bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4456: Prevention of MICA shedding from HBV infected hepatocytes to activate NK cells for better clearance of malignant foci and virus-infected cells
Authors: Ohno Motoko , Otsuka Motoyuki , Kishikawa Takahiro , Yoshikawa Takeshi , Takata Akemi , Koike Kazuhiko 
Published: August 2015

Abstract
Introduction: Hepatocellular carcinoma (HCC) is an important issue to public health of the world. By a genome-wide association study, we previously identified that a single nucleotide polymorphism (SNP) in the promoter region of the MHC class I polypeptide-related sequence A (MICA) gene is significantly associated with the risk of hepatitis-virus-related HCC. MICA is a ligand for NKG2D, a cell receptor of NK cells, which activates NK cells to clear the pathogenic cells expressing MICA such as infected cells or malignant cells as a “danger” signal. However, unexpectedly, the Hepatitis B virus (HBV)-infected patients with risk allele of MICA gene showed higher levels of serum MICA. This suggested that the serum MICA, which is excreted from the infected hepatocytes by a shedding mechanism, may work as a decoy for NK cells and inhibit their activities. Therefore, increasing cellular MICA levels by preventing those shedding and release may contribute to the clearance of the pathogenic cells and the prevention of HCC. In this study, we constructed a convenient MICA shedding assay system and, by a comprehensive screening, we identified several compounds which may prevent MICA shedding from the cells.
Methods: We constructed lentivirual vector expressing MICA protein tagged with nano-luciferase (nanoLuc) in its N terminal because N terminal of MICA is excreted from the cells by shedding. We expressed this construct in HBV replicating cells, HepG2.2.15, and after adding compounds, we determined the luciferase activities in the supernatant and cell lysates.
Results: We picked up the samples which showed low activities in supernatant with high activities in the cell lysates, indicating low levels of shedding and high levels of remaining cellular MICA. Out of over 1,000 compounds screened, we determined four candidate compounds which efficiently prevented MICA shedding. We confirmed the effects of these compounds in other cell systems infected with HBV.
Conclusion: Because these compounds enhanced the expression levels of cellular MICA and decreased its shedding in HBV-replicating human hepatocytes, using these compounds may be favorable during HBV chronic infection to enhance the NK cell-mediated clearance of the pathogenic hepatocytes and to prevent HCC.
Citation Format: Motoko Ohno, Motoyuki Otsuka, Takahiro Kishikawa, Takeshi Yoshikawa, Akemi Takata, Kazuhiko Koike. Prevention of MICA shedding from HBV infected hepatocytes to activate NK cells for better clearance of malignant foci and virus-infected 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 4456. doi:10.1158/1538-7445.AM2015-4456
Abstract 4464: Effect of bacterial quorum sensing lactones on human pancreatic carcinoma cells
Authors: Kumar Senthil R. , Bryan Jeffrey 
Published: August 2015

Abstract
INTRODUCTION
Pancreatic cancer (PC) is the fourth leading cause of cancer related mortality in the United States. In spite of the discovery of gemcitabine, administered either alone or in combination with other drugs, the survival rate of 5% has remained unchanged for several decades now. In this study, we hypothesize that bacterial quorum sensing molecules such as N-3-oxo-dodecanoyl-L-homoserine lactone (O-DDHSL) could affect pancreatic carcinoma cell phenotype and characteristics. Elucidation of the mechanism of action of O-DDHSL could lead to the development of more effective analogs and novel therapeutic targets in PC.
MATERIALS AND METHODS
Human pancreatic carcinoma cells (Panc-1 and Aspc-1) was grown in DMEM-F12 media with 10% FBS at 37oC. Normal pancreatic ductal epithelial cells (HPDE) were maintained in keratinocyte serum free media. Total RNA was extracted from the cells and converted to cDNA which served as a template for qRT-PCR amplification in the presence of various gene primers. The effect of O-DDHSL on pancreatic carcinoma cell phenotype, apoptosis, viability, migration, proliferation and colony forming ability was investigated.
RESULTS
Both Panc-1 and Aspc-1 cell viability decreased in a concentration dependent manner in the presence of O-DDHSL (IC50 = 120 ± 5 μM; P ≤ 0.02) and (IC50 = 48 ± 8 μM; P ≤ 0.02), respectively. O-DDHSL had only minimal effect on HPDE cell viability. Apoptosis and inhibition of cell migration in Panc-1 and Aspc-1 cells was observed in the presence of O-DDHSL. Variable effect on migration associated genes such as IQGAP-1, cofilin and rhoC was noted in these cells upon O-DDHSL treatment as determined by qRT-PCR as well as protein expression by Western analysis.
CONCLUSIONS
In conclusion, the combined findings from our study demonstrate that O-DDHSL decreases pancreatic carcinoma cell viability, promotes apoptosis by activating caspases, and inhibits cell migration. O-DDHSL also modulates genes responsible for migration such as RhoC, cofilin and IQGAP-1 in these cells.
Citation Format: Senthil R. Kumar, Jeffrey Bryan. Effect of bacterial quorum sensing lactones on human pancreatic carcinoma 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 4464. doi:10.1158/1538-7445.AM2015-4464
Abstract 4466: New biomarkers to optimize preclinical development of the PDI inhibitor XCE853
Authors: Prevost Gregoire Pierre , Garrido Marine , Xu Shili , Lefebvre Celine , Chauchereau Anne , Carniato Denis , Briand Jean François , Gutmann Mathieu , Serova Maria , Tijeras-Raballand Annemilai , De Grammont Armand , Raymond Eric , Gespach Christian , Sabbah Michèle , Neamati Nouri , Pitty Marc-Henry , Foster Paul 
Published: August 2015

