bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1762: Verbascoside promotes apoptosis by regulating HIPK2-p53 signaling in human colorectal cancer
Authors: Zhou Lihong , Feng Yuanyuan , Jin Yongjie , Liu Xuan , Sui Hua , Chai Ni , Chen Xingzhu , Liu Ningning , Wang Yan , Li Qi 
Published: August 2015

Abstract
Background: We investigated the role of the HIPK2-p53 signaling pathway in tumorigenesis and resistance to the drug Verbascoside (VB) in colorectal cancer (CRC), using in vivo and in vitro experiments.
Methods: Primary human CRC samples and normal intestinal tissues from patients were analyzed for HIPK2 expression by immunohistochemistry (IHC) and its expression was correlated against patients’ clinicopathological characteristics. Human CRC HCT-116 cells were implanted in BALB/c nude mice; mice with xenografted tumors were randomly administrated vehicle (control), 20, 40, or 80 mg/mL VB, or 1 mg/mL fluorouracil (5-FU). HIPK2, p53, Bax, and Bcl-2 expression in these tumors were determined by IHC. In vitro effects of VB on CRC cell proliferation and apoptosis were measured by CCK-8 assay and flow cytometry; HIPK2, p53, p-p53, Bax, and Bcl-2 were measured by western blot.
Results: IHC analysis for 100 human CRC tumor samples and 20 normal intestinal tissues, showed HIPK2 expression to inversely correlate with Dukes stage and depth of invasion in CRC (P &lt;0.05). In vivo, the inhibition rates of 20, 40, and 80 mg/mL VB on CRC xenograft tumor weight were 42.79%, 53.90%, and 60.99%, respectively, and were accompanied by increased expression of HIPK2, p53, and Bax, and decreased Bcl-2 expression in treated tumors. In vitro, VB significantly inhibited proliferation of CRC cell lines HCT-116, HT-29, LoVo, and SW620, in a time- and dose-dependent manner. The apoptosis rates of 25, 50, and 100 μM VB on HCT-116 cells were 10.83 ± 1.28, 11.25 ± 1.54, and 20.19 ± 2.87%, and on HT-29 cells were 18.92 ± 6.12, 21.57 ± 4.05, and 25.14 ± 6.73%, respectively. In summary, VB treatment significantly enhanced the protein expression of pro-apoptotic HIPK2, p53, p-p53, Bax, and decreased anti-apoptotic Bcl-2 expression in CRC cells.
Conclusions: HIPK2 protein modulates the phosphorylation status of p53, and levels of Bax and Bcl-2 in CRC. We also found that VB effectively activated the HIPK2-p53 signaling pathway, resulting in increased CRC cells apoptosis.
Note: This abstract was not presented at the meeting.
Citation Format: Lihong Zhou, Yuanyuan Feng, Yongjie Jin, Xuan Liu, Hua Sui, Ni Chai, Xingzhu Chen, Ningning Liu, Yan Wang, Qi Li. Verbascoside promotes apoptosis by regulating HIPK2-p53 signaling in human colorectal cancer. [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 1762. doi:10.1158/1538-7445.AM2015-1762
Abstract 1773: MHY-449 induces apoptotic cell death through ROS- and caspase-dependent pathways in AGS human gastric cancer cells
Authors: Choi Yung Hyun , Kang Yong Jung , Kim Seon Hee , Sung Bokyung , Kim Dong Hwan , Hwang Seong Yeon , Kim Minjung , Lim Hyun Sook , Yoon Jeong-Hyun , Moon Hyung Ryong , Chung Hae Young , Kim Nam Deuk 
Published: August 2015

