bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4463: Riluzole effectively modulates cell cycle and cell death in a molecularly diverse set of breast cancer cell lines
Authors: Dolfi Sonia C. , Medina Daniel J. , Ganesan Shridar , Vazquez Alexei , Hirshfield Kim M. 
Published: August 2015

Abstract
Metabotropic glutamate receptor 1 (GRM1) has an established oncogenic role in melanoma. Growing evidence supports a similar role in breast cancer. We have previously shown that GRM1 is not only expressed in human breast cancers, but that levels of expression correlate with clinical outcomes with tamoxifen treatment, and that GRM1 knockdown reduces breast cancer cell viability and growth. Others have shown that GRM1 modulating drugs also reduce viability and growth of estrogen receptor (ER) negative breast cancer cell lines. Riluzole, a postulated inhibitor of glutamate release, has been evaluated in pre-clinical studies in melanoma. Early clinical trials have shown promising results for this disease. However, the mechanistic effects of riluzole have not been well-defined. Therefore, we evaluated the functional activity of riluzole in breast cancer.
A molecularly diverse set of ER+ and ER- breast cancer cell lines with variable GRM1 expression were evaluated. Cell lines were treated with either riluzole or BAY 36-7620 (non-competitive GRM1 antagonist) or their combination. Treatment with either drug reduces cell number and viability, inhibits cell proliferation, and alters expression of cell cycle and apoptotic pathway genes as determined by gene microarray analysis. Drug treatment produces cell line-dependent effects on markers for proliferation, cell cycle, DNA damage, and apoptosis. Riluzole induces G2/M arrest in all cell lines tested. More specifically, riluzole induces mitotic arrest as demonstrated by changes in histone H3 phosphorylation at serine 10 and cyclin B level. Treatment with BAY 36-7620 induces a modest G2/M arrest and increase in the sub G1 population in a subset of cell lines. However, BAY 36-7620 does not induce mitotic arrest. The combination of riluzole and BAY 36-7620 results in increased cell death and decreased proliferation in all cell lines tested.
Our data suggest that either riluzole or BAY 36-7620 induce breast cancer cell death. However, riluzole may modulate the activity of intracellular targets independent of GRM1. As riluzole is an FDA-approved drug, it could be quickly moved into a clinical trial and may provide a novel therapeutic approach in the treatment of breast cancer.
Citation Format: Sonia C. Dolfi, Daniel J. Medina, Shridar Ganesan, Alexei Vazquez, Kim M. Hirshfield. Riluzole effectively modulates cell cycle and cell death in a molecularly diverse set of breast cancer cell lines. [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 4463. doi:10.1158/1538-7445.AM2015-4463
Abstract 4474: Dual targeting of the stress-p53 pathway as a potential anti-cancer therapy
Authors: Lu Hua , Zhang Qi , Zeng Shelya X. , Wu Rui-Zhi , Zhang Yiwei , Nguyen Daniel , Zhou Xiang , Liao Jun-ming , Cao Bo 
Published: August 2015

Abstract
The “ribosomal stress (RS)-p53 pathway” is triggered by any stressor or genetic alteration that disrupts ribosomal biogenesis, and mediated by several ribosomal proteins (RPs), such as RPL11 and RPL5, which inhibit MDM2 and activate p53. IMPDH2 is a rate-limiting enzyme in de novo guanine nucleotide biosynthesis and crucial for maintaining cellular guanine deoxy- and ribonucleotide pools needed for DNA and RNA synthesis. It is highly expressed in many malignancies. We previously showed that inhibition of IMPDH2 leads to p53 activation by causing RS. Surprisingly, our current study reveals that Inauzhin (INZ), a novel non-genotoxic p53 activator by inhibiting SIRT1, can also inhibit cellular IMPDH2 activity, and reduce the levels of cellular GTP and GTP-binding nucleostemin that is essential for rRNA processing. Consequently, INZ induces RS and the RPL11/RPL5-MDM2 interaction, activating p53. These results support the new notion that INZ suppresses cancer cell growth by dually targeting SIRT1 and IMPDH2.
Note: This abstract was not presented at the meeting.
Citation Format: Hua Lu, Qi Zhang, Shelya X. Zeng, Rui-Zhi Wu, Yiwei Zhang, Daniel Nguyen, Xiang Zhou, Jun-ming Liao, Bo Cao. Dual targeting of the stress-p53 pathway as a potential anti-cancer therapy. [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 4474. doi:10.1158/1538-7445.AM2015-4474
Abstract 4493: Ironing out breast cancer: investigation of a novel iron chelator
Authors: Greenshields Anna , Hoskin David , Coombs Melanie , Grant Taryn 
Published: August 2015

