bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5526: Deciphering the basis of CendR-mediated penetration into tumors
Authors: Pang Hongbo , Braun Gary B. , Friman Tomas , Ruoslahti Erkki 
Published: August 2015

Abstract
Cell-penetrating peptides (CPPs) have proven their usefulness in overcoming barriers (such as the cell membrane) of drug delivery into tumor cells. We recently discovered a novel class of cell-penetrating peptides that also have tumor-penetrating properties. These so-called, CendR peptides,bind to neuropilin-1 (NRP1) and initiate an active endocytic process into tumor cells. Subsequent studies showed that CendR-initiated endocytosis is a receptor-dependent macropinocytosis process, and that its activity is stimulated by mTOR inhibition and nutrient deprivation. In vivo, CendR peptides penetrate across tumor vessels deeply into the extravascular tumor tissue, and show ability to improve the tumor accumulation and antitumor efficacy of coupled, and even co-administrated, drugs. Further understanding of the CendR-mediated cell and tissue penetration is of value to cell biology and cancer therapy.
Here, we report ultrastructural studies to unveil the subcellular transport route for CendR peptide. After synchronized cell entry, transmission electron microscopy (TEM) imaging shows that CendR cargo is transported from early endosomes to late endosomes and lysosomes. We have also identified some of the genes important for this transport. Moreover, magnetic isolation of intracellular vesicles containing CendR cargo and proteomics analysis identified signature molecules associated with these vesicles. Studies with TAT peptide comprised of D-amino acids (D-TAT), included in these studies as a non-CendR CPP, indicate that D-TAT also penetrates into tumor cells through a variation of macropinocytosis independent of NRP1. The uniqueness of CendR pathway lies in the linkage of CendR endocytosis to mTOR and cellular nutrient status. We provide evidence that a transcription factor, Sp1, serves as a link between mTOR and CendR endocytosis by regulating the NRP1 level on the cell surface. Additionally, we have shown the intercellular transport of CendR cargo that affords tissue penetration and is also stimulated by nutrient deprivation. Here we identify genes critical to the export and re-entry of CendR cargo during intercellular transport. These results shed light into the mechanism of action of CPPs, and endocytosis in general. They also have implications in cancer metabolism and drug delivery.
Citation Format: Hongbo Pang, Gary B. Braun, Tomas Friman, Erkki Ruoslahti. Deciphering the basis of CendR-mediated penetration into tumors. [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 5526. doi:10.1158/1538-7445.AM2015-5526
Abstract 5538: A pH-responsive doxorubicin-lipid conjugate loaded nanomedicine for breast cancer treatment
Authors: Li Feng , Saulsbury Marilyn , Heyliger Simone , Bondarev Mikhail , Du Chengan , Ramaley Corinne C. , Lemieux KiTani P. 
Published: August 2015

