bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1932: Phenylmethimazole decreases constitutively high basal levels of Interleukin 6 (IL-6) in a triple negative breast cancer cell line
Authors: O'Brien John D. , Goetz Douglas J. , Alapati Anuja , Deosarkar Sudhir P. , Kohn Leonard D. , McCall Kelly D. 
Published: August 2012

Abstract
Interleukin 6 (IL-6) is a pro-inflammatory cytokine that plays an important role in the progression of many types of cancers by regulating macrophage recruitment and differentiation, as well as modulating the activation of the JAK/Stat signal cascade, and inducing pro-angiogenic factors. Several studies have correlated a negative prognosis in cancer with a high level of IL-6 in patient serum. Triple (i.e. progesterone, human epidermal growth factor-2, and estrogen receptor) negative breast cancer has been reported to be highly aggressive and invasive. MDA-MB-231, a triple negative breast cancer cell line, expresses high basal levels of IL-6. Recently our laboratory demonstrated that phenylmethimazole (C10), a novel toll-like receptor inhibitor, diminishes basal expression of IL-6 in pancreatic cancer and melanoma cells as well as their growth and migration. Based on these observations, we sought to test the hypothesis that C10 inhibits IL-6 expression in MDA-MB-231 cells. Here we report that triple negative breast cancer cells express considerably higher levels of IL-6 than estrogen receptor positive breast cancer cells and that C10 significantly reduces IL-6 expression in the triple negative breast cancer cells. This inhibition was observed at both the RNA and protein level. Given the importance of IL-6 in cancer progression, and our finding that C10 attenuates IL-6 expression in the MDA-MB-231 cell line, this study suggests that C10 may have therapeutic potential for triple negative breast cancers. Additional studies are currently underway to further explore these hypotheses.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1932. doi:1538-7445.AM2012-1932
Abstract 1968: Nanoparticle mediated measurement of target-drug binding in cancer cells
Authors: Ullal Adeeti V. , Reiner Thomas , Yang Katherine S. , Gorbatov Rostic , Min Changwook , Issadore David , Lee Hakho , Weissleder Ralph 
Published: August 2012

Abstract
Responses to molecularly targeted therapies can be highly variable and depend on mutations, fluctuations in target protein levels in individual cells and drug delivery. The ability to rapidly quantitate drug response in cells harvested from patients in a point-of-care setting would have far reaching implications. Capitalizing on recent developments with miniaturized diagnostic NMR (DMR) technologies, we have developed a magnetic nanoparticle based approach to directly measure both target expression and drug binding in freshly harvested human cancer cells. The method involves covalent conjugation of a small molecule drug to a magnetic nanoparticle that is then used as a read-out for target expression and drug binding affinity. Using poly(ADP-ribose) polymerase (PARP) inhibition as a model system, we developed an approach to distinguish differential expression of PARP across various cell lines with excellent correlation of DMR measurements to gold standards such as flow cytometry (r2 = 0.97) and western blotting (r2 = 0.92). We also sought to mimic drug pharmacodynamics ex-vivo through competitive target-drug binding and could quantify the relative binding affinities of several PARP inhibitors (e.g. Olaparib, Velaparib, AG-014699, and 3-aminobenzamide) in whole cells. Finally, we demonstrate the potential to perform such measurements directly in clinical samples. Further applications of the assay could result in a drug development platform to probe drug binding in cells, the identification of resistant cancer cells, and the ability to determine whether a drug has reached its target.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1968. doi:1538-7445.AM2012-1968
Abstract 1970: Liposomal nanoparticle siRNA delivery systems for in vivo silencing of the androgen receptor in human prostate cancer
Authors: Zhang Kevin X. , Lee Justin B. , Tam Yuen Yi C. , Tam Ying K. , Cullis Pieter R. , Rennie Paul S. 
Published: August 2012