Abstract
Introduction: Breast cancer is the second leading cause of cancer-related death in women. Current breast cancer therapy is hindered by dose-limiting toxicities, demonstrating the need for less toxic alternatives. As cancer cells have an increased requirement for iron, we hypothesized that iron withdrawal using a highly selective iron chelator (DIBI) developed by Chelation Partners Incorporated (CPI) would enhance breast cancer cell killing by chemotherapeutic drugs and ionizing radiation.
Results: DIBI inhibited the growth of a panel of breast cancer cell lines while similar doses had limited effects on the growth of normal fibroblasts. In breast cancer cells, DIBI-mediated iron chelation increased transferrin receptor 1 mRNA expression and decreased the expression of ferroportin1 mRNA, which is indicative of decreased intracellular iron stores. Iron citrate reversed the inhibitory effect of DIBI, confirming the iron-specific activity of the compound. On the basis of iron-binding capacity, a comparison between DIBI and two conventional iron chelators demonstrated that DIBI was more effective at inhibiting breast cancer cell proliferation. DIBI-treated breast cancer cells showed a dose-dependent reduction in rounds of cell division, as well as arrest in the S-phase of the cell cycle. Higher doses of DIBI also induced apoptosis in breast cancer cells. In addition, DIBI treatment of breast cancer cells induced double-stranded DNA breaks, which are likely important for its anticancer activity. Pretreatment of breast cancer cells with DIBI enhanced the grow-inhibitory effects of ionizing radiation and conventional chemotherapeutic agents, suggesting that DIBI may increase the effectiveness of current breast cancer therapies. Combination treatment with cisplatin and DIBI demonstrated that DIBI enhanced both the cytotoxic and cytostatic anticancer effects of cisplatin.
Conclusion: These findings suggest that selective sequestration of iron from the tumor microenvironment may prevent or diminish tumor progression. In the future, treating patients with this novel iron chelator in combination with conventional therapies may increase the effectiveness of current breast cancer treatments.
Citation Format: Anna Greenshields, David Hoskin, Melanie Coombs, Taryn Grant. Ironing out breast cancer: investigation of a novel iron chelator. [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 4493. doi:10.1158/1538-7445.AM2015-4493
Abstract 4496: Genomics-based resistome analysis revealed endogenous adenosine kinase levels as a chief determinant of specificity for a novel nucleoside analog lymphoma inhibitor
Authors: Nayar Utthara , Reichel Jonathan , Sadek Jouliana , Hernandez-Hopkins Denise , Akar Gunkut , Zhou Hufeng , Sahai Michelle A. , Barelli Peter , Guasparri Ilaria , Totonchy Jennifer , Hassane Duane , Sei Shizuko , Shoemaker Robert H. , Warren J. David , Elemento Olivier , Kaye Kenneth M. , Cesarman Ethel 
Published: August 2015

Abstract
We used KSHV-infected primary effusion lymphoma (PEL) cells as a model to search for novel drugs through a combination of screening and genomic approaches. We discovered 6-ethylthioinosine (6-ETI), a nucleoside analog, as a highly effective and selective inhibitor of PEL. This compound induces necrosis accompanied by S-phase arrest without affecting known oncogenic viral proteins. To understand the selectivity towards PEL, we performed unbiased genomic analysis of 6-ETI-resistant subclones using RNASeq, which revealed that 6-ETI is activated through phosphorylation by cellular adenosine kinase (ADK). PEL cell lines have higher basal levels of ADK than resistant lymphoma cell lines, and resistant lymphoma cell lines could be sensitized by cell crowding-induced ADK upregulation. Finally, 6-ETI was shown to be highly efficacious against incipient and established tumors in a mouse model of PEL, with no apparent toxicity. Thus, we have successfully used RNASeq-based “resistome” analysis to identify the mechanism of specificity for a new and preclinically effective nucleoside analog.
Citation Format: Utthara Nayar, Jonathan Reichel, Jouliana Sadek, Denise Hernandez-Hopkins, Gunkut Akar, Hufeng Zhou, Michelle A. Sahai, Peter Barelli, Ilaria Guasparri, Jennifer Totonchy, Duane Hassane, Shizuko Sei, Robert H. Shoemaker, J. David Warren, Olivier Elemento, Kenneth M. Kaye, Ethel Cesarman. Genomics-based resistome analysis revealed endogenous adenosine kinase levels as a chief determinant of specificity for a novel nucleoside analog lymphoma 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 4496. doi:10.1158/1538-7445.AM2015-4496
Abstract 4505: Activity and avascular penetration of FTY720 (fingolimod) and its non-immune suppressant analogue (OSU2S) within three dimensional tissue culture model of colorectal cancer
Authors: Zaahkouk Samir A. , Elbehairi Serag Eldin I. , El-Sayed Aly F. , Bakry Sayed , Khedr Alaa , Omar Hany A. , Al-Abd Ahmed M. 
Published: August 2015