Abstract
Doxorubicin (DOX) is a chemotherapeutic agent widely used in the treatment of various cancers. However, its clinical use is restricted due to serious cardiotoxicity and the development of drug resistance. Many delivery strategies, including the use of liposomes, micelles, and polymer drug conjugates, have been used to improve the therapeutic efficacy and reduce the toxicity of DOX. Recently, lipid-drug conjugates have also been investigated for the delivery of anticancer drugs. The conjugation of lipids with DOX can increase its lipophilicity, thus enhance its loading in lipid-based nanoparticles, facilitate interaction with cells, and improve pharmacokinetic properties. In this study, we developed a micelle formulation with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-amino polyethylene glycol-2000 (DSPE-PEG) to deliver a DOX-lipid conjugate to treat breast cancers. DOX was conjugated with palmitic acid (PA) through a pH sensitive hydrazone bond to yield a lipophilic pro-drug of DOX (PA-DOX). PA-DOX (Log P = 2) showed significantly increased lipophilicity than DOX (Log P = - 0.5). The micelles were prepared using a thin-film dispersion method. Due to the lipophilic nature of PA-DOX, it can be efficiently loaded into the hydrophobic core of DSPE-PEG micelles. In addition, the micelle formulation demonstrated superior stability, showing no leakage or precipitation of PA-DOX for at least two weeks during storage at 4°C. In vitro drug release was tested in sodium phosphate buffer (pH 7.5) and sodium acetate buffer (pH 5.0), respectively. DOX-PA was stable at pH 7.4 and showed minimal DOX release (less than 10% at 24 hours). The release of DOX was significantly increased at pH 5 (approximately 75% at 24 hours). Anticancer activities were evaluated with MCF-7 breast cancer cells and MCF-7/MDR drug-resistant breast cancer cells. Cell viability was determined by a MTT assay. PA-DOX showed similar anticancer activity on MCF-7 cells as DOX itself. Anticancer activity of PA-DOX was significantly reduced in MCF-7/MDR cells but restored when used in combination with lapatinib.
Citation Format: Feng Li, Marilyn Saulsbury, Simone Heyliger, Mikhail Bondarev, Chengan Du, Corinne C. Ramaley, KiTani P. Lemieux. A pH-responsive doxorubicin-lipid conjugate loaded nanomedicine for breast cancer treatment. [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 5538. doi:10.1158/1538-7445.AM2015-5538
Abstract 5539: Antiproliferative and apoptotic effects of some African natural products in solid and hematopoietic malignant cell lines
Authors: Akanni Olufemi E. , Berger Martin R. 
Published: August 2015

Abstract
Background: Natural products have played a very important role in health care from time immemorial in curation and prevention of diseases. Antiproliferative and apoptotic effects of extracts of some African natural products like Hymelocardia acida, Moringa oleifera leaves as well as Pleurotus pulmonarius mushroom metabolites were studied in a panel of solid and hematopoietic malignant derived cell lines such as SUIT2-007, MDA-MB 231, SW480, K562 and HL60 cells.
Methods: MTT assay was used to determine the growth inhibition of respective cells in vitro. Apoptosis of the cells was demonstrated by fluorescence microscopy and Hoechst 33342 staining, DNA ladder formation assay and flow cytometry with propidium iodide staining.
Results: MTT results showed that extracts of Hymelocardia acida stem, Moringa oleifera leaves as well as Pleurotus pulmonarius metabolites could inhibit the proliferation of SUIT2-007, MDA-MB 231, SW480, K562 and HL60 cells in a time and dose dependent manner. Our results show that the ethanol extract of Hymelocardia acida stem had a positive effect and induced apoptosis as shown by fluorescence microscopy and flow cytometry assay. Apoptotic effects were demonstrated by nuclear staining with Hoechst showing clear signs for nuclear fragmentation in cells treated with Hymelocardia acida stem and Moringa oleifera leaves extracts. FACS analysis with propidium iodide showed that the sub G1 fraction increased in treated cells. DNA ladder formation, however, showed no clear DNA fragmentation, which does not exclude a clearer picture with isolated compounds.
Conclusion: The present study indicates that the extracts studied can effectively inhibit proliferation and induce apoptosis in cells of panel of tumor cell lines investigated.
Citation Format: Olufemi E. Akanni, Martin R. Berger. Antiproliferative and apoptotic effects of some African natural products in solid and hematopoietic malignant 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 5539. doi:10.1158/1538-7445.AM2015-5539
Abstract 554: Detection and separation of live circulating tumor cells using lipid dye
Authors: Mitra Ranjana , Goodman Jr Oscar , Le Thuc Timothy 
Published: August 2015