Abstract
We previously reported on the anticancer effect of the diastereoisomeric compound MHY-449, a novel dihydrobenzofuro[4,5-b][1,8] naphthyridin-6-one derivative, in various human cancer cells such as HCT116 human colon cancer cells (Int J Oncol 41: 2057-64, 2012) and PC3 human prostate cancer cells (Int J Oncol 44: 905-11, 2014). In this study, we investigated whether MHY-449 has anticancer properties in AGS human gastric cancer cells, and if so, what the molecular mechanisms are. Treatment with MHY-449 inhibited cell growth and induced apoptotic cell death in a concentration-dependent manner. The induction of apoptosis was determined by morphological changes, Hoechst 33342 staining, DNA fragmentation, increase of late apoptosis and sub-G1 DNA which were detected by flow cytometry analysis. Western blot analysis showed that MHY-449 upregulated the levels of Fas, FasL, p53, p21WAF1/CIP1, p27KIP1 and the ratio of Bax/Bcl-2 and downregulated the levels of procaspase-8, -9 and -3 and the cleavage of poly(ADP-ribose) polymerase (PARP). The apoptotic cell death induced by MHY-449 was accompanied by the activation of caspase-8, -9 and -3, which was completely abrogated by the pan-caspase inhibitor, z-VAD-FMK. In addition, treatment with MHY-449 elevated the level of cellular ROS generation. These data were further confirmed by incubating the cells with N-acetyl-L-cysteine (NAC), which is a scavenger of ROS. Pretreatment with NAC protected against MHY-449-induced cytotoxicity. Similarly, pretreatment of NAC abolished MHY-449-induced downregulation of pro-caspase-8, -9 and -3 and PARP cleavage. Taken together, these findings suggest that MHY-449 induces apoptosis via caspase- and ROS-dependent pathways in AGS human gastric cancer cells.
Citation Format: Yung Hyun Choi, Yong Jung Kang, Seon Hee Kim, Bokyung Sung, Dong Hwan Kim, Seong Yeon Hwang, Minjung Kim, Hyun Sook Lim, Jeong-Hyun Yoon, Hyung Ryong Moon, Hae Young Chung, Nam Deuk Kim. MHY-449 induces apoptotic cell death through ROS- and caspase-dependent pathways in AGS human gastric 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 1773. doi:10.1158/1538-7445.AM2015-1773
Abstract 1775: Inhibition of breast cancer cell proliferation by diarylthiourea analog, SL1-18
Authors: Fallatah Maryam , Louie Maggie C. , Liu Shengquan 
Published: August 2015

Abstract
Breast cancer is the most common malignancy that occurs in women in the US and has the second highest cancer-associated mortality rate. Depending on the expression of estrogen receptor α (ERα), breast cancer can be classified as ER positive or negative. Current drugs used to treat ER+ cancers include selective estrogen receptor modulators (SERMs) and selective estrogen receptor down-regulators (SERDs). Unfortunately, prolonged exposure to these drugs often leads to the development of acquired resistance. Consequently, there is a great need to develop alternative therapeutic options. Flexible heteroarotinoids (Flex-Hets) are compounds derived from retinoids that have been shown to display anti-cancer activity. These compounds tend to exhibit lower toxicity in comparison to their retinoid precursor. The objective of this study is to investigate the anti-cancer effects of SL1-18 — a novel heteroarotinoid — on ER+ breast cancer. Our data suggest that treatment of MCF-7 with SL1-18 inhibit cell growth with a GI50 of 5μM. In order to understand the mechanism of action, we evaluated the effects of SL1-18 on the expression of cell cycle regulators, and our results suggest that SL1-18 decreases the expression of cyclin A, cyclin B, cyclin D1 and cdk2. Furthermore, cell cycle analysis revealed that SL1-18 reduces the number of cells going through the S phase when compared to mock-treated controls. Taken together, these preliminary results suggest that the SL1-18 may be a potent inhibitor of breast cancer cell growth, but further research is necessary to determine its mechanism of action.
Citation Format: Maryam Fallatah, Maggie C. Louie, Shengquan Liu. Inhibition of breast cancer cell proliferation by diarylthiourea analog, SL1-18. [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 1775. doi:10.1158/1538-7445.AM2015-1775
Abstract 1778: Selectively targeting the DNA-binding domain of the androgen receptor as a prospective therapy for prostate cancer
Authors: Dalal Kush , Roshan-Moniri Mani , Sharma Aishwariya , Li Huifang , Ban Fuqiang , Hassona Mohamed D. , Hsing Michael , Singh Kriti , LeBlanc Eric , Dehm Scott , Tomlinson Guns Emma , Cherkasov Artem , Rennie Paul S. 
Published: August 2015

