bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 862: Purified recombinant Maspin is processed through the endosomal pathway in breast cancer cells.
Authors: Bodenstine Thomas M. , Seftor Richard E. B. , Seftor Elisabeth A. , Khalkhali-Ellis Zhila , Samii Nicole A. , Monarrez J. Cesar , Pemberton Philip A. , Hendrix Mary J. C. 
Published: August 2014

Abstract
Maspin (Mammary Serine Protease Inhibitor), a gene involved in mammary gland development and morphogenesis, has been shown to act as a tumor suppressor in multiple cancers by inhibiting the aggressive cancer cell phenotype. Recombinant Maspin (rMas) added to cell culture media is internalized by cancer cells and capable of recapitulating many of the effects of endogenously re-expressed Maspin in Maspin-null cancer cells, including the inhibition of cell invasion, migration and induction of angiogenesis. Importantly, these effects are mediated by purified rMas without the need for post-translational modifications prior to application, increasing the future therapeutic potential for utilizing rMas as an adjuvant therapy. However, the therapeutic use of rMas is limited by its rapid clearance from cancer cells, and many of the molecular mechanisms regarding rMas internalization and processing remain to be determined. Building on preliminary data, we hypothesized that rMas is processed by the endosomal pathway. We demonstrate localization of rMas in Rab9 late-endosomes and Lamp-1 positive lysosomes following treatment of 10 μg/ml
rMas in BT549, Hs578T and MDA-MB-231 human breast cancer cell lines. rMas internalization was reduced when incubated at 4oC, and increased at temperatures of 20oC and 37oC, with the highest rates of internalization at 37oC, indicative of endocytosis. Furthermore, depletion of K+ decreased rMas internalization in Hs578T and
MDA-MB-231, suggestive of clarthrin-mediated endocytosis. Our data show that
rMas is capable of acting at the membrane to mediate effects on invasion and migration, but may not be functional once internalized due to rapid degradation by the lysosome. Interestingly, this may provide a plausible explanation for previously reported data in which rMas was not able to reproduce the effects of endogenous Maspin re-expression on cancer cell apoptosis sensitivity, which require cytosolic and mitochondrial mechanisms. Our data provide evidence that strategies which induce endosomal escape of rMas will intensify its anti-tumor effects on cancer cells, and further enhance its potential therapeutic applications.
Citation Format: Thomas M. Bodenstine, Richard E. B. Seftor, Elisabeth A. Seftor, Zhila Khalkhali-Ellis, Nicole A. Samii, J. Cesar Monarrez, Philip A. Pemberton, Mary J. C. Hendrix. Purified recombinant Maspin is processed through the endosomal pathway in breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 862. doi:10.1158/1538-7445.AM2013-862
Abstract 864: ANG4043: A new brain-penetrant peptide-antibody conjugate that reduces tumor growth in a HER2-positive orthotopic tumor model.
Authors: Lachowicz Jean E. , Demeule Michel , Che Christian , Tripathy Sasmita , Currie Jean-Christophe , Regina Anthony , Nguyen Tran , Lord-Dufour Simon , Castaigne Jean-Paul 
Published: August 2014

Abstract
While monoclonal antibodies to receptor tyrosine kinases such as HER2 have been demonstrated to reduce tumor size and increase survival, these agents achieve little to no brain penetration, making them ineffective against metastatic brain tumors. The blood-brain barrier (BBB), which restricts entry of proteins such as mAbs into the brain, is comprised of capillary endothelial cells with tight junctions and efflux pumps. Brain entry of nutrients, hormones, and other required molecules is accomplished by processes such as receptor-mediated transcytosis. As low-density lipoprotein receptor-related protein 1 (LRP1) is known to perform this function in BBB endothelial cells, we have created a family of peptides (Angiopeps) designed for LRP1 recognition. These proprietary Angiopeps can be used to create novel Peptide-Drug Conjugates that successfully cross the BBB by LRP1-mediated transcytosis. Here we describe chemical conjugation of Angiopep-2 (An2) to a mAb against HER2. This Peptide-Antibody Conjugate, ANG 4043, displays HER2 binding affinity and in vitro cytotoxic potency similar to that of native anti-HER2. ANG4043 demonstrates a high rate of entry into the brain, consistent with achieving therapeutic concentrations. The plasma half-life of ANG4043 is similar to that of Anti-HER2 in mouse. Mice with intracranially implanted BT-474 cells showed reduced brain tumor size when dosed with ANG4043 compared to controls. Overall, these data demonstrate that a brain-penetrant Peptide-Antibody Conjugate is efficacious in a mouse HER2-positive tumor model. These results extend the validation of An2 conjugation beyond small molecules and peptides to include larger molecules such as therapeutic mAbs for development of new brain-penetrant antitumor therapeutics.