Abstract
Purpose: Separation of live circulating tumor cells (CTC) for culturing and monitoring treatment response is highly desirable. We have shown previously that CTC could be distinguished from peripheral blood mononuclear cells (PBMC) based on the intracellular lipid content. This study utilizes intracellular lipid as a biomarker to separate live CTC from PBMC for culturing and assessing treatment response.
Methods: We used Bodipy dye, a fluorescent fatty acid analog that undergoes native transport and metabolism in living cells, to label lipid-rich CTC. LNCaP cells incubated with 50% plasma for 16 hours were used as mock CTC. Test samples contained PBMC (106 cells) spiked with mock CTC (500 cells), which were stained with Bodipy and antibodies against CD45, a biomarker for leukocytes (PBMC). Bodipy+/CD45- CTC were detected and then sorted using a flow cytometer. The sorted Bodipy+/CD45- cells were evaluated for cell viability and their suitability for culturing with trypan blue staining.
Results: The Bodipy/CD45 staining permitted detection and sorting of 375 mock CTC from total 500 spiked LNCAPs (75% efficiency). These cells remained live as confirmed by trypan blue staining indicating suitability for culturing. All sorted cells were further confirmed to be epithelial LNCaP cells with pan-cytokeratin (CK) staining, a biomarker for epithelial cells. The recovery efficiency for live CTC sorting using Bodipy/CD45 staining is comparable with existing methods for isolation of fixed (non-live) CTC using CK/CD45 staining (85%).
Conclusion: Bodipy-positive stain together with CD45 negative stain provided an inexpensive and reliable means to isolate live CTC.
Citation Format: Ranjana Mitra, Oscar Goodman Jr, Thuc Timothy Le. Detection and separation of live circulating tumor cells using lipid dye. [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 554. doi:10.1158/1538-7445.AM2015-554
Abstract 5551: Anti-tumorigenic function of polyphenolic compounds on gefitinib resistant lung cancer
Authors: Phan Ai N. H. , Jeong Yangsik 
Published: August 2015

Abstract
EGFR-mutant non-small cell lung cancer (NSCLC) is initially very sensitive to EGFR tyrosine kinase inhibitors (TKIs). Even with the remarkable effect of EGFR TKIs, patients eventually acquire resistance to gefitinib or elortinib, leading to a clinical challenge for overcoming TKI resistance. Some polyphenolic compounds are known as potential anti-tumorigenic compounds, such as resveratrol, curcumin or EGCG. However the function of these natural compounds in resistant NSCLC remains to be elucidated.
Here, we identified a polyphenolic compound (named as compound A) from screening a set of natural compounds for anti-cancer effects on NSCLC. We found that compound A is a potential anticancer agent both in vivo and in vitro. Moreover, the growth inhibition of compound A turns out to be selective for cancer cells. Next, we further evaluated the growth inhibitory effect of compound A in two sets of NSCLC panels which are either sensitive or resistant to gefitinib treatment. Interestingly, the cell lines which are resistant to gefitinib are highly sensitive to compound A treatment, whereas the gefitinib-sensitive (GS) cell lines are not responsive to the compound A treatment. In gefitinib resistant (GR) cells, compound A increases expression of autophagy markers, p62 and LC3, which might result in the growth inhibition of the GR panel of cells but not in the GS cell panel.
Moreover, we profiled the metabolic genes in the GR and GS cell lines. Surprisingly, compound A treatment significantly reduces the expression of a subset of enzymes associated with Warburg effect, which includes GLUT1, LDHA, PDK1, HK1, and HK2. As a result, compound A decreases Warburg effect, subsequently suppressing cell proliferation, especially of the GR cell lines.
Taken together, compound A decreases Warburg effect and up-regulates autophagy process that may contribute to tumor suppression function of compound A in gefitinib-resistant cancer.
Citation Format: Ai N. H. Phan, Yangsik Jeong. Anti-tumorigenic function of polyphenolic compounds on gefitinib resistant lung 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 5551. doi:10.1158/1538-7445.AM2015-5551
Abstract 5559: Novel synthetic pyridyl analogues of CDDO-Im with improved stability and their potential use in cancer prevention
Authors: Cao Martine , Onyango Evans , Williams Charlotte , Royce Darlene , Gribble Gordon , Sporn Michael , Liby Karen 
Published: August 2015