Abstract
Fingolimod (FTY-720) and its non-immunosuppressive analogue (OSU2S) possess anticancer activity against hepatocellular carcinoma attributed to interference with protein kinase Cδ (PKCδ) signaling. Avascular penetration represents a major limitation for the treatment of solid tumors nonetheless colorectal cancer. Herein, we are assessing the differential antiproliferative activity of OSU2S compared to FTY720 against multicellular spheroids of HCT-116 and HT-29 colorectal cancer cell lines. In addition, we are comparing the avascular penetration properties of OSU2S to FTY720 within the avascular multicellular layers model.
The IC50's of FTY720 and OSU2S were calculated in monolayer and spheroid culture models of HCT-116 and HT-29 cells using Emax model. Generally, OSU2S was found to be 1.5 to 3 folds more potent than FTY720 in both cell lines using monolayer and spheroid culture systems. The ratios between the IC50's of FTY720 in spheroid compared to monolayer cultures of HCT-116 and HT-29 cells were found to be to 5.7 and 3.4 folds, respectively. On the other hand, the ratios between the IC50's of OSU2S in spheroid compared to monolayer cultures of HCT-116 and HT-29 cells were found to be 4.5 and 3.4 folds, respectively. This might be attributed to avascular penetration problem for OSU2S and FTY720 in colorectal cancer. The pre-calculated IC50's of FTY720 and OSU2S induced significant increase in the cleaved fraction of PKCδ in both monolayer and spheroid model in HCT-116 and HT-29 cells. The influence of FTY720 and OSU2S on cell cycle analysis was studied using DNA flow cytometry analysis. Both FTY720 and OSU2S changed the cell cycle distribution of both HCT-116 and HT-29 cell lines in the monolayer culture and to a lesser extent in the spheroid culture model. The avascular penetration of OSU2S through multicellular layers of HCT-116 was 1.9 and 1.2 fold faster than FTY720 after 12 and 24 h of penetration, respectively. Also, OSU2S was faster than FTY720 in penetrating multicellular layers of HT-29 by 2.1 to 1.7 folds after 12 and 24 h of penetration, respectively. In conclusion, OSU2S possess better antiproliferative and avascular penetration profile within colorectal cancer cells compared to FTY720.
Citation Format: Samir A. Zaahkouk, Serag Eldin I. Elbehairi, Aly F. El-Sayed, Sayed Bakry, Alaa Khedr, Hany A. Omar, Ahmed M. Al-Abd. Activity and avascular penetration of FTY720 (fingolimod) and its non-immune suppressant analogue (OSU2S) within three dimensional tissue culture model of 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 4505. doi:10.1158/1538-7445.AM2015-4505
Abstract 4538: Multivalent targeting based delivery of therapeutic peptide using AP1-ELP carrier for effective cancer therapy
Authors: Devi Sarangthem V. , Kim Yun Jae , Lee Young-Jin , Hur Kuen , Lee Byung-Heon , Park Rang Woon 
Published: August 2015