Citation Format: Jean E. Lachowicz, Michel Demeule, Christian Che, Sasmita Tripathy, Jean-Christophe Currie, Anthony Regina, Tran Nguyen, Simon Lord-Dufour, Jean-Paul Castaigne. ANG4043: A new brain-penetrant peptide-antibody conjugate that reduces tumor growth in a HER2-positive orthotopic tumor model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 864. doi:10.1158/1538-7445.AM2013-864
Abstract 867: IGF-I receptor targeting therapy for esophageal carcinomas.
Authors: Adachi Yasushi , Yamamoto Hiroyuki , Ohashi Hirokazu , Matsunaga Yasutaka , Nosho Katsuhiko , Suzuki Hiromu , Taniguchi Hiroaki , Arimura Yoshiaki , Endo Takao , Kato Yasuo , Imai Kohzoh , Carbone David P. , Shinomura Yasushisa 
Published: August 2014

Abstract
Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for tumorigenicity and cancer development of many malignancies, however this pathway has not been well studied in human esophageal carcinomas. Esophageal cancer is one of worst prognostic disease, main types of which are squamous cell carcinomas (ESCC) and adenocarcinoma (EAC). Previously we have reported that the IGF axis may play a key role in tumor progression of ESCC and its detection may be useful for the prediction of recurrence and poor prognosis and possibly for selecting patients for targeting therapy for IGF-IR. We have previously shown successful therapy for several gastrointestinal cancers using recombinant adenoviruses expressing dominant negative forms of IGF-IR (Ad-IGF-IR/dn). In this study, we wanted to develop potential targeted therapeutics to IGF-1R; therefore, we assessed the effect of IGF-IR blockade in both types of esophageal cancer. We analyzed immunohistochemical expression of IGF-IR in a tissue array. A tyrosine kinase inhibitor, BMS-536924, and Ad-IGF-IR/dn were used to treat several ESCC lines, such as TE1, TE8, TT, TTn, and EAC lines, including OE19 and OE33. We assessed the effect of both IGF-IR blockade on signal transduction, growth, and apoptosis. IGF-IR is expressed frequently in esophageal tumors, but not in normal mucosa. IGF-IR was produced in ESCC more than EAC, and is detected in metastasized similar to the primary site. IGF-IR inhibition suppressed proliferation and colony formation in both types of cancer. Blockade of IGF-IR up-regulated both stress- and chemotherapy-induced apoptosis in both esophageal tumor type. Although IGF-IR/dn blocked ligand-induced activation of Akt-1 mainly, BMS-536924 effectively blocked both activation of Akt and MAPK. Thus, the IGF axis may play a key role in tumor progression of human esophageal carcinomas. The IGF-IR targeting strategies might be useful anticancer therapeutics which can be used widely for human esophageal malignancies.
Citation Format: Yasushi Adachi, Hiroyuki Yamamoto, Hirokazu Ohashi, Yasutaka Matsunaga, Katsuhiko Nosho, Hiromu Suzuki, Hiroaki Taniguchi, Yoshiaki Arimura, Takao Endo, Yasuo Kato, Kohzoh Imai, David P. Carbone, Yasushisa Shinomura. IGF-I receptor targeting therapy for esophageal carcinomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 867. doi:10.1158/1538-7445.AM2013-867
Abstract 874: Mutations of aromatic amino residue to polar residue in NBDs alter the transport properties of ABCC10.
