We found that Snail activation was sufficient to induce an EMT and increased expression of both AR-FL and AR-V7 as compared to pre-EMT cells. Nuclear localization of AR, migration and invasion were also increased in post-EMT cells. Importantly, cells were more resistant to enzalutamide treatment. Likewise, in a second model of acquired enzalutamide resistance, we found that Snail, AR-FL and AR-V7 were upregulated in enzalutamide resistant vs. sensitive cell lines.
Conclusion: Our study suggests that Snail activation promotes both an aggressive and therapy resistant tumor cell through the induction of EP and both AR-FL and AR-V7 isoforms.
Citation Format: Kathryn E. Ware, Daneen Schaeffer, Tian Zhang, Mariano A. Garcia-Blanco, Andrew J. Armstrong. AR-V7 regulation during epithelial plasticity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1847. doi:10.1158/1538-7445.AM2015-1847
Abstract 1848: PPARγ function is attenuated by full length androgen receptor and the AR-V7 variant in human prostate cancer cells
Authors: Olokpa Emuejevoke , Stewart Lamonica V. 
Published: August 2015

Abstract
The peroxisome proliferator activated receptor gamma (PPARγ) is a ligand-activated transcription factor that regulates in vitro and in vivo growth of castration-resistant human prostate cancer (PCa) cells. However, the factors that control expression of PPARγ within human PCa have not been characterized. We have previously shown that the androgen dihydrotestosterone decreases PPARγ levels and transcriptional activity in human PCa cells. Dihydrotestosterone serves as a high affinity ligand for the 110 kD form of the androgen receptor (AR-FL). Recent studies have shown the development of castration-resistant forms of prostate cancer is not only due to reactivation of AR-FL but also results from the expression of androgen receptor splice variants (ARVs) that lack the ligand-binding domain of the receptor. The goal of this study is to define the extent to which AR-FL and an ARV found in castration-resistant prostate cancer, AR-V7, regulate PPARγ expression and function. We first examined the role of AR-FL in the AR-positive C4-2 cell line. siRNA-mediated knockdown of endogenous AR-FL within C4-2 cells increased PPARγ protein and transcriptional activity. We next used reporter assays to further define the role of AR-FL and AR-V7 in PPARγ function. In these experiments, we first transfected plasmid vectors that express the AR-V7 or AR-FL into the AR null PC-3 prostate cancer cell line. A luciferase-based reporter assay was then used to measure alterations in PPARγ transcriptional activity within transfected cells. The addition of AR-FL to PC-3 cells resulted in reduced basal PPARγ luciferase activity. The ability of the ligand rosiglitazone to increase PPARγ activation was also suppressed in AR-FL positive PC-3 cells. A comparable decrease in ligand-induced PPARγ activation was detected in PC-3 cells that expressed AR-V7. The reduction in PPARγ activity produced by AR-FL and AR-V7 was likely not due to alterations in PPAR gamma expression, for we did not detect a consistent reduction in PPARγ mRNA and protein in transfected cells. Overall these data suggest that both AR-FL and AR-V7 are negative regulators of PPARγ function. Moreover, the AR-V7 stimulated reduction in PPARγ activity does not require the presence of AR-FL. Studies currently are underway to define the effect of endogenous AR-V7 on PPARγ expression and activity. This project was supported by NIGMS RISE grant (2R25GM059994-13), a NCI Mentored Career Development Award (K01CA114253), and the Vanderbilt CTSA grant UL1 RR024975-01 from NCRR/NIH.
Citation Format: Emuejevoke Olokpa, Lamonica V. Stewart. PPARγ function is attenuated by full length androgen receptor and the AR-V7 variant in human prostate cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1848. doi:10.1158/1538-7445.AM2015-1848