Abstract
Protein disulfide isomerase (PDI) is a chaperone protein that regulates oxidative protein folding as well as cell viability. Increased PDI levels have been documented in a variety of human cancers, including ovarian, prostate, and lung cancers. Inhibition of PDI activity leads to apoptosis in cancer, suggesting that PDI is a promising druggable target. XCE853 was originally identified within a family of synthetic compounds displaying a preferential antiproliferative activity on drug-resistant human cancer cells (Gutmann et al, AACR annual meeting, 2013). XCE853 inhibits in vitro recombinant PDI activity and blocks in vitro proliferation of human tumor cells with IC50s in the nanomolar range through an irreversible cytolysis (Prevost et al, AACR annual meeting, 2014). By contrast, XCE853 has no or limited antiproliferative activity on several human non-tumoral immortalized cells (MCF10, RPE1 or RWPE1) even at high concentrations. The ex-vivo approach using fresh human hepatocellular carcinoma explants incubated 48h with XCE853 (100nM) has shown the decrease of the proliferation (KI-67 labeling) with an apoptosis induction (Caspase-3 labeling). In addition, XCE853 which displayed an excellent oral bioavailability in mouse blocks growth of human ovarian cancer using the in vivo OVCAR-3 xenograft model leading to complete tumor growth arrest even after the cessation of treatment.
To optimize the preclinical and clinical development, we are now characterizing new biomarkers to 1) stratify the tumors which are sensitive and non-sensitive to XCE853 and to 2) identify the optimal dose regimen.
Altogether, these data support further efforts on XCE853 preclinical studies to prepare the Phase-I clinical study entry.
Citation Format: Gregoire Pierre Prevost, Marine Garrido, Shili Xu, Celine Lefebvre, Anne Chauchereau, Denis Carniato, Jean François Briand, Mathieu Gutmann, Maria Serova, Annemilai Tijeras-Raballand, Armand De Grammont, Eric Raymond, Christian Gespach, Michèle Sabbah, Nouri Neamati, Marc-Henry Pitty, Paul Foster. New biomarkers to optimize preclinical development of the PDI inhibitor XCE853. [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 4466. doi:10.1158/1538-7445.AM2015-4466
Abstract 4467: Targeting of chemokine receptor CXCR4 inhibits invasion and sensitizes melanoma cells to chemotherapeutic agents
Authors: Pandey Manoj K. , Karelia Deepkamal , Kale Vijay P. , Gowda Krishne , Sharma Arun K. , Neves Rogerio I. , Amin Shantu G. 
Published: August 2015