Authors: Malofeeva Ekaterina V. , Hopper-Borge Elizabeth 
Published: August 2014

Abstract
ABCC10 is an efflux pump that confers multidrug resistance to cells by extruding a variety of natural and nucleosides analogues using energy from ATP hydrolysis. The objective of this project is to understand the detailed relationship between ATP hydrolysis and drug transport for ABCC10 and how ABCC10’s ATPase activity is regulated. For this study, we mutated aromatic residues to polar residues in the Nucleotide Binding Domains (NBDs) of ABCC10 to determine how these residues are involved in the transport of ABCC10 substrates. Prior, structural analyses of several bacterial ABC-transporters indicated that aromatic amino acid residues in NBDs are needed for ATP binding and ATP hydrolysis. In these studies, substitution of these aromatic residues completely abolished ATP-dependent transport. Prior work on ABCC1 has shown that substitutions such as W (tryptophan) to C (cytidine) or Y (tyrosine) to C (cytidine) decreased ABCC1’s affinity for ATP, and ATP-dependent LTC4 transport activities. Analogous substitutions of W (tryptophan) residues to polar residues in the NBD2 of ABCC2 eliminated estradiol glucuronide and leukotriene C4 transport. Based on these data, we hypothesize that mutating aromatic to polar residues in the NBDs of ABCC10 will modulate the biochemical and cellular transport activities of this efflux pump.
At present we have generated mutant-ABCC10 constructs by site-directed mutagenesis. Specifically, we mutated the aromatic Tyr747 (NBD1), Trp607 (NBD1) and Tyr1255 (NBD2) residues to polar cysteine residues. We then examined all ABCC10-mutant, wild-type ABCC10 and empty-vector constructs using immunofluorescence, ATPase assays, sensitivity and transport assays. We observed that the mutant ABCC10 proteins localized predominantly to the membranes. Further, ABCC10-mutant cells, except for the W607C mutant clone, showed less sensitivity than empty vector-transfected cells. Using accumulation assays we also demonstrated that substitutions of aromatic to polar residues, such as W607C and Y1255C, decreased the ability of ABCC10 to transport, docetaxel and Ara-C, however transport was not completely abolished. Using our ABCC10 mutants we found that aromatic to polar residue substitutions eliminated the stimulatory effects of docetaxel and Ara-C on ATPase activity of ABCC10.
Taken together, these results demonstrate that these aromatic residues are involved in the ATP binding process and mutations of these residues cause of reduction in ABCC10 transport of docetaxel and Ara-C from cells.
Citation Format: Ekaterina V. Malofeeva, Elizabeth Hopper-Borge. Mutations of aromatic amino residue to polar residue in NBDs alter the transport properties of ABCC10. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 874. doi:10.1158/1538-7445.AM2013-874
Abstract 876: Molecular mechanisms of paclitaxel-resistance and resveratrol sensitivity in MDA-MB-231 breast cancer cells.
Authors: Sprouse Alyssa A. , Herbert Brittney-Shea 
Published: August 2014

Abstract
Treatment of drug-resistant cancer cells remains a difficult problem in cancer therapy because most resistant cells can pump out drugs or upregulate other survival pathways to bypass a targeted therapy. To study cancers that are resistant to the common cancer drug, paclitaxel, a novel paclitaxel-resistant cell line was generated from the breast cancer cell line MDA-MB-231. A “spiking” method of paclitaxel treatment was used to select for a population of cells that are resistant to the drug. This method mimics the development of resistance in recurrent tumors in patients. The IC50 of paclitaxel in these cells was 75 μM compared to the 0.037 μM IC50 of the parent cell line, a 2000-fold increase in resistance. In this very heterogeneous population, the mechanism of resistance was not due to increased protein levels of the efflux protein, p-glycoprotein, as quantitated by western blot analysis. To better study these cells, the paclitaxel-resistant cell line was cloned using a limiting dilution method to provide more homogeneous populations of resistant cells. The 29 clones obtained exhibited a paclitaxel IC50 range of 8 μM to 78 μM which was equivalent to a 200- to 2000-fold increase in resistance compared to the parent line. It has been suggested that the polyphenol natural compound, resveratrol, which has been shown to inhibit cell growth of multiple cancer types, may be useful as a combination anti-cancer treatment or novel therapeutic for drug-resistant cancer cells. There was no significant difference among the 72 hour IC50 of resveratrol in the parent line, the heterogeneous resistant line, the least paclitaxel-resistant clone or the most paclitaxel-resistant clone. We observed that treatment with 10-100 μM concentrations of resveratrol in all cell lines showed a reduction in cell proliferation and increased apoptosis within 72 hours (p&lt;0.05), with the paclitaxel-resistant cells to a greater extent. In addition, resveratrol decreased the ability of the parent, heterogeneous resistant and the highest resistant clone cells to form colonies (an indication of reduced cell survival capacity). To better characterize the molecular mechanisms of the paclitaxel-resistant cell line and the effects of resveratrol treatment, RNA sequencing will reveal the unique transcriptome and pre-miRNA changes in the resistant cells compared to the parent as well as changes in both cell lines due to resveratrol treatment. This resistant cell line and its clones provide a powerful tool to study paclitaxel-resistance in and therapeutics for breast cancer.