Abstract
The main objectives of drug delivery for almost all cancer therapies are to improve the therapeutic index of anticancer drugs by increasing the amount of drug delivered to the specific tumor site and decreasing its exposure to healthy tissues. Elastin like Polypeptides (ELPs) retain all the advantages of polymeric drug delivery systems, as they are composed of non-toxic and biodegradable amino acid, derived from mammalian tropoelastin. IL-4 receptors (IL-4R) are found to be highly expressed in a wide variety of human tumors and studies have reported that IL-4/IL-4R interactions amplify the expression of some anti-apoptotic proteins, so prevent drug-induced cancer cell death. Thus we have designed multivalent IL-4R targeted based macromolecular carriers, AP1-ELP polymers, in order to examine the therapeutic efficacy in delivering the therapeutic peptide (KLAKLAK)2 to tumor cells. As for the study AP1-ELP polymer, containing six IL-4R binding peptide (AP1) was conjugated with proapoptotic peptide (KLAKLAK)2 on the C-terminal site by cloning. The resultant AP1-ELP-(KLAKLAK)2 construct was successfully expressed and purified from E coli using inverse temperature cycling method. Confocal imaging verified the better cellular accumulation of AP1-ELP-(KLAKLAK)2 in IL-4R highly expressing cancer cells. The cytotoxic effect towards IL-4R highly expressing tumor cells were highly enhanced when treated with AP1-ELP-(KLAKLAK)2 compared to control. FACS analysis data confirmed the significant increase of apoptotic cells when treated with AP1-ELP-(KLAKLAK)2 compared to ELP-(KLAKLAK)2 in dose dependent manner. Ex vivo biodistridution study displayed an increase in intra-tumoral uptake and localization of FNR-675 labeled AP1-ELP-(KLAKLAK)2 than ELP-(KLAKLAK)2. Additionally, AP1-ELP-(KLAKLAK)2 significantly inhibit the tumor growth when injected intravenously in MDA-MB 231 xenograft mouse model. Thus AP1-ELP-(KLAKLAK)2 polymer enhanced apoptotic and antitumor activity against IL-4R highly expressing tumor cells suggesting the clinical potential of our polymer.
Citation Format: Sarangthem V. Devi, Yun Jae Kim, Young-Jin Lee, Kuen Hur, Byung-Heon Lee, Rang Woon Park. Multivalent targeting based delivery of therapeutic peptide using AP1-ELP carrier for effective cancer therapy. [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 4538. doi:10.1158/1538-7445.AM2015-4538
Abstract 4539: Nitroxide-aspirin conjugates: A new class of NSAIDs
Authors: Moody Terry W. , Jensen Robert T. , Thomas Komba , Fairfull-Smith Kathryn E. , Bottle Steven E. , Ridnour Lisa , Wink David A. 
Published: August 2015

Abstract
Novel nitroxide-aspirin conjugates were synthesized and tested using human lung cancer cell lines. Previously, cyclooxygenase (COX2) was found to be elevated in lung cancer biopsy specimens relative to normal tissue (He et al., 2012; PlosOne 7:e31087). Lung cancer cellular proliferation is inhibited by nonsteroidal anti-inflamatory drugs (NSAIDs) such as indomethacin and aspirin (Hida et al., 1998; Anticancer Res. 18: 775). Dithiolethione-valproate conjugates inhibit COX-2 activity, increase E-cadherin expression and decrease the proliferation of non-small cell lung cancer (NSCLC) cells (Moody et al., 2010, Lung Cancer 68: 154). Here the effects of nitroxide-aspirin conjugates were investigated on NSCLC cells. 1KT121A, a 4-carboxy Tempo-aspirin conjugate, inhibited the proliferation of NCI-H1299 or A549 cells with IC50 values of 125 uM using the MTT assay whereas aspirin and tempol had IC50 values of 750 and &gt;1000 uM, respectively. 1KT121A, which has an ester link, was approximately 5-fold more potent at inhibiting NSCLC cellular proliferation than aspirin plus tempol or 2KT106A, which is a Tempo-aspirin conjugate with an amide link. 1KT121A was more potent than 2KT106A or tempol plus aspirin at reducing prostaglandin E2 levels in A549 cells. Similar results were obtained if the nitroxide moiety was changed from 4-carboxy Tempo to 3-carboxy proxyl or 5-carboxy-1,1,3,3-tetramethylisoindolin-yloxyl (CTMIO). 1KT121A potentiated the ability of gefitinib, an EGF receptor tyrosine kinase inhibitor, to kill NSCLC cells. Because 1KT121A increased E-cadherin and reduced vimentin, it may impair epithelial-mesenchymal transitions of NSCLC cells. All of the nitoxide analogues were antioxidants based on the ability to inhibit reactive oxygen species in NSCLC cells treated with hydrogen peroxide. Nitroxide-aspirin conjugates represent a novel class of NSAIDs which are antioxidants that inhibit NSCLC proliferation.
Citation Format: Terry W. Moody, Robert T. Jensen, Komba Thomas, Kathryn E. Fairfull-Smith, Steven E. Bottle, Lisa Ridnour, David A. Wink. Nitroxide-aspirin conjugates: A new class of NSAIDs. [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 4539. doi:10.1158/1538-7445.AM2015-4539
Abstract 4543: Characterization of the liposomal formulation of eribulin mesylate (E7389) in mice
Authors: Asano Makoto , Hyodo Kenji , Yu Yanke , Schuck Edgar , Matsui Junji , Ishihara Hiroshi , Kikuchi Hiroshi , Nomoto Kenichi 
Published: August 2015

