bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4231: A 3′-substituted 7-bromoindirubin induces apoptosis of human melanoma cells via inhibition of STAT3 and AKT signaling
Authors: Liu Lucy , Nam Sangkil , Wu Jun , Wang Yan , Skaltsounis Leandros , Jove Richard 
Published: July 2012

Abstract
Small-molecule inhibitors of STAT3 or AKT signaling represent potential molecular-targeted cancer therapeutic agents. Here, we investigated the role of STAT3 and AKT signaling in growth inhibition of human melanoma cells by a 3′-substituted 7-bromoindirunin derivative (MLS2438). Effects of MLS2438 on cell viability, apoptosis and expression of signaling proteins were evaluated by MTS cell viability assay, Annexin V staining and immunobloting analysis respectively in human melanoma cells. SRC and AKT in vitro kinase assays were conducted using recombinant kinases, substrates and 33P-labeled ATP. Immunodeficient NOD/SCID/IL2Rgamma null (NSG) mice were used in the animal studies. We show that MLS2438 inhibits STAT3 and AKT signaling, and induces apoptosis of human melanoma cells. MLS2438 directly inhibits SRC and AKT kinase activity both in vitro and in intact cancer cells. Moreover, MLS2438-induced apoptosis of human melanoma cells is associated with reduced phosphorylation of SRC, JAK, STAT3 and AKT in both dose- and time-dependent manners. Consistent with inhibition of STAT3 and AKT signaling, the anti-apoptotic protein Mcl-1 and pro-proliferative protein c-Myc were down-regulated. In contrast to the decreased phosphorylation levels of SRC, JAK, STAT3 and AKT, phosphorylation levels of the MAPK (Erk1/2) signaling protein were not inhibited in cells treated with MLS2438. Importantly, MLS2438 suppressed tumor growth in vivo with low toxicity in an A2058 human melanoma xenograft mouse model. Our data demonstrate that MLS2438, a novel natural product derivative, induces apoptosis of human melanoma cells associated with inhibition of STAT3 and AKT signaling. Our findings support further development of MLS2438 as a potential small-molecule inhibitor that targets STAT3 and AKT signaling in tumor cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4231. doi:10.1158/1538-7445.AM2011-4231
Abstract 4232: Naematoloma sublateritium extracts suppresses TNF-alpha-induced expression of adhesion molecules through down-regulation of NF kappa B in human umbilical vein endothelial cells
Authors: Lee Yu Ran , Jang Hyun Jae , Jeon Byeong Hwa , Kim Tae Woong , Kim Ji Hong , Choi Jong Woon , Choi Sunga 
Published: July 2012

Abstract
Inflammation is considered to play an important role in the cancer pathophysiology as a result of chronic reaction in vivo. Chronic inflammation has been involved in carcinogenesis including cellular transformation, proliferation, invasion, angiogenesis and metastasis as well as vascular diseases. During the carcinogenesis, several kinds of pro-inflammatory cytokines and chemokines which were produced by tumor-infiltrating inflammatory cells can activate NFκB transcriptional factor influencing proliferation, differentiation and movement of tumor cells. Therefore, the regulation of NFκB signaling pathway and might be a therapeutically impact diseases associated with cancer. Naematolma (=Hypholoma) is a basidiomycete of the fungus that is known to produce antitumor compound, clavaric acid. In this present study, we report for the first time that Naematoloma sublateritium butanol fraction (NSBF) dose-dependently inhibited TNF alpha-induced monocyte adhesion to endothelial cells. Anti-adhesive activity of NSBF was correlated with the suppressed expression of monocyte chemoattractant protein-1, interleukin-8, vascular cell adhesion molecule-1 and intercellular cell adhesion molecule-1 at both mRNA and protein levels. In addition, NSBF significantly regulated nuclear factor (NF)-kB activation by TNF-alpha in luciferase reporter assay. Interestingly, NSBF also inhibited cyclooxygenase-2 expression in dose-dependent manner. It suggests the down-regulation of cyclooxygenase-2 might be correlated with inhibition of proliferation in human breast cancer cell lines, MCF7 and MDA-MB-231. In conclusion, we propose that NSBF may be a safe and potential therapeutic agent against chronic inflammation such as cancers.
* This study was supported by Forest Sceince & Technology Projects (NO. S120910L110000) KFS (Korea Forest Service)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4232. doi:10.1158/1538-7445.AM2011-4232
Abstract 4234: Ursolic acid induces apoptosis in pancreatic cancer cells associated with inhibition of STAT3 and down-regulation of Bcl-XL
Authors: Leal Ana S. , Salvador Jorge , Jing Yongkui 
Published: July 2012