Abstract
Malignant melanoma is highly metastatic and resistant to conventional therapies. Although numerous clinical approaches for treating melanoma have been adopted, none led to a remarkable therapeutic effect. Recently new drugs have been developed for treatment of metastatic melanoma, and hold great promise; however complete effects are still distant dream because of resistance. We have learnt that the most aggressive melanomas are generally resistant to strategies which target one signaling pathway. Thus an agent targeting multiple signaling pathways would maximize therapeutic outcome. We have identified one such agent named as gambogic acid (GA) that is natural and derived from medicinal plant Garcinia hanburyi (also called mangosteen or kokum). Moreover this agent has a potential to target several pathways responsible for survival and chemoresistance of several cancers including melanoma. Stromal cell-derived factor 1α (SDF-1α) and its receptor, CXC chemokine receptor 4 (CXCR4), has been associated with inferior survival, poor prognosis, chemoresistance and metastasis of malignant melanoma. We, therefore, investigated whether GA could inhibit CXCR4 signaling and suppress invasion of malignant melanoma cells. Through docking studies we predicted that GA directly interacts with CXCR4. This xanthone down-regulates the expression of CXCR4 on melanoma cells in a dose- and time-dependent manner. Suppression of CXCR4 expression by GA correlated with both inhibition of SDF-1α-induced invasion of melanoma cells. GA also inhibited expression of MMP-9, VEGF, c-Myc and phosphorylation of Erk1/2 in melanoma cells. Importantly, GA markedly enhances the efficacy of PLX-4032 and dacarbazine against melanoma cells.
Citation Format: Manoj K. Pandey, Deepkamal Karelia, Vijay P. Kale, Krishne Gowda, Arun K. Sharma, Rogerio I. Neves, Shantu G. Amin. Targeting of chemokine receptor CXCR4 inhibits invasion and sensitizes melanoma cells to chemotherapeutic agents. [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 4467. doi:10.1158/1538-7445.AM2015-4467
Abstract 4470: Targeting autophagy and apoptosis to enhance anticancer effect on esophageal carcinoma in vitro
Authors: Cai Yan , Cai Jiajing , Ma Qiang , Xu Yuan , Wang Dongsheng , Guo Xiaolan 
Published: August 2015

Abstract
Esophageal cancer is one of the malignancies threatening human health with high incidence and a very low 5-year survival rate with poor outcomes in the developing countries. As one of the main treatment for esophageal cancer, chemotherapy has been played indispensable roles along with more and more chemoresistance and side effects arised though. Recent studies showed that induction of autophagy has emerged as a drug resistance mechanism that promotes cancer cell survival via self-digestion. Therefore targeting autophagy in cancer might be another promising approach of therapeutics. In this study, chloroquine (CQ) was used as the autophagy inhibitor, which has been the anti-malarial drug with 60 years history and safety performance, to study esophageal carcinoma cells EC109 in vivo and explore the potential molecular mechanisms. Chloroquine was employed to treat EC109 cells at different dosages and time points, and MTT results showed that the viability of EC109 was reduced dramatically in a dose dependent manner after 24 hours treatment. Moreover, we found that CQ could inhibit the migration and invasion abilities through scratch test and cell invasion Transwell chamber test, also significantly suppressed the colony formation using soft agar assay. Further investigation showed that mTOR pathway was activated with CQ exposure, and autophagy marker LC3I/II conversion decreased at early-stage, with obvious elevation eventually. More interestingly, we observed that CQ promoted the EC109 cells apoptosis by flow cytometry, also the mRNA expression of apoptosis associated proteins, such as Fas and Bax were increased. According to our findings, chloroquine showed its anticancer effect through modulating autophagy and promoting cell apoptosis, which might have promising therapeutic benefits for esophageal carcinoma.
Citation Format: Yan Cai, Jiajing Cai, Qiang Ma, Yuan Xu, Dongsheng Wang, Xiaolan Guo. Targeting autophagy and apoptosis to enhance anticancer effect on esophageal carcinoma in vitro. [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 4470. doi:10.1158/1538-7445.AM2015-4470
Abstract 4479: ONC201 is non-toxic at efficacious doses in vitro and in vivo
Authors: Allen Joshua E. , El-Deiry Wafik S. 
Published: August 2015