Abstract
E7389 (eribulin mesylate, Halaven, Eisai) is a fully synthetic analog of the marine sponge natural product halichondrin B. It has been approved in US and more than 50 countries worldwide for treatment of advanced breast cancer. To improve the therapeutic index of E7389, a liposomal formulation of E7389, E7389-LF is under development. In this study, we characterized the pharmacokinetics of E7389-LF and E7389 (aqueous formulation) in mice and evaluated the anti-tumor activity of E7389-LF and E7389 in mouse xenograft model. In general the pharmacokinetics of E7389-LF was characterized by a small volume of distribution, slow clearance, and slow elimination in all liposomal formulations tested. Plasma AUC of E7389-LF was more than 600 fold larger than that of E7389 in tumor bearing mice. Tumor AUC of E7389-LF was also observed. Moreover, free E7389 (not liposome encapsulated and not protein bound) was measured in mouse plasma by ultracentrifugation method. The concentration ratio of E7389 in ultracentrifuged mouse plasma (UCM) vs E7389 in plasma after a 2 mg/kg i.v. of E7389 ranged from 54.19% to 65.41%, which was similar to the free fraction in the mouse plasma. The respective concentration ratio of E7389 in UCM vs E7389 in plasma after a 2 mg/kg i.v. of E7389-LF ranged from 0.07% to 0.59%, and the exposure, expressed as AUC, of UCM/plasma ratio was determined to be 0.2%. The free E7389 exposure, measured by UCM, after E7389-LF administration was about 1.5 fold of that after E7389 administration. Anti-tumor activity of E7389-LF and E7389 was evaluated in a human pharynx carcinoma, FaDu, xenograft model. E7389-LF showed dose-dependent anti-tumor effect with regression of tumors at 2.5 mg/kg dose, which was significantly better than that after E7389 administration in this model. These findings suggest that E7389-LF showed better anti-tumor activity than that of E7389 in human FaDu xenograft mouse model.
Citation Format: Makoto Asano, Kenji Hyodo, Yanke Yu, Edgar Schuck, Junji Matsui, Hiroshi Ishihara, Hiroshi Kikuchi, Kenichi Nomoto. Characterization of the liposomal formulation of eribulin mesylate (E7389) in mice. [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 4543. doi:10.1158/1538-7445.AM2015-4543
Abstract 4552: Apatorsen enhances 5-FU sensitivity in colon cancer cell SW480
Authors: Shimada Takehiro , Tsuruta Masashi , Akimoto Shingo , Koishikawa Kaoru , Okabayashi Koji , Hasegawa Hirotoshi , Kitagawa Yuko 
Published: August 2015

Abstract
[Background] Heat Shock Protein (HSP) 27 is a chaperone protein of small molecular weight, which protects cells in response to various stresses. Previously we elucidated that HSP27 was a key molecule in determining 5-Fluorouracil (5-FU) resistance in colorectal cancer (CRC). Thus, apatorsen, an antisense oligonucleotide that suppresses HSP27 levels intracellularly, might overcome 5-FU resistance in CRC. In this basic research, we evaluated the feasibility of adding apatorsen with 5-FU against CRC.
[Methods] Human CRC cell line SW480 was treated with apatorsen (1nM, 10nM, 100nM) for 48 hours continuously. HSP27 protein level was determined by immunoblot and densitometry analysis. Next, the cells were exposed by various concentrations of 5-FU for 48 hours following treatment with apatorsen. The in vitro growth inhibition rates (IR) were assessed by MTT assay and we evaluated the change of 5-FU resistance, which was estimated as the drug concentration inducing 50% IR (IC50).
[Results] Apatorsen (0, 1, 10, 100nM) successfully suppressed HSP27 protein levels (100, 86.6, 61.0, 50.5%) in a dose-dependent manner. In cell viability assays, apatorsen changed the IC50 of 26.65μg/ml in control into 15.55 (58.3%), 11.28 (42.3%), and 9.18 (34.4%) respectively.
[Summaries] Apatorsen significantly enhanced 5-FU sensitivity in the CRC cell line SW480 by suppressing HSP27 levels. HSP27 may serve as a reliable target in enhancing 5-FU chemotherapy for CRC. Therefore, apatorsen is a promising treatment requiring further investigation.
Citation Format: Takehiro Shimada, Masashi Tsuruta, Shingo Akimoto, Kaoru Koishikawa, Koji Okabayashi, Hirotoshi Hasegawa, Yuko Kitagawa. Apatorsen enhances 5-FU sensitivity in colon cancer cell SW480. [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 4552. doi:10.1158/1538-7445.AM2015-4552