Citation Format: Alyssa A. Sprouse, Brittney-Shea Herbert. Molecular mechanisms of paclitaxel-resistance and resveratrol sensitivity in MDA-MB-231 breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 876. doi:10.1158/1538-7445.AM2013-876
Abstract 877: Efficacy of Salmonella typhimurium A1-R on chemoresistant stem-like human pancreatic cancer cells.
Authors: Hiroshima Yukihiko , Zhao Ming , Zhang Yong , Maawy Ali , Hassanein Mohamed , Suetsugu Atsushi , Chishima Takashi , Tanaka Kuniya , Bouvet Michael , Endo Itaru , Hoffman Robert M. 
Published: August 2014

Abstract
We have previously developed the genetically-modified Salmonella typhimurium A1-R (A1-R) strain that selectively targets tumors. We have also previously reported that XPA1 human pancreatic cancer cells are dimorphic (spindle and round shape), with the spindle-shaped cancer cells having the greater capability for distant metastasis, suggesting they are stem-like cells. The aim of this study is to examine whether spindle-shaped XPA1 cells are chemo-resistant and if they are sensitive to A1-R. Serial dilution was performed to obtain clones of both cellular morphologies. To determine chemosensitivity, in vitro IC50 values were obtained for both types of XPA1 cells for (1) Cisplatin (CDDP); (2) 5-fluorouracil (5FU); (3) Gemcitabine (GEM); and (4) A1-R. The efficacy of these drugs was also determined for both types of XPA1 cells in vivo. IC50 values of spindle-shaped and round XPA1 cells, respectively, were 2.65 ± 0.22 μg/ml and 1.43 ± 0.36 μg/ml for CDDP (p = 0.012); 2.44 ± 0.25 μg/ml and 1.48 ± 0.19 μg/ml for 5FU (p = 0.007); 3.17 ± 0.15 ng/ml and 2.70 ± 0.29 ng/ml for GEM (p = 0.133); and (19.7 ± 1.46) x 108 cfu/ml and (17.8 ± 9.78) × 108 cfu /ml for A1-R (p = 0.771). In vivo, 5FU and A1-R significantly reduced the tumor weight of round cells (5FU; p = 0.028; A1-R; p = 0.011). However, only A1-R significantly reduced the tumor weight of spindle-shaped cells (p = 0.012). The spindle-shaped XPA1 cells were thus chemo-resistant and sensitive to A1-R, suggesting A1-R could be a promising therapy for chemo-resistant human pancreatic cancer stem-like cells.
Citation Format: Yukihiko Hiroshima, Ming Zhao, Yong Zhang, Ali Maawy, Mohamed Hassanein, Atsushi Suetsugu, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. Efficacy of Salmonella typhimurium A1-R on chemoresistant stem-like human pancreatic cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 877. doi:10.1158/1538-7445.AM2013-877
Abstract 881: Hyperthermic isolated intraperitoneal chemoperfusion (HIPEC) for treatment of patients with peritoneal carcinosis - Analysing negative influencing cellular mechanisms in the tumor cells.
Authors: Gasser Martin , Lazariotou Maria , Vetterlein Malte , Grimmig Tanja , Germer Christoph T. , Pelz Joerg , Waaga-Gasser Ana Maria 
Published: August 2014

Abstract
Background: In patients with isolated peritoneal carcinosis (PC) of gastric, colorectal and ovarian cancer hyperthermic intraperitoneal chemotherapy (HIPEC) represents a promising treatment option integrated into multimodal concepts. We analyzed relevant heat shock proteins (HSPs) that confer resistance to physical stress like hyperthermia as well as specific multidrug resistence (MDR) genes in patients with PC.
Materials/Methods: Patients with different adenocarcinomas and additional PC that underwent HIPEC therapy between 09/09 and 03/11 in our department (gastric, colorectal and ovarian cancer) were included in the study. HIPEC therapy was performed under specific conditions (1hr permanent chemotherapeutical flux via external pump into the abdominal cavity after resection of relevant tumor masses with elevated temperature up to 43°C). Tumors before and after HIPEC therapy were analyzed for HSPs, ABC transporter and CD133 expression by immunohistochemistry, Western Blot, and RT-qPCR. Additionally, HT29 tumor cells were exposed in vitro to different conditions of hyperthermia up to 43°C for 60 minutes and comparably analyzed. Tumor cells were counted and studied for apoptosis.
Results: HSP70/72, HSP90 and CD133 expression was upregulated in the investigated tumors, in particular post HIPEC therapy. Upregulated protein and gene expression was also shown for MDR genes ABCB5, ABCG2 and ABCC5. Hyperthermia induced upregulated protein and gene expression in HT29 tumor cells dependent on incubation temperature, mainly for HSPs observed in western blot, immunohistochemistry and RT-qPCR. Furthermore, cell viability decreased with increasing incubation temperature.
Conclusion: Therapeutic approaches like HIPEC to achieve antiproliferative and apoptosis inducing cellular effects in patients with PC seem to be negatively influenced by highly conserved HSP mechanisms as well as multidrug resistance genes. Studying HSP and MDR expression profiles both in patient tumors and in vitro are valuable tools to further clarify the effects of hyperthermia and chemotherapeutical agents in context with the treatment of HIPEC therapy in the affected patients.
Citation Format: Martin Gasser, Maria Lazariotou, Malte Vetterlein, Tanja Grimmig, Christoph T. Germer, Joerg Pelz, Ana Maria Waaga-Gasser. Hyperthermic isolated intraperitoneal chemoperfusion (HIPEC) for treatment of patients with peritoneal carcinosis - Analysing negative influencing cellular mechanisms in the tumor cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 881. doi:10.1158/1538-7445.AM2013-881
Abstract 882: Functional investigation of a novel cancer specific organic anion transporting polypeptide 1B3 variant 1 (OATP1B3 V1) in colon and pancreatic cancer.
Authors: Thakkar Nilay , Kim Kyungbo , Jang Eun Ryoung , Han Songhee , Kim Kyunghwa , Kim Donghern , Merchant Nipun , Lockhart A. Craig , Lee Wooin 
Published: August 2014

Abstract
OATP1B3 is a member of the Organic Anion Transporting Polypeptide (OATP) superfamily that mediates the uptake of numerous endogenous and xenobiotic compounds. Initially, OATP1B3 was reported to be expressed exclusively in the normal hepatocytes. Subsequent studies have reported that OATP1B3 is frequently expressed in multiple types of cancer tissues derived from gastrointestinal tract, pancreas, prostate, lung and breast. Some reports have also suggested that OATP1B3 may be associated with differing clinical outcomes. However, so far the biological functions of OATP1B3 in cancer have not been elucidated. In this study, we confirmed that colon and pancreatic cancer cells express variant forms of OATP1B3, different from OATP1B3 wildtype (WT) expressed in normal liver. OATP1B3 variant 1 (V1) is the most prevalent form among the variants containing the alternate exon 2a, instead of exons 1 and 2 as in OATP1B3 WT. The translated protein sequence of OATP1B3 V1 is similar to OATP1B3 WT except lacking the first 28 amino acids at the N-terminus. OATP1B3 V1 has a limited transport activity toward cholecystokin-8 (CCK-8, a prototype OATP1B3 substrate) in contrast to OATP1B3 WT which showed a markedly efficient uptake of CCK-8. Consistent with these results, OATP1B3 V1 was localized mainly in the cytoplasm with a much lower extent of trafficking to the surface membrane compared to OATP1B3 WT. In summary, our results demonstrate that colon and pancreatic cancer cells express variant forms of OATP1B3 with a limited transport activity and different subcellular localization compared to OATP1B3 WT. These observed differences at molecular and functional levels will be important considerations for further investigations of the biological and clinical significance of OATP1B3 expression in cancer.
Citation Format: Nilay Thakkar, Kyungbo Kim, Eun Ryoung Jang, Songhee Han, Kyunghwa Kim, Donghern Kim, Nipun Merchant, A. Craig Lockhart, Wooin Lee. Functional investigation of a novel cancer specific organic anion transporting polypeptide 1B3 variant 1 (OATP1B3 V1) in colon and pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 882. doi:10.1158/1538-7445.AM2013-882