Abstract
Synthetic oleanane triterpenoids are non-cytotoxic, multifunctional drugs with a broad spectrum of applications for prevention and treatment of cancer and for many other chronic diseases. CDDO-Im, 1[2-Cyano-3,12-dioxooleana-1,9(11-dien-28-oyl] imidazole, synthesized more than a decade ago, is one of the most potent triterpenoids known to date with marked anti-inflammatory, cytoprotective, antiproliferative, differentiative and proapoptotic activity on various human and murine tumor cell lines. However, pharmacokinetics of CDDO-Im are not optimal. Therefore, three new pyridyl analogues of CDDO-Im, namely CDDO-3P-Im, CDDO-2P-Im and CDDO-4P-Im, have been synthesized and screened for their possible use as chemopreventive or chemotherapeutic drugs. At low nanomolar concentrations, they were equivalent to CDDO-Im for induction of differentiation in U937 leukemia cells and at higher doses they induced apoptosis. As inflammation and oxidative stress contribute to carcinogenesis, we also assessed their cytoprotective potential. The new compounds suppressed inducible nitric oxide synthase expression in RAW264.7 macrophage-like cells and significantly induced heme oxygenase-1 and NADPH quinone reductase mRNA and protein levels in lung cancer cells as well as in various mouse tissues. Most importantly, pharmacokinetic studies performed in vitro in human plasma and in vivo revealed superior stability for each new analogue. While CDDO-Im was almost completely degraded after 30 min (&lt; 12% of starting material remaining) in human plasma, the new compounds were more stable with &gt; 50% still detectable. Six hours after gavage, much higher concentrations of the new derivatives were found in mouse liver, lung, pancreas and kidney in contrast to CDDO-Im. Thus, the new pyridyl analogues have better bioavailability, and because of their potent anti-inflammatory activity and improved stability, they will be tested in vivo in relevant carcinogenesis models.
Citation Format: Martine Cao, Evans Onyango, Charlotte Williams, Darlene Royce, Gordon Gribble, Michael Sporn, Karen Liby. Novel synthetic pyridyl analogues of CDDO-Im with improved stability and their potential use in cancer prevention. [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 5559. doi:10.1158/1538-7445.AM2015-5559
Abstract 5561: Violacein inhibits matrix metalloproteinase mediated CXCR4 expression: Potential anti-tumor effect in cancer invasion and metastasis
Authors: Tiriveedhi Venkataswarup 
Published: August 2015

Abstract
Matrix metalloproteinases (MMP-2 and -9) play an important role in the tumor metastasis through cleavage of proinflammatory chemokines. Violacein a small molecule naturally produced by Chromobacterium violaceum has been implicated with anti-tumor effects. In this study we investigated the molecular basis of violacein mediated downregulation of CXCL12-CXCR4, chemokine-receptor expression. Gelatin zymography analysis demonstrated that violacein significantly inhibited the cytokine (TNFα and TGFβ) mediated MMP-2 activation in MCF-7 breast cancer cell line. MMP-2 plays a critical role in the secretion of inflammatory CXCL12 a cell migration chemokine. ELISA analysis demonstrated that violacein induced significantly decreased secretion of CXCL12 from cytokine induced MCF-7 cells. Further, we show that MMP-2 and MMP-9 act synergistically at two distinct steps towards the membrane expression of the tumor metastasis chemokine receptor, CXCR4. Violacein efficiently downregulated the CXCR4 membrane expression through MMP-9 inhibition. Taken together, these studies demonstrate the unique mechanism of action of violacein towards potential anti-tumor effect through reduction of CXCL12-CXCR4 expression by inhibition of proteolytic MMP activity. Based on these studies violacein could offer a novel therapeutic venue in cancer therapy.
Citation Format: Venkataswarup Tiriveedhi. Violacein inhibits matrix metalloproteinase mediated CXCR4 expression: Potential anti-tumor effect in cancer invasion and metastasis. [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 5561. doi:10.1158/1538-7445.AM2015-5561
Abstract 557: A novel integrated i-FISH technology to detect and characterize non-hematopoietic heteroploid CTC subtypes with or without expressing vimentin or other tumor biomarkers
Authors: Lin Peter 
Published: August 2015

Abstract
Most of the current circulating tumor cell (CTC) detection technologies rely on expression of EpCAM and cytokeratins (CK) as well as the size of tumor cells shed into peripheral blood of cancer patients or tumor animal models. However, it has been demonstrated that expression of EpCAM and/or cytokeratins in CTCs might be down-regulated or absent during epithelial-mesenchymal transition (EMT), potentially resulting in significant false negative detection of CTCs. Whereas expression of vimentin in EMT tumor cells has been reported. In this study, a new strategy integrating phenotypic immunofluorescent staining of vimentin and karyotypic FISH has been well developed to detect and characterize CTC and its subtypes isolated by subtraction enrichment in various biofluid samples including blood, bone marrow, malignant pleural effusion and ascites as well as cerebrospinal fluid of cancer patients or blood samples of mice bearing human tumors. Both large and small and clusters of vimentin positive or negative non-hematopoietic CTCs with heteroploid chromosome(s) were identified. The similar procedure has also been successfully extended to other desired single or combined tumor biomarkers in addition to vimentin as needed. The established SET-iFISH® platform will help identify and characterize diversified CTC subtypes which may possess distinct clinical significance in terms of drug sensitivity, resistance, and tumor metastasis as well as recurrence, respectively.
Citation Format: Peter Lin. A novel integrated i-FISH technology to detect and characterize non-hematopoietic heteroploid CTC subtypes with or without expressing vimentin or other tumor biomarkers. [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 557. doi:10.1158/1538-7445.AM2015-557
Abstract 5571: Technologies for molecular epidemiology in cancer
Authors: Divi Rao L. , Verma Mukesh , Dickherber Anthony 
Published: August 2015

Abstract
Future success in molecular epidemiology depends on how quickly epidemiology adopts, optimizes and validates emerging technologies for molecular-scale analysis. In order to advance molecular epidemiology in cancer, the National Cancer Institute (NCI) supports the development of novel, next-generation, and cutting-edge molecular and cellular analysis technologies. Here we present past and present technology development efforts and their impact on cancer epidemiology. Some of the technologies, whose early-stage development was supported by the NCI, such as resequencing arrays, gene expression assay system, technologies which enable next generation sequencing, RNA preservative, rolling circle amplification of DNA, digital PCR system, functionalization of quantum dots, chromatin immunoprecipitation with next gen Sequencing, and multidimensional protein identification technology are now mainstay in basic and clinical research laboratories for genomic, epigenomic, transcriptomic and proteomic analysis. Additionally, these technologies have significantly contributed in identifying molecular determinants of cancer, and in assessing risk, disease progression and prognosis in large scale cancer epidemiology. Current awards support developing technologies for single cell analysis which can capture heterogeneity, simultaneous detection of multiple oncogenes, sensitive sequencing of geneomic/somatic mutations, targeted sequencing, rare variant detection, sequencing of ultralow-frequency mutations, epigenetic changes, kinome, multiplexed detection of microRNA, proteins, cytokines and metabolites, circulating tumor cells, and highthroughput protein-DNA interactions assessment. In addition, several novel biospecimen collection, preservation and processing technologies are also being supported with the potential to define the future of molecular epidemiology. Collectively, these technology development efforts supported by NCI provide a tremendous opportunity for molecular epidemiologists wishing to study archived samples collected in large-scale epidemiology efforts, and optimize and validate them for new molecular analyses.
Citation Format: Rao L. Divi, Mukesh Verma, Anthony Dickherber. Technologies for molecular epidemiology in 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 5571. doi:10.1158/1538-7445.AM2015-5571