Abstract
Pancreatic cancer is the fourth leading cause of cancer death and without effective medical therapy. New agents acting on novel targets need to be developed. Natural products provide a promising source for developing effective anticancer agents. Oleanolic acid (OA) and ursolic acid (UA) are two natural triterpenoids with reported antitumor activities in several types of cancer. The antitumor effects of OA, oleanolic acid methyl ester (OAME) and UA were determined in pancreatic cancer Aspc-1 cells. Cell growth inhibition of the three compounds was determined using the MTT assay. The IG50s of OA, OAME and UA after treatment with UA for 4 days are &gt;30, 8.9, 12.5 μM, respectively. OA is a weak cell growth inhibitor and methyl esterification improves its antitumor activity. UA is more effective than OA to inhibit cell growth in Aspc-1 cells and was used to study the mechanism of action. Aspc-1 cells treated with UA at a concentration higher than 25 uM induced apoptosis as determined by PARP cleavage detection. Western blot analysis revealed that the levels of procaspase-3, -9 and Bcl-XL were markedly decreased while the levels of Mcl-1, XIAP and survivin were weakly or not decreased. Correlated with the decrease in the level of Bcl-XL, the level of phosphorylated STAT3 was significantly inhibited. STAT3 is activated in pancreatic cancer cells and contributes to pancreatic tumorigenesis. Activated STAT3 increases the levels of antiapoptotic protein such as Bcl-XL, Mcl-1 and survivin, are being considered as a target for developing agents for pancreatic cancer treatment. Our data suggest that UA is a lead candidate for targeting STAT3 and structural modification of UA may result in a new group of compounds with improved antitumor activity in pancreatic cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4234. doi:10.1158/1538-7445.AM2011-4234
Abstract 4248: Antiangiogenic mechanisms of Aflibercept in mouse hepatoma model
Authors: Torimura Takuji , Ueno Takato , Iwamoto Hideki , Nakamura Toru , Koga Hironori , Yano Hirohisa , Sata Michio 
Published: July 2012

Abstract
[Background/Aim] VEGF plays a critical role in vascular development in tumor tissues. A new angiogenic inhibitor, aflibercept is a soluble decoy VEGF receptor created by fusing the Ig domains of VEGF receptor1 and 2 and captures VEGF and PlGF in the blood stream. We have reported that aflibercept suppresses tumor growth by inhibiting vascular development in mouse hepatoma model. In the present study, we investigated the precise antiangiogenic mechanisms of aflibercept in mouse hepatoma model.
[Materials and methods] in vitro study: The inhibitory effects of aflibercept on cell proliferation of HUVEC and on phosphorylation of VEGF receptor 1 and 2 were evaluated. Influence of VEGF, PlGF and aflibercept on the phosphorylation of VEGF receptor 1 and 2, PI3K, AKT, and mTOR and the expression of VEGF by murine hepatoma cell line (Hepa1-6) were evaluated. The inhibitory effect of aflibercept on endothelial progenitor cells (EPC) differentiation was evaluated by colony-forming units (CFU) of EPC. I n vivo study: Aflibercept was injected intraperitoneally twice a week into tumor bearing nude mice of hepatoma cells (HuH-7, HAK1-B, KYN-2, Hepa1-6). Microvessel density in tumor tissue was counted. Hepa1-6 was implanted to GFP-bone marrow transplanted (BMT) mice to investigate the inhibitory effect of aflibercept on homing of EPC to tumor tissues. The expression of PlGF, VEGF in tumor tissue and Hepa1-6 cells was evaluated.
[Results] in vitro study: Although VEGF stimulated the cell proliferation of HUVEC, PlGF did not upregulate the cell proliferation. Aflibercept suppressed the phosphorylation of VEGF receptor-1 and 2 and also inhibited the cell proliferation of HUVEC. In Hepa1-6 cells, VEGF phosphorylated VEGF receptor-1 and 2. PlGF phosphorylated VEGF receptor-1. VEGF and PlGF phosphorylated PI3K, AKT and mTOR. Aflibercept suppressed the phosphorylation of VEGF receptor-1, 2, PI3K, AKT and mTOR. Aflibercept suppressed the upregulated VEGF production by PlGF in Hepa1-6 cells. in vivo study: Aflibercept suppressed the homing of bone marrow cells to tumor tissues, the differentiation of bone marrow cell to EPC and also reduced microvessel density. The expression of VEGF in tumor tissue was suppressed by aflibercept administration.
[Conclusion] Aflibercept suppresses the vascular development in hepatoma by inhibiting endothelial cells proliferation, VEGFavailability, homing of bone marrow cells to tumor tissue and EPC differentiation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4248. doi:10.1158/1538-7445.AM2011-4248
Abstract 4249: NGR-TNF, a novel direct-acting vascular targeting agent, does not induce “cytokine-rebound” recruitment of pro-angiogenic bone-marrow derived cells
Authors: Matteo Paola Di , Hackl Christina , Jedeszko Christopher , Valentinis Barbara , Bordignon Claudio , Traversari Catia , Kerbel Robert S. , Rizzardi Gian-Paolo 
Published: July 2012