Abstract
Prostate cancer is the most commonly diagnosed non-skin cancer in men and one of the leading causes of cancer-death. While frequently curable by surgical or radiation ablation, recurrent or metastatic disease is usually managed with androgen withdrawal therapies (medical castration), which block the growth promoting effects of androgens on the androgen receptor (AR). Unfortunately, the cancers eventually progress to the lethal castration-resistant state. Previously, we reported that knocking down the AR by RNA interference using small hairpin RNA (shRNA) inhibits this progression and, in about 50% of tumours, causes complete regression. In this study, we investigated the ability of small interfering RNA (siRNA) encapsulated in lipid nanoparticle (LNP) to silence AR in human prostate cancer cell lines and xenograft tumours following intravenous injections. In vitro screening studies with prostate cancer cell lines using a panel of cationic lipids demonstrated that siRNA formulated in LNPs containing the ionizable cationic lipid 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA) exhibited the most potent AR silencing effects. This is attributed to an optimized ability of DLin-KC2-DMA-containing LNP to enter into cells and to release the siRNA into the cell cytoplasm following endocytotic uptake. DLin-KC2-DMA LNPs were also effective in silencing the AR in a wild-type AR expressing cell line, LAPC-4, and a variant AR expressing cell line, CWR22Rv1. Importantly, we found that LNP AR-siRNA systems containing DLin-KC2-DMA could silence AR gene expression in distal LNCaP xenograft tumors and decrease serum PSA levels following intravenous injection. The 5′RACE experiments further confirmed that siRNA-induced specific cleavage of AR mRNA was the primary mechanism of action. In conclusion, these results indicate that in vivo delivery of siRNA to knockdown AR using our LNP formulations causes a decrease in serum PSA and provides proof in principle that this approach may offer a therapeutic strategy for treating advanced prostate cancer. (Funded by Canadian Institutes for Health Research and a PCF-STAR Project from Prostate Cancer Canada with the support of Safeway Canada)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1970. doi:1538-7445.AM2012-1970
Abstract 1972: Active targeting, fluorescence imaging, and NIR photothermal therapy of malignant tumors
Authors: Green Hadiyah-Nicole , Grizzle William E. , Rosenthal Eben L. , Mirov Sergey B. , McNally Lacey R. 
Published: August 2012

Abstract
We combine active targeting, fluorescent imaging, and subsequent photothermal treatment of malignant cells as a viable approach for the treatment of a variety of cancer types that over-express the epidermal growth factor including head and neck, colorectal, ovarian, cervical, breast, bladder, pancreatic, and prostate cancers. In our photothermal therapy experiments, the use of a near infrared (NIR) laser enables us to take advantage of both the plasmon resonance absorption peak of gold nanorods (GNR), ∼785 nm with aspect ratio of ∼ 4, as well as the absorption peak of the fluorescent dye, ∼774 nm. We used a 785 nm NIR laser with fluence of ∼9.5 W/cm2 and a 4 minute exposure time. Anti- epidermal growth factor receptor (EGFR) antibody, which targets the epidermal growth factor receptor over-expressed on malignant head and neck cancer cells, was labeled with a fluorescent dye and conjugated to GNR. We have studied the conjugation parameters for GNR and anti-EGFR antibodies and used nearest neighbor approximations to analyze the nanorod-to-antibody ratio from transmission electron microscope images. The optimal conjugation of dye:antibody:GNR facilitates active targeting of the nanorods to the tumor site. This active targeting is more efficient than previously reported results that rely solely on the enhanced permeability and retention effect. We demonstrate that PEGylating the GNR before conjugation to antibodies improves the quality of the conjugation. We also show that binding ability of the conjugated antibody to the epidermal growth factor receptor has not been affected. In addition, cell death by NIR photothermal therapy and gold nanorods is not compromised following conjugation of gold nanorods to a fluorescently labeled antibody. NIR photothermal treatment with the dye-antibody-nanorod conjugate selectively heated the GNR, excited fluorescence, and was sufficient to kill nearly 90% of tumor cells comparable to photothermal therapy with the GNR alone.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1972. doi:1538-7445.AM2012-1972
Abstract 1991: Effects of isoliquiritigenin (ISL) on VEGF secretion in Human breast cancer cell line MDA-MB-231
Authors: Hsia Shih-Min , Shieh Tzong-Ming , Shih Yin-Hua 
Published: August 2012

Abstract
Breast cancer is the most frequent cause of mortality among females in the world. The death reasons of most breast cancer patients were due to the tumor metastasis from breast to other organs. The principal mechanisms involved in metastasis are migration and invasion. Unfortunately, there are almost no efficacious therapeutic modalities. Thus, it is imperative to develop novel targets and agents to prevent invasion and metastasis of breast cancer cells.This purpose of this study is to investigate the anti-metastatic potency of ISL via modulation of the expression of VEGF and MMP in the highly metastatic human breast cancer cell line MDA-MB-231. Based on ELISA and western blot analysis, ISL treatment (0.1-10 μM) for 24 h and 48 h reduced secretions and protein levels of VEGF in a time- and dose-dependent manner. ISL decreased the hypoxia-inducible factor 1-alpha (HIF-1α) protein expression, which is the up-regulator of VEGF. According to chamber migration assay and wound migration assay, ISL significantly suppressed the migration of MDA-MB-231 cells at 24 h and 48 h. Among human MMPs, MMP-2 and MMP-9 have been of particular interest because they efficiently cleave the major components of ECM. As confirmed by western blot and gelatin zymography assay, ISL inhibited the protein expression and gelatinolytic activity of MMP-2/-9 at 48 h. To further clarify the signal pathway responsible for ISL-downregulated cell migration in MDA-MB-231 cells, we examine the effect of ISL on PI3K/Akt pathway and MAPK pathway, as well as the NF-κB. The expression of PI3K and phosphorylation of p38 mitogen-activated protein kinase and Akt kinase were suppressed after ISL treatment. In addition, NF-κB DNA binding assay demonstrated that NF-κB DNA binding activity was inhibited after ISL treatment. Taken together, these findings suggest the ISL inhibits p38, PI3K/Akt, and NF-κB signaling, resulting in the inhibition of VEGF, HIF-1α, MMP-9, and MMP-2, and thus suppresses migration of MDA-MB-231 cells. We believe that these findings will provide the potential application of ISL on the treatment of metastatic breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1991. doi:1538-7445.AM2012-1991
Abstract 1992: Ganoderma lucidum (Reishi) induces autophagy in inflammatory breast cancer by regulation of the mTOR signaling pathway
Authors: Rosario-Acevedo Raysa , Suárez-Arroyo Ivette , Aguilar-Pérez Alexandra , Cubano Luis A. , Martínez-Montemayor Michelle M. 
Published: August 2012

Abstract
The control of cell growth by the mammalian target of rapamycin (mTOR) signaling pathway and autophagy are relevant to disease, as altered regulation of either pathway may result in tumorigenesis. Autophagy is a regulated pathway involving the lysosomal degradation of cytoplasmic components and organelles. Activation of the human autophagy-initiation kinase (ULK1) is directly controlled by mTOR and is a critical part of the autophagy machinery. In this study we test the autophagy inducing effects of the medicinal mushroom Ganoderma lucidum (Reishi) in the patient derived inflammatory breast cancer (IBC) cell line SUM-149 and in the non-cancerous mammary epithelial cell line MCF10A. IBC is a rare, lethal and aggressive form of locally advanced breast cancer that has a poor prognosis and no targeted therapy. Herein, we demonstrate that Reishi modulates the expression of autophagy related molecules depending on treatment time. At 2h post-Reishi treatment SUM-149 cells show that ULK1, Atg5, Atg12, Beclin1 and the microtubule-associated protein 1 light chain 3 (LC3) are α1.2 fold upregulated. Furthermore, autophagosomal structures were identified in SUM-149 but not in MCF10A Reishi treated cells. At 4h post-Reishi Atg5 and Atg12 (required for phagophore formation) are ∼1.5 fold upregulated, while at 6h LC3 expression (involved in autophagosome formation) is ∼2 fold upregulated compared to vehicle. We also show that autophagy induction in SUM-149 cells is mediated via downregulation of the PI3K/mTOR signaling pathway. Reishi downregulates PI3K (p85 and p110), mTOR phosphorylation and reduces the expression of Raptor, which is the regulatory subunit of mTORC1, the complex that directly regulates proteins involved in autophagy. Rictor, the regulatory subunit of the mTORC2 complex, which inhibits autophagy indirectly through Akt is also downregulated by Reishi. We demonstrate that Reishi has great potential to be used as an anti-IBC-therapeutic. This project was sponsored by Title V PPOHA grant number P031M105050 from the US Dept of Education to UCC, and NIH/RCMI 2G12RR003035 to UCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1992. doi:1538-7445.AM2012-1992
Abstract 1996: Anticancer efficacy and mechanism of action of novel ginsenoside 25-OCH3-PPD, a natural product MDM2 inhibitor
Authors: Wang Wei , Wang Hui , Zhang Ruiwen 
Published: August 2012

Abstract
Ginseng and related herbs have been used for various health benefits in over 2000 years. However, their mechanisms of action are not fully understood. In our laboratory, we have been isolating and characterizing ginsenosides as anticancer agents. 20(S)-25-methoxyl-dammarane-3α, 12α, 20-triol (25-OCH3-PPD), a newly identified natural product from Panax notoginseng, has shown activities against a variety of cancer cells in vitro and in vivo. However, the mechanisms of action for the novel anticancer agent are largely unknown. In this study, we discovered a novel mode of action for 25-OCH3-PPD: direct inhibition of the MDM2 oncoprotein. It is well established that the MDM2 oncogene plays a major role in human cancer development and progression. Its tumorigenic properties are associated with both p53-dependent and -independent pathways. We first demonstrated that, in a dose-dependent manner, 25-OCH3-PPD inhibited MDM2 expression in human breast cancer cell lines with different p53 backgrounds, including MCF-7 (p53 wild type and p53 knockout) and MDA-MB-468 (p53 mutate) cells. We further found that 25-OCH3-PPD inhibited MDM2 expression at the transcriptional level, affecting MDM2 promoter activity. We also observed that 25-OCH3-PPD decreased the survival, inhibited proliferation, induced apoptosis and led to G1 cell cycle arrest in the test breast cancer cells. The anti-cancer activities of 25-OCH3-PPD were reduced in MCF7 inducible MDM2-overexpression cells, further supporting the relevance of the MDM2 inhibitory effect to its anti-cancer activity. Moreover, 25-OCH3-PPD inhibited the growth of breast cancer xenograft tumors in vivo which was associated with its MDM2 inhibitory effects. 25-OCH3-PPD demonstrated low toxicity to non-cancer cells, and did not have any observable toxicity in animals. In summary, our preclinical data indicate that 25-OCH3-PPD is a potential therapeutic agent and that further preclinical and clinical development of this agent is warranted. These results also provide an example of a natural product/oncogene interaction as a novel mechanism of action for chemotherapeutic agents. (This work was supported by NIH/NCI grants R01 CA112029 and R01 CA121211 and a grant (BCTR070731) from Susan G Komen for the Cure.)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1996. doi:1538-7445.AM2012-1996
Abstract 2: FGFR3 as a therapeutic target in squamous cell lung carcinoma
Authors: Liao Rachel , Hammerman Peter , Sivachenko Andrey , Greulich Heidi , Getz Gad , Liu Qingsong , Gray Nathanael , Meyerson Matthew 
Published: August 2012

Abstract
Squamous cell lung carcinoma (lung SCC) is the second most common subtype of non-small cell lung cancer with, 40,000 new cases diagnosed every year in the United States. Unlike lung adenocarcinoma, few targetable genomic events are known drivers of lung SCC, and therefore, therapeutic options are limited for patients with this disease. As part of The Cancer Genome Atlas (TCGA) project, we have analyzed the entire coding sequence of 196 lung SCCs for mutated genes which may be amenable to targeted therapeutics. In the 108 patient samples analyzed to date, we have observed mutations in the Fibroblast Growth Factor Receptor 3 (FGFR3) kinase gene in six cases at four sites, or 3% of samples. The observed FGFR3 mutations are present in both the extracellular domain and the kinase domain of the protein, an observation that is consistent with activating mutations in FGFR3 that are known to drive bladder cancer, and in fact, two of the observed mutations are at sites previously observed in bladder cancer. We therefore hypothesized that these mutations are oncogenic and may be driving transformation in a subset of lung SCC patients. Expression of mutated FGFR3 in NIH-3T3 cells led to anchorage-independent colony formation, which was inhibited by treatment with a pan-FGFR inhibitor. A known mechanism of FGFR3 activation is the constitutive dimerization of receptors with mutated extracellular domains via intermolecular disulfide bond formation, and we have observed this phenomenon in our ECD mutants as well. These data suggest that mutations in the FGFR3 gene are sufficient to transform cells. This finding, along with recently published data suggesting that FGFR1 amplification is also able to drive lung SCC development, demonstrates that the FGFR family may be a promising therapeutic target in lung SCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2. doi:1538-7445.AM2012-2
Abstract 2010: Development of a cytotoxic peptide based on the C-terminal domain of Bax
Authors: Boohaker Rebecca , Zhang Ge , Nemec Kathleen , Khaled Annette R. 
Published: August 2012

Abstract
The Bcl-2 family proteins maintain the balance of life and death in a cell. Bax, a pro-apoptotic member, translocates to the mitochondrial membrane in response to diverse death stimuli, initiating a cascade of programmed events that lead to cell death. Tumor progression involves deregulation of this process, in part, through mutations that cause aberrant expression of anti-apoptotic members of the Bcl-2 family that normally sequester and inhibit Bax. This study seeks to identify functional domains of Bax that can be developed into therapeutic peptides to promote the death of cancer cells resistant to existing chemotherapeutics. Our goal was to generate a peptide, much like antimicrobial peptides, that could target and disrupt mitochondrial membranes. To this end, we discovered that the C-terminal, alpha-9 helix of Bax (CT20), when tagged to EGFP or a destabilization domain (DD), could bind mitochondria and cause cell death, mimicking the activity of full-length Bax. Cell death was measured by morphological changes, such as membrane blebbing, as well as DNA fragmentation. Targeted mutagenesis of two adjacent lysines at the carboxyl end of the CT20 peptide demonstrated that these residues enabled mitochondrial membrane association. Expression of the CT20 peptide in the presence or absence of endogenous Bax resulted in cytotoxicity, indicating that the death mechanism engaged could function independently of the Bcl-2 family. These findings suggest the CT20 peptide has the potential to be developed into a viable therapeutic agent in the treatment of a broad range of cancer types.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2010. doi:1538-7445.AM2012-2010