Abstract
ONC201 is a small molecule that is entering clinical trials based on its favorable preclinical profile that includes robust anti-tumor activity in several preclinical models of advanced cancers. Despite inducing a strong cytotoxic response in tumor cells, ONC201 does not induce cell death in normal cells under the same conditions. In addition to a lack of cytoxicity towards normal cells, ONC201 also does not appear to be genotoxic based on gamma-H2AX assessment. Recent mechanistic studies have implicated the early stage induction of the ER stress response by ONC201, which includes induction of DR5 as part of its pro-apoptotic response. Biochemical studies reveal that ONC201 does not induce DR5 in normal cells at doses that cause strong DR5 induction in tumor cells.
In accordance with in vitro profile, efficacious ONC201 dose schedules in murine models are also well tolerated without apparent alterations of normal tissue histology or significant loss of body weight. Similar observations were revealed in GLP toxicology studies in beagle dogs and Sprague-Dawley rats. Dogs received a single dose of 0, 4.2, 42, or 120 mg/kg by oral gavage, which represents a human equivalent of 0, 125 mg, 1.25 g, and 3.57 g, respectively. Rats received 0, 12.5, 125, or 225 mg/kg ONC201 by oral gavage, which represents a human equivalent of 0, 125 mg, 1.25 g, and 2.25 g, respectively. There were no deaths or dose-limiting toxicities. The only findings that were observed in both rats and dogs occurred at the highest doses tested and were mild and reversible: decreased activity (no indications of anemia), decreased food consumption (weight loss only seen in rats), and salivation. The NOAEL was at least 42 mg/kg in dogs and at least 125 mg/kg in rats.
In summary, these in vitro and in vivo studies support that ONC201 has a large and favorable therapeutic index that is compelling given its powerful single agent anti-tumor efficacy. The coupling of the strong efficacy and safety profile of ONC201 is unique among cancer therapies and opens a broad range of clinical applications for its future development, including potential for combinatorial therapeutics.
Citation Format: Joshua E. Allen, Wafik S. El-Deiry. ONC201 is non-toxic at efficacious doses in vitro and in vivo. [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 4479. doi:10.1158/1538-7445.AM2015-4479
Abstract 4485: Anticancer effect of platinum(IV) complex against cisplatin-resistant human ovarian cancer
Authors: Okamoto Yoshinori , Tobe Takao , Ueda Koji , Kojima Nakao 
Published: August 2015

Abstract
Background: Platinum(IV) [Pt(IV)] complexes are one of the attractive next-generation anticancer drugs. Beside Pt(II)-based drugs such as cisplatin, carboplatin, and oxaliplatin, Pt(IV) complexes show less adverse effects and can be administrated orally. In addition, because Pt(IV) complexes adopt octahedral coordination geometry, it also have an advantage that can be coordinated with more functional ligands than Pt(II) complexes. These different features prompted us to investigate the effectiveness of Pt(IV) complexes on cisplatin-resistant cancer cells with its mechanisms. This study aims to elucidate the anti-cancer effects of Pt(IV) complexes. Materials and Methods: The cytotoxicity of cis-diammine-tetrachloro-Pt(IV) [cis-Pt(IV)] and cisplatin was determined using human ovarian cancer cell lines (A2780), and its cisplatin-resistant subline (A2780cis), with their influx/efflux patterns using ICP-MS. Pt-DNA-crosslink formation was also determined by agarose gel electrophoresis, in which the crosslink was quantified by decrease of ethidium bromide staining of DNA. Results and Discussion: Cisplatin completely failed to decrease the survival of A2780cis cells at a concentration that killed A2780, whereas cis-Pt(IV) exerted cytotoxicity in both cell lines. Pt-DNA-crosslink formation assay showed cis-Pt(IV) bound to DNA only in the presence of reductant such as glutathione (GSH) or ascorbic acid, indicating cisplatin production. However, it is also known excess amount of GSH suppress DNA binding of cisplatin. Indeed, intracellular GSH level in A2780cis cells was about 3 times higher as compared with A2780 cells; therefore cisplatin would be inactivated in A2780cis cells. These findings suggest that cis-Pt(IV) is actually reduced to cisplatin in GSH-rich environment and then induce cytotoxicity by somehow escaping from GSH-dependent inactivation. Pt(IV)-specific subcellular distribution might contribute this paradoxical advantageous effect of GSH on cis-Pt(IV). Intracellular accumulation of Pt was reduced by competing a related transporter CTR1 by copper in cis-Pt(IV) treatment, whereas cytotoxicity was not suppressed. Therefore CTR1 is involved in the intake of Pt complexes including cis-Pt(IV), but the alternative pathway(s) could be responsible for anti-cancer effect of Pt(IV) complexes.
Citation Format: Yoshinori Okamoto, Takao Tobe, Koji Ueda, Nakao Kojima. Anticancer effect of platinum(IV) complex against cisplatin-resistant human ovarian 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 4485. doi:10.1158/1538-7445.AM2015-4485
Abstract 4488: Folate receptor targeted therapy using small molecule drug conjugates constructed with high affinity antifolate ligands
Authors: Leamon Christopher P. , Reddy Joseph A. , Vlahov Iontcho R. , You Fei , Klein Hanna F. , Kleindl Paul J. , Nelson Melissa , Vetzel Marilynn , Klein Patrick J. , Matherly Larry H. , Gangjee Aleem 
Published: August 2015

Abstract
Folate receptor (FR)-targeted small molecule drug conjugates (SMDC) have shown promising clinical results. To date, all related SMDCs have been constructed with folic acid. Whereas folic acid displays very high affinity for the FR (kd ∼ 0.1 nM), antifolates with similar high binding affinity and specificity have also been reported. This knowledge prompted our investigation towards substituting the folic acid targeting moiety in our SMDCs with high affinity antifolates, such as CB3717 (a thymidylate synthase inhibitor), and the glycinamide ribonucleotide formyltransferase (GARFTase) inhibitors, AG94 and AG147, thereby testing the hypothesis that greater antitumor activity should result from the combination of inhibitors. Using mice bearing FR-positive human tumor xenografts, we observed curative activity with a CB3717-based vinca alkaloid SMDC under conditions where no cures resulted with vintafolide (EC145) treatment. Similarly, tubulysin SMDCs constructed with AG94 and AG147 were found to produce curative activity using a dosing regimen where a folic acid-tubulysin conjugate did not. Of note, treatment of mice with simple co-mixtures of the antifolates and untargeted drugs was found to be ineffective, thereby confirming the need for linking the two moieties together to produce maximal activity. Taken together, these studies demonstrate that high affinity antifolates can be used in an SMDC format serving as both a high affinity targeting ligand and as a second drug having different, and perhaps a complementary mechanism of action to yield greater antitumor activity.
Citation Format: Christopher P. Leamon, Joseph A. Reddy, Iontcho R. Vlahov, Fei You, Hanna F. Klein, Paul J. Kleindl, Melissa Nelson, Marilynn Vetzel, Patrick J. Klein, Larry H. Matherly, Aleem Gangjee. Folate receptor targeted therapy using small molecule drug conjugates constructed with high affinity antifolate ligands. [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 4488. doi:10.1158/1538-7445.AM2015-4488
Abstract 4500: Nisin ZP, a food preservative, has antitumor potential for head and neck cancer and extends survival
Authors: Kamarajan Pachiyappan , Hayami Takayuki , Matte Bibiana , Liu Yang , Ramamoorthy Ayyalusamy , Worden Francis P. , Kapila Sunil , Kapila Yvonne 
Published: August 2015

Abstract
The use of small antimicrobial agents or bacteriocins, like nisin, to treat cancer is a new approach that holds great promise. Nisin exemplifies this new approach because it has been used safely in humans for many years as a food preservative, and recent laboratory studies support its anti-tumor potential in head and neck cancer. Previously, we showed that nisin (2.5%, low content) has antitumor potential in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo. The current studies explored a naturally occurring variant of nisin (nisin ZP; 95%, high content) for its antitumor effects in vitro and in vivo. Nisin ZP induced the greatest level of apoptosis in HNSCC cells compared to low content nisin. HNSCC cells treated with increasing concentrations of nisin ZP exhibited increasing levels of apoptosis and decreasing levels of cell proliferation and clonogenic capacity. Nisin ZP-induced apoptosis was defined by increased ethidium bromide and acridine orange (EB/AO) staining and by increased levels of calpain-dependent PARP cleavage. Importantly, nisin ZP also induced apoptosis dose-dependently in HUVEC endothelial cells and concomitant decreases in vascular sprout formation. Nisin ZP inhibited sphere formation of HNSCC cells in vitro and tumorigenesis in vivo and long term treatment extended survival. In summary, nisin ZP exhibits greater antitumor effects than low content nisin, and thus has the potential to serve as a novel therapeutic for HNSCC.
Note: This abstract was not presented at the meeting.
Citation Format: Pachiyappan Kamarajan, Takayuki Hayami, Bibiana Matte, Yang Liu, Ayyalusamy Ramamoorthy, Francis P. Worden, Sunil Kapila, Yvonne Kapila. Nisin ZP, a food preservative, has antitumor potential for head and neck cancer and extends survival. [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 4500. doi:10.1158/1538-7445.AM2015-4500