Abstract
The androgen receptor (AR) is a hormone-activated transcription factor implicated in the development and progression of prostate cancer. The AR contains an N-terminal domain (NTD), followed by DNA binding (DBD) and ligand-binding (LBD) domains. Upon binding of androgens to the LBD, the AR moves into the nucleus where it interacts with target genes via the conserved AR-DBD. Prostate cancer treatment involves the use of small-molecules to block androgen production or to compete with androgens for binding to the AR-LBD. Drug-resistance occurs when LBD mutations render small-molecule treatment ineffective or when constitutively active AR splice variants, lacking the LBD, become overexpressed. We recently identified a surface pocket on the AR-DBD that may serve as an alternative drug-target site. The DBD-specific, small molecule compounds presented here block transcriptional activity of full-length and splice variant AR forms across multiple cell lines and show no cross-reactivity with related steroid nuclear receptors. The inhibition is lost when residues in the binding pocket are mutated or when the AR-DBD is replaced with a different DNA binding domain. Biophysical techniques were used to explore the interaction of these compounds with the purified, recombinant DBD protein. Gene expression analysis demonstrated the down-regulation of AR target genes following compound treatment, without any obvious expression signature associated with toxicity. The compounds affected DNA binding in vitro and also blocked interactions of the AR with chromatin inside the nucleus. Finally, the lead compound suppressed the growth of LNCaP tumor xenografts and was accompanied by down-regulation of AR target genes, such as PSA. These results suggest a mechanism whereby our developed inhibitory compounds interfere with DNA binding by the AR, potentially leading to effective treatment of advanced, castration-resistant prostate cancers.
Citation Format: Kush Dalal, Mani Roshan-Moniri, Aishwariya Sharma, Huifang Li, Fuqiang Ban, Mohamed D. Hassona, Michael Hsing, Kriti Singh, Eric LeBlanc, Scott Dehm, Emma Tomlinson Guns, Artem Cherkasov, Paul S. Rennie. Selectively targeting the DNA-binding domain of the androgen receptor as a prospective therapy for prostate cancer. [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 1778. doi:10.1158/1538-7445.AM2015-1778
Abstract 178: Targeting of multiple oncogenic miRNAs on NUMB gene to mediate head and neck carcinogenesis
Authors: Chou Chung-Shan , Chang Kuo-Wei , Lin Shu-Chun 
Published: August 2015

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the 6th leading malignancy in the world. MicroRNAs (miRNAs) are small, non-coding RNAs, which are associated with the genesis and progression of cancers. NUMB is a multi-functional adaptor protein, which can activate E3 ubiquitin ligase and degrade target proteins to modulate pathogenesis. In silico modules predict that miR-31, miR-96, miR-182 and other miRNAs might target NUMB. This study investigates the concordant targeting of multiple oncogenic miRNAs to NUMB, and to verify the roles of NUMB in HNSCC. miR-31, miR-96 and miR-182 were found up-regulated in the vast majority of HNSCC tissues. On the contrary, NUMB expression was largely down-regulated in the tumors. A reverse correlation was noted between miR-31 expression and NUMB expression. Reporter assays using wild type and mutant constructs specified that these oncogenic miRNAs directly target the sequences in the 3′UTR of NUMB gene. However, miR-31 was unable to target a predicted site in the coding sequence of NUMB gene to mediate regulation. Exogenous expression of these miRNAs decreased NUMB expression and increased the migration of HNSCC cells. Knockdown of NUMB expression enhanced oncogenicity of HNSCC cells. However, the exogenous NUMB expression decreased the migration and anchorage-independent growth of HNSCC cells. The oncogenicity induced by these oncogenic miRNAs was attenuated by NUMB expression. This study provides in vitro and in vivo clues demonstrating that miR-31, miR-96 and miR-182 co-target NUMB gene in HNSCC. The coordinative abrogation of these miRNAs together with NUMB enhancement may be contributive to new therapeutic intervention against head and neck cancers.
Citation Format: Chung-Shan Chou, Kuo-Wei Chang, Shu-Chun Lin. Targeting of multiple oncogenic miRNAs on NUMB gene to mediate head and neck carcinogenesis. [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 178. doi:10.1158/1538-7445.AM2015-178
Abstract 1782: Post-translational regulation of cyclins by Aspirin through 26S proteasome: Implications in chemoprevention
Authors: Dachineni Rakesh , Ai Guoqiang , Tummala Hemachand , Gunaje Jayarama B. 
Published: August 2015

Abstract
Recent studies have shown that, regular use aspirin for 5 years or more, decreases the occurrence of cancer of the colon, skin, breast, prostate and lung tissues. However, the mechanism of its anti-cancer effects are not completely understood. We hypothesized that Aspirin's chemo preventive action may involve proteins important in the regulation of cell cycle. Using multiple colon and skin cancer cells, we studied whether aspirin modulates the expression of cyclin B1. Cyclin B1 is a regulatory protein involved in mitosis and promotes the passage of cell cycle from G2 to M phase. Cyclin B1 along with Cyclin dependent Kinase 1(CDK1) regulates chromosomal condensation, nuclear envelope break down and spindle pole assembly in early mitosis. We demonstrate that, in HT-29 human colon and Sk-Mel 28 skin cancer cells, aspirin dose dependently decreased the levels of cyclin B1. This was further confirmed using immunofluorescence studies. To determine the involvement of proteases, we determined whether the lactacystin, a 26S proteasomal inhibitor, would reverse the inhibitory effect of aspirin on cyclin B1. We observed that pretreatment of cells with lactacystin completely reversed the decrease in levels of cyclin B1 in aspirin treated cells. Transfection of the DDK tagged cyclin B1 into HT-29 cells were carried out to establish whether the decrease observed occurs through a nuclear independent and post-translational mechanism. We observed that, aspirin significantly decreased the exogenously transfected DDK tagged cyclin B1 protein. Our results, for the first time show that anticancer effects of aspirin may occur through cyclin B1 degradation mediated by 26S proteasomes.
Citation Format: Rakesh Dachineni, Guoqiang Ai, Hemachand Tummala, Jayarama B. Gunaje. Post-translational regulation of cyclins by Aspirin through 26S proteasome: Implications in chemoprevention. [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 1782. doi:10.1158/1538-7445.AM2015-1782
Abstract 1790: Caloric restriction can increase the efficacy of radiation in both hormone-sensitive and hormone-resistant prostate cancers by downregulating the IGF-1R pathway
Authors: Han Sunny Y. , Dan Tu D. , De Angelis Tiziana , Han John Y. , Sarich Mak , Carroll Peter , Knudsen Karen , Dicker Adam , Simone Nicole L. 
Published: August 2015

Abstract
Locally advanced prostate cancers (LAPC) are aggressive, have poor prognosis, and are associated with high recurrence rates and conversion to castrate resistance. The molecular underpinnings of LAPC are being investigated to identify novel therapeutics. Animal models have shown that caloric restriction (CR) can potentially prevent the initiation of prostate cancer. We propose that CR may be used as a novel therapeutic intervention to enhance outcomes of radiation treatment by altering the molecular profile of prostate tumors.
To assess the effect of CR with radiation in vivo, eighty 6 week old male nude mice were injected with LNCaP (hormone sensitive) or PC3 (hormone refractory) tumor cells. Once tumors were palpable, mice were randomized to be treated with one of 4 conditions: ad libitum (AL) diet, 8Gy of radiation (RT), 30% reduction in caloric intake (CR), or CR+RT. CR was associated with significant reduction in tumors. After PC3 tumor injection, compared with AL, the mice had a 22% reduction in tumor size with radiation, 77% with CR (p&lt;0.01 by Student's t-test) and an 80% reduction with CR+RT (p&lt;0.01). After LNCaP tumor injection, compared with ad libitum, the mice had a 49% reduction in tumor size with CR and a 55% reduction with CR+RT (p&lt;0.01). Tissue evaluation of mice treated with CR or CR+RT from both the LNCaP and PC3 models revealed decreased proliferation via Ki-67 and increased apoptosis with cleaved caspase-3 levels. In addition, significant downregulation of multiple members of the IGF-1R pathway was seen, including downregulation of IGF-1R, IRS-1, PI3K and pAKT. Serum evaluation revealed decreased IGF-1:IGF-BP3 in serum.
For the first time, we have shown that the efficacy of radiation can be increased by decreasing calories by 30% in both hormone-sensitive and hormone-refractory prostate cancer models. Future clinical trials for both hormone-sensitive and hormone-resistant prostate cancers should consider the innovative use of CR to augment standard cancer therapy as it has the potential to change the biology of tumors and enhance the opportunity for clinical benefit.
Citation Format: Sunny Y. Han, Tu D. Dan, Tiziana De Angelis, John Y. Han, Mak Sarich, Peter Carroll, Karen Knudsen, Adam Dicker, Nicole L. Simone. Caloric restriction can increase the efficacy of radiation in both hormone-sensitive and hormone-resistant prostate cancers by downregulating the IGF-1R pathway. [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 1790. doi:10.1158/1538-7445.AM2015-1790
Abstract 1801: Biological validation of a novel high-throughput irradiator for predictive radiation sensitivity bioassays
Authors: Bailey Alison , Fowler Tyler , Nickel Kwangok P. , Bednarz Bryan , Kimple Randall J. 
Published: August 2015

Abstract
Purpose: To improve our ability to study radiation response and screen for radiosensitizing compounds, we have developed a high-throughput variable dose rate microirradiator. We sought to use several assays of radiation induced cellular damage to validate the ability of this system to be used for high-throughput assays.
Methods: Immortalized human tonsillar epithelial cells were cultured in 96-well microtiter plates and irradiated in groups of eight wells to absorbed doses of 0, 1, 2, 4, and 8 Gy. Chloromethyl-H2DCFDA, a fluorescent reactive oxygen species (ROS) marker, was used to measure relative changes in ROS. Single cell gel electrophoresis (aka Comet assay, neutral) was used to detect physical DNA double-strand breaks. High-throughput immunofluorescent microscopy was used to detect γH2AX foci, a early marker of DNA double-strand breaks.
Results: Over the range of radiation doses tested, we confirmed increasing ROS generation as measured by CM-H2DCFDA fluorescence (R2 = 0.969). Over 1,450 comets were analyzed over a range of radiation doses and the Olive Tail Moment (OTM) calculated. A linear increase in OTM with radiation dose was seen (R2 = 0.991). A linear increase in γH2AX foci was seen with increasing radiation dose as measured by cell average γH2AX fluorescence (R2 = 0.999) Conclusions: We have developed a robust platform for high-throughput assays of radiation sensitivity allowing rapid assessment of effects over a range of radiation doses. This system provides a powerful tool for increasing the efficacy of genetic and pharmacologic modifiers of radiation response.
Citation Format: Alison Bailey, Tyler Fowler, Kwangok P. Nickel, Bryan Bednarz, Randall J. Kimple. Biological validation of a novel high-throughput irradiator for predictive radiation sensitivity bioassays. [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 1801. doi:10.1158/1538-7445.AM2015-1801
Abstract 1808: Enhancing the Stupp regimen in glioblastoma cancer cells with a T-type calcium channels inhibitor
Authors: Dziegielewski Jaroslaw , Dziegielewska Barbara , Gray Lloyd S. 
Published: August 2015

Abstract
Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor. Although introduction of the Stupp regimen combining radiation (IR) with concomitant and adjuvant temozolomide (TMZ) led to increased patient survival, the cure rate of GBM is disappointing. We postulated that sensitization of cancer cells to therapy can be achieved by targeting intracellular pathways and processes. Recently, T-type Ca2+ channels have been proposed as a molecular target for GBM sensitization to chemo- and radiotherapy (Keir et al., 2013; Sheehan et al., 2013). In the present studies, we investigated the effects of T-type channel inhibition on GBM cells’ responses to the Stupp regimen. GBM cells differing in their resistance to TMZ and IR were treated with theT-type channel antagonist, mibefradil, either concomitantly with TMZ or sequentially (Interlaced TherapyTM). Cell viability and clonogenic survival were determined, demonstrating significant enhancement of the Stupp regimen's anticancer effects with co-treatment with T-type channels inhibitors. Importantly for DNA-targeted therapies, we observed a decrease in cells’ ability to repair DNA damage in the presence of mibefradil. The molecular mechanism of this decrease was investigated by assessing expression levels, localization and phosphorylation status of ATM, DNA-PK, γH2AX, Chk1/2, Kap1, p53, Rad51. These mechanistic studies demonstrated that inhibiting T-type Ca2+ channels in GBM affects DNA damage signaling and repair through reduction of repair protein activation and changes their cellular localization. The observed effects are specific for T-type channels inhibition, since L-type channels inhibitors had no effect. Our study provide a rational molecular mechanism for sensitization of GBM to the Stupp regimen by T-type Ca2+ channel inhibition, which will facilitate current and future clinical trials and potentially lead to new treatment options for this deadly brain tumor.
Citation Format: Jaroslaw Dziegielewski, Barbara Dziegielewska, Lloyd S. Gray. Enhancing the Stupp regimen in glioblastoma cancer cells with a T-type calcium channels inhibitor. [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 1808. doi:10.1158/1538-7445.AM2015-1808