Abstract
NGR-TNF, presently in advanced clinical development, is a direct-acting vascular targeting agent coupling the CNGRCG peptide (NGR), homing to angiogenic blood vessels, and tumour necrosis factor alpha (TNF). In order to further elucidate the mechanism of action, we investigated whether NGR-TNF mobilizes bone-marrow derived cells (BMDCs) and growth factors. Herein, treatment with either certain chemotherapy drugs at maximum tolerated dose (e.g. paclitaxel, cyclophosphamide, 5-FU), vascular-disrupting agents (VDAs; e.g. fosbretabulin, Oxi4503), or local irradiation can rapidly induce mobilization and subsequent tumor homing of proangiogenic BMDCs, such as circulating endothelial progenitor cells (CEPs), CD11b/Tie-2-expressing monocytes (TEMs), CD11b+Gr1+ neutrophils and myeloid-derived suppressor cells (MDSCs), and CD11b+F4/80+ macrophages. Increase in several growth factors and chemokines, such as SDF-1, G-CSF as well as osteopontin, contribute to the mobilization of BMDCs that colonize the tumour site and induce angiogenesis and rapid tumor regrowth. Lewis lung carcinoma (LLC) cells were subcutaneously implanted into immunocompetent C57BL/6J mice or into GFP+ bone marrow-chimeric mice, obtained by transplanting into lethally irradiated C57BL/6J mice bone marrow cells from UBI-GFP/BL6 donors. Blood was obtained 4 or 24 hours after treatment with either NGR-TNF, VDA, an anti-VEGFR2/flk-1 antibody or saline, by either cardiac puncture or retro-orbital sinus bleeding. Using flow cytometry (LSRII), CEPs were defined as CD45-/CD13+/flk-1+/CD117+/7AAD-, TEMs as CD45+/CD11b+/Tie2+/flk-1+ and MDSCs as CD45+/CD11b+/Gr1+ cells. Levels of circulating growth factors were assessed by ELISAs. When administrated at low doses (optimal biological dose), comparable to doses being used in clinical trials, NGR-TNF causes a decrease of tumor blood vessels density and induces apoptosis of tumor cells and tumor endothelial cells in vivo. It is worth noting that, unlike the above-mentioned treatments, NGR-TNF fails to mobilize or recruit to the tumor site different subtypes of pro-angiogenic BMDCs nor induces growth factors. Therefore, low doses of NGR-TNF exert an antitumor activity without inducing reactive a pro-angiogenic host response, which is likely an important feature for preventing/overcoming resistance and for designing combination therapeutic strategies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4249. doi:10.1158/1538-7445.AM2011-4249
Abstract 425: Alteration of ADAM9 and integrin interaction regulated cancer invasion and metastasis potential
Authors: He Yun-Chi , Liu Jer-Ming , Sung Shian-Ying 
Published: July 2012

Abstract
Alteration of integrin composition is highly correlated with cancer malignancy and metastasis. Recent evidence demonstrated the metastasis activities involved the interaction of integrin and ADAM gene family, such as ADAM8, ADAM9, ADAM10 and ADAM17. These may either stabilized or cleavage of integrin-matrice interaction at the lamellipodia of cancer cell. Mahimakar et al., recently demonstrated the interaction of ADAM9 with integrins alpha3, alpha6 and beta1 by pull down assay, suggests ADAM9 might work together with β1 class integrins. To further analyze their roles and possible downstream regulatory proteins, we perform knockdown of ADAM9 using shRNA and determine its role in cancer metastasis both in vitro and in vivo. Western blotting confirmed the knockdown of ADAM9 in prostate cancer, and oral cell carcinoma. Cell migration assay was performed using micro-slide Chemotaxis chambers either with or without collagen coating. Time-Lapse microscope analysis of cell migration was plotted and analyzed. Interestingly, we observed the opposite cell migration behavior in which faster and longer cell migration activities was observed in cancer cell with knockdown of ADAM9 expression in the chamber coated with collagen, whereas less migration activities was observed in chamber without collagen coating. This may reflect the possible role of ADAM9 in alteration of integrin composition or function. Flