bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1659: Characterizing cytokine secretion in response to dsRNA treatment in ovarian cancer cells
Authors: Muccioli Maria , Pate Michelle , Benencia Fabian 
Published: May 2015

Abstract
Ovarian cancer exhibits the lowest long-term survival rates amongst all gynecological cancers, warranting more research directed at finding novel therapies, especially for late-stage disease. Inflammation is known to affect cancer progression, with tumor-promoting or repressive effects possible in different contexts, where the types of leukocytes at the tumor site are heavily implicated in disease prognosis. Tumor-associated macrophages and T-regulatory cells, for example, are known to promote tumor growth by inhibiting the anti-cancer response and by secreting pro-angiogenic factors. Importantly, the specific processes and cellular signaling pathways leading up to leukocyte infiltration in different cancer types remain to be fully elucidated. We hypothesize that dsRNA in the vicinity of ovarian cancer cells (such as from a viral infection or cellular debris) can activate pro-inflammatory regulators in tumor cells, in particular the NF-KB transcription factor, the aberrant over-activation of which is implicated in many cancers. NF-KB activation results in increased production and secretion of numerous cytokines that can in turn recruit pro-angiogenic leukocytes to the tumor microenvironment, thus favoring cancer progression. Herewith, we evaluated the production of numerous cytokines after dsRNA treatment in mouse and human ovarian cancer cells. Additionally, we determined which of the four known dsRNA receptors contributes most to this process. Consistently with our hypothesis, we have shown an increase in several pro-inflammatory cytokines (eg. CCL5 and IL6) in response to dsRNA treatment in both human and mouse ovarian cancer cell lines. We have also determined that the dsRNA receptor MDA5 contributes the most to dsRNA-induced cytokine secretion in both human and mouse ovarian cancer cell lines employing siRNA-directed knock-down of each receptor. Altogether, these data suggest that dsRNA-induced signaling in ovarian cancer cells may facilitate a tumor-favoring environment; thus dsRNA-sensing receptors may constitute attractive therapeutic targets for cancer immunotherapy. Further studies in our lab will determine the specific signaling pathways responsible for the upregulated cytokines as well as use a mouse model to examine the effect of dsRNA receptor knock-down in the cancer cells on tumor growth, angiogenesis, and the leukocyte infiltration profile.
Citation Format: Maria Muccioli, Michelle Pate, Fabian Benencia. Characterizing cytokine secretion in response to dsRNA treatment in ovarian cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1659. doi:10.1158/1538-7445.AM2014-1659
Abstract 1673: Alternative NF-κB signaling promotes inflammatory cell recruitment and lung tumor formation
Authors: Ausborn Jamie Alicyn , Cheng Dong-Sheng , Polosukhin Vasiliy , Han Wei , Yull Fiona , Blackwell Timothy 
Published: May 2015

Abstract
Nuclear factor-κB (NF-κB) is a transcription factor that can be activated through either the classical or alternative signaling pathways. In lung tumors, high levels of classical and alternative pathway components have been observed. While many studies have demonstrated that classical NF-κB signaling is a central pathway regulating inflammation and tumorigenesis, the role of alternative NF-κB signaling remains undefined. We hypothesize that alternative NF-κB signaling in the lung epithelium plays a key role in inflammation and lung tumor formation through paracrine signaling to the inflammatory microenvironment. To investigate alternative NF-κB signaling in the lung epithelium, we generated a transgenic mouse model with doxycycline (dox)-inducible expression of the alternative pathway component p52 in airway epithelial cells (designated ALTA for alternative pathway trans-activated). When placed on dox, nuclear p52 is increased in the lungs of ALTA mice with no effect on activation of other NF-κB components. Surprisingly, alternative pathway activation alone did not cause a significant increase in inflammatory cell recruitment. However, in conjunction with the inflammatory stimulus lipopolysaccharide (LPS), alternative pathway activation caused increased mortality, which was associated with a significant increase in inflammation and increased lung permeability. To determine the effect of alternative pathway activation on lung tumor formation, mice were injected with the lung carcinogen urethane. Six weeks after urethane administration, ALTA mice demonstrated an increased number of bronchoalveolar lavage neutrophils, and by 6 months post-urethane, ALTA mice had an increased number of tumors, increased tumor size, and more advanced lesions. Together, these data suggest that alternative NF-κB signaling plays an important role in stimulus-induced inflammatory cell recruitment and that alternative pathway activation can promote lung tumor formation and progression. By defining the role of alternative NF-κB signaling in tumor formation, we hope to gain insight into the role of inflammation in lung carcinogenesis and to identify novel pathways and signaling targets that could potentially serve as therapeutic targets.
Citation Format: Jamie Alicyn Ausborn, Dong-Sheng Cheng, Vasiliy Polosukhin, Wei Han, Fiona Yull, Timothy Blackwell. Alternative NF-κB signaling promotes inflammatory cell recruitment and lung tumor formation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1673. doi:10.1158/1538-7445.AM2014-1673
Abstract 1688: Overcoming drug resistance to gemcitabine in pancreas cancer cells by targeting activated PI3K/mTOR pathway
Authors: Murakami Yuichi , Shinoda Ai , Watari Kosuke , Nabeshima Hiroshi , Kawahara Akihiko , Nagayama Daisuke , Naito Yoshiki , Higaki Koichi , Inoue Masako , Kuwano Michihiko , Ono Mayumi 
Published: May 2015

Abstract
Pancreas cancer is one of the most difficult neoplasms to treat curatively and 5-year survival rate is only 5%. Gemcitabine, a difluorinated deoxycitidine, has been first reported to improve pancreas cancer both response rate and median overall survival of patients with pancreas cancer. Treatment with combination of gemcitabine and erlotinib was reported to prolong survival compared with gemcitabine alone against pancreas ductal adenocarcinoma, but its benefit is modest. Further development of potent combination therapeutics with gemcitabine should be very useful for treatment of pancreas cancer.
In our present study, we examined whether the cytotoxic effect of gemcitabine could be potentiated when combined with other anticancer drugs including molecular targeted drugs and cytotoxic anticancer agents, and also whether such combination could overcome drug resistance to gemcitabine. We observed following findings [1]We first screened various anticancer agents that could synergistically potentiate cytotoxic effect of gemcitabine against pancreas cancer cell lines in culture, and observed that mTOR inhibitors, such as rapamycin, everolimus and AZD8055, synergistically enhanced the anti-proliferative effect of gemcitabine. [2] PI3K/mTOR/S6K-driven signaling pathway for de novo pyrimidine biosynthesis was markedly blocked when combined with gemcitabine and mTOR inhibitors. [3] We also observed that mTOR/S6K-driven de novo pyrimidine synthetic pathway was markedly activated in drug-resistant cancer cells as compared to their parental cell line. [4] Immunohistochemical analysis of clinical samples derived from resected pancreas tumors showed that mTOR was highly expressed in progressive pancreas cancer. Combination of gemcitabine and drugs targeting mTOR-driven signaling pathway will further provide potent therapeutics against both gemcitabine-sensitive and -resistant pancreas cancer. Furthermore, personalized therapeutics against pancreas cancer patients by this combination will be discussed based on expression levels of activated PI3K/mTOR/S6K in tumors.
Citation Format: Yuichi Murakami, Ai Shinoda, Kosuke Watari, Hiroshi Nabeshima, Akihiko Kawahara, Daisuke Nagayama, Yoshiki Naito, Koichi Higaki, Masako Inoue, Michihiko Kuwano, Mayumi Ono. Overcoming drug resistance to gemcitabine in pancreas cancer cells by targeting activated PI3K/mTOR pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1688. doi:10.1158/1538-7445.AM2014-1688
Abstract 1689: Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma
Authors: Lee Dhong Hyun Tony , Qi Jun , Bradner James , Said Jonathan , Doan Ngan , Forscher Charles , Koeffler H Phillip 
Published: May 2015

Abstract
Bromodomain and extra terminal domain (BET) proteins are important epigenetic regulators facillitating the transcription of genes in chromatin areas linked to acetylated histones. JQ1, a BET protein inhibitor, has antiproliferative activity againts many hematological and solid cancers, mainly through inhibition of c-myc and upregulation of p21. In this research, we investigated the use of JQ1 for human osteosarcoma (OS) treatment, due to the frequent copy number gain and overexpression of c-myc in OS cells. JQ1 significantly inhibited the proliferation and survival of seven OS cells (U2OS, G292, MG-63, HT-161, MNNG/HOS, SAOS-2, SJSA), at a relatively higher dose than other cancers (median IC50 = 7.35 μM). JQ1 induced G1 cell cycle arrest and premature senescence of OS cells, but produced little apoptosis. Interestingly, c-myc protein levels in JQ1-treated cells remained unchanged, whereas the upregulation of p21 protein was still observable, as noted by Western blots. Although effective in vitro, JQ1 failed to reduce the size of the MNNG/HOS xenografts in immunocompromised mice in vivo.
To overcome the resistance of OS cells to JQ1 treatment, we tested JQ1 in combination with rapamycin. Rapamycin inhibits the assembly of mTOR complexes which is one of the important growth signaling pathways in many cancers including OS. JQ1 and rapamycin synergistically inhibited the growth and survival of OS cells in vitro. The drug combination nearly abrogated expression of c-myc protein, enhanced levels of p21, and induced apoptosis in OS cells in vitro. After 24 days of treatment in vivo, JQ1 (50mg/kg body weight) or rapamycin (1.5 mg/kg body weight) alone showed little effect on the size of human OS xenografts in nude mice. However, combination of both drugs significantly inhibited tumor growth by 85% and 73% (p&lt;0.05 for both) compared to either JQ1 or rapamycin alone, respectively.
In conclusion, JQ1 inhibited proliferation and survival of OS cells in vitro but failed to reduce growth of OS xenografts in immunodeficient mice. When combined with rapamycin, JQ1 synergistically inhibited proliferation of OS cells both in vitro and in vivo.
Citation Format: Dhong Hyun Tony Lee, Jun Qi, James Bradner, Jonathan Said, Ngan Doan, Charles Forscher, H Phillip Koeffler. Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1689. doi:10.1158/1538-7445.AM2014-1689
Abstract 1698: Identification of drugs with eribulin combinatorial activity that kill both eribulin-sensitive and eribulin-insensitive tumor cells
Authors: Uenaka Toshimitsu , Rickles Richard , Funahashi Yasuhiro , Zhu Ping , Grenier Jill M. , Steiger Janine , Zhao Nanding , Littlefield Bruce A. , Matsui Junji , Nomoto Kenichi 
Published: May 2015

Abstract
Eribulin mesylate, a nontaxane microtubule dynamics inhibitor with a mechanism distinct from most other antitubulin therapeutics, is clinically used in the United States for treatment of certain patients with locally advanced or metastatic breast cancer. Eribulin has broad anticancer activity in a wide variety of preclinical cancer models; as a result, numerous clinical trials are ongoing to investigate efficacy in other non-breast tumor types. We have examined eribulin sensitivity in a panel of 25 human cancer cell lines representing a variety of tumor types albeit with a preponderance of breast and lung cancer cell lines. As expected, the cell lines vary in sensitivity to eribulin at clinically relevant concentrations. To identify combination drugs capable of increasing anticancer effects in patients already responsive to eribulin, as well as inducing de novo anticancer effects in non-responders, we performed a combinatorial high throughput screen to identify drugs that combine with eribulin to selectively kill tumor cells. Among other observations, we found that inhibitors of ErbB1/ErbB2 (lapatinib, BIBW-2992, erlotinib), MEK (E6201, trametinib), PI3K (BKM-120), mTOR (AZD 8055, everolimus), and PI3K/mTOR (BEZ 235), and a BCL2 family antagonist (ABT-263) show combinatorial activity with eribulin. In addition, antagonistic pairings with other agents, such as topoisomerase I inhibitors (topotecan hydrochloride), an HSP-90 inhibitor (17-DMAG), and gemcitabine and cytarabine, were also identified. In summary, the preclinical studies described here have identified several combination drugs that have the potential to either augment or antagonize eribulin's anticancer activity. Further elucidation of the mechanisms responsible for such interactions may be important for identifying valuable therapeutic partners for eribulin.
Citation Format: Toshimitsu Uenaka, Richard Rickles, Yasuhiro Funahashi, Ping Zhu, Jill M. Grenier, Janine Steiger, Nanding Zhao, Bruce A. Littlefield, Junji Matsui, Kenichi Nomoto. Identification of drugs with eribulin combinatorial activity that kill both eribulin-sensitive and eribulin-insensitive tumor cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1698. doi:10.1158/1538-7445.AM2014-1698
Abstract 17: Hepatitis C virus (HCV) core protein potentiates proangiogenic activity of hepatocellular carcinoma (HCC) cells
Authors: Shao Yu-Yun , Huang Chung-Yi , Chen Jun-Wei , Hsu Chih-Hung , Cheng Ann-Lii 
Published: May 2015

Abstract
Background: Recent clinical trials found that sorafenib may have better efficacy for HCV-related HCC than HCC with other etiologies. HCV core protein has been found to influence the mitogen-activated protein kinase pathway, which is one of the targets of sorafenib. We thus planned this study to examine the effect of HCV core protein overexpression on HCC cells.
Methods: We stably expressed HCV core protein in Huh7, a HCC cell line, using a lentivirus based vector S2. Two stable clones were selected for experiments. One clone (Huh7-core-high) expressed a higher amount of HCV core protein than the other (Huh7-core-low). Huh7 expressing the empty vector (Huh7-S2) served as a control. We compared the cytotoxicity of sorafenib in these cells using the MTT assay. Tube formation analysis and Matrigel plug assay were performed to evaluate the angiogenic activity.
Results: Huh7-core-high and Huh7-core-low cells did not show increased cell proliferation compared to Huh7-S2 cells. Sorafenib showed similar in vitro cytotoxicity for Huh7-core-high, Huh7-core-low, and Huh7-S2 cells. Overexpression of HCV core protein potentiates proangiogenic activity of Huh7 cells dose-dependently. In tube formation analysis, Huh7-core-high induced more potent angiogenesis than Huh7-S2 cells with more total tube lengths (p = 0.02), mean tube lengths (p = 0.04), mean tube areas (p = 0.04), branch points (p = 0.03), and nodes (p &lt; 0.01). Huh7-core-low cells induced stronger angiogenesis than Huh7-S2 cells with more total tube lengths (p = 0.05) and branch points (p = 0.01). By Matrigel plug assay, Huh7-core-high and Huh7-core-low cells dose-dependently induced stronger angiogenesis in mice compared to Huh7-S2 cells with significantly higher hemoglobin levels in the Matrigel plugs.
Conclusions: HCV core protein expression potentiates the proangiogenic activity of HCC, both in vitro and in vivo. (This work was supported by grants NSC98-3112-B-002-038, NSC101-2314-B-002-141, 100CAP1020-2 & 102-2314-B-002-120.)
Citation Format: Yu-Yun Shao, Chung-Yi Huang, Jun-Wei Chen, Chih-Hung Hsu, Ann-Lii Cheng. Hepatitis C virus (HCV) core protein potentiates proangiogenic activity of hepatocellular carcinoma (HCC) cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 17. doi:10.1158/1538-7445.AM2014-17
Abstract 1700: A combination of two tropical spice compounds potentiates chemotherapy response in castration-resistant prostate cancer cells
Authors: Mendha Taaha A. , Nagarajarao Shamaladevi , Lokeshwar Balakrisha L. 
Published: May 2015

Abstract
Introduction: Patients with castration resistant advanced prostate cancer (CRPC) respond poorly to potent chemotherapeutic drugs (e.g., Docetaxel or Mitoxantrone) with survival advantages that last less than 4 months. Since chemotherapy itself has morbidity in the elderly patients, adding another such drug is unlikely to improve the outcome. We investigated the potential therapeutic benefits of treating CRPC with a combination of two natural dietary anti-proliferative compounds: Curcumin and Piperine. They are derived from the tropical spices, turmeric and black pepper, respectively. Both are orally bioavailable and can be consumed over a long period of time.
Materials and methods: The cytotoxicity of Curcumin, Piperine, and Docetaxel were individually tested on a CRPC cell line PC-3, which was incubated for 48 hours or 72 hours. Cytotoxicity was evaluated by cell counting, a colorimetric assay and by clonogenic survival, colony-formation assay. Enhancement of Docetaxel cytotoxicity by natural compounds was evaluated by treating cells with these compounds 24 hours before adding Docetaxel or with co-incubation. The potential mechanism of cytotoxicity was examined by an apoptosis assay and changes in cell cycle phase-fractions. The efficacy of the combination was evaluated by Isobologram analysis and ANOVA.
Results: All three drugs tested on PC-3 showed cytotoxicity, Docetaxel was the most cytotoxic (IC50∼ 25 nM) and Piperine was the least cytotoxic (IC50∼ 100 μM). Curcumin alone was significantly cytotoxic to PC-3 cells at 10 μM but it enhanced the cytotoxicity of Docetaxel. Piperine, when combined with Curcumin or Docetaxel, significantly increased the cytotoxicity by 50%. Prior exposure to Piperine resulted in enhanced cytotoxicity of Docetaxel and Curcumin more than when in co-incubation. The increased cytotoxicity in combination therapy was mainly due to increased apoptotic activity.
Conclusion: This study demonstrated that combining diet-derived antiproliferatinve compounds with a chemotherapy drug can potentially enhance tumoricidal activity and therefore, potentially reduce morbidity and mortality of patients with CRPC. Pretreatment with dietary compounds could potentially enhance subsequent treatment with chemotherapy agents.
Citation Format: Taaha A. Mendha, Shamaladevi Nagarajarao, Balakrisha L. Lokeshwar. A combination of two tropical spice compounds potentiates chemotherapy response in castration-resistant prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1700. doi:10.1158/1538-7445.AM2014-1700
Abstract 1701: A synthetic flavonoid abrogates doxorubicin resistance through inhibition of focal adhesion kinase and P-glycoprotein activity in breast cancer cells
Authors: Datta Amrita , Rider Barbara J. , Elmageed Zakaria Y. Abd , Kim Hogyoung , Mondal Debasis , Mageed Asim B. Abdel 
Published: May 2015

Abstract
Chemotherapy is a mainstay in the treatment of breast cancer. FDA approved, Doxorubicin (Dox) is considered to be the most effective chemotherapeutic agent for the treatment of solid tumors like breast cancer. However, resistance to Dox impairs successful treatment. The increased expression of multidrug-resistance P-glycoprotein (P-gp) pump that constantly efflux drugs, such as Dox, is a well documented mechanism of resistance.
Flavonoids as a class have been implicated in the inhibition of ABC transporters such as BCRP, P-gp and MRP-1, have potent anxiolytic activity, protect against anthracycline induced cardiotoxicity, and improve general health.
Our current study proposes to examine the efficacy of a synthetic flavonoid, SF as a chemotherapeutic agent alone and in combination with Dox in a xenograft nude mouse model and to delineate the specific molecular targets involved. Treatment with a combination of Dox and SF lead to significant cell death in the Dox resistant, MCF-7/Dox cells as compared to treatment with Dox alone. In vivo studies using a xenograft nude mouse model corroborated these findings. Also, mice treated with SF alone and in combination with Dox showed improved overall health. SF also inhibited P-gp pump activity and increased Dox sequestration in cancer cells, leading to chemosensitization. Moreover, SF alone or in combination with Dox caused remarkable de-phosphorylation of constitutively active FAK(Focal Adhesion Kinase) in MCF-7/Dox cells. In conclusion, our study beings forth an excellent prototype candidate, SF- as an anti-tumor agent with little to no toxicity and provides new insights into previously uncharacterized mechanisms for the anti-cancer activity of SF alone and in combination with Dox in resistant breast cancer cells. The desirable traits of endowed pleiotropic activities, safety, synergistic action with therapeutic agents make SF attractive for clinical use.
Citation Format: Amrita Datta, Barbara J. Rider, Zakaria Y. Abd Elmageed, Hogyoung Kim, Debasis Mondal, Asim B. Abdel Mageed. A synthetic flavonoid abrogates doxorubicin resistance through inhibition of focal adhesion kinase and P-glycoprotein activity in breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1701. doi:10.1158/1538-7445.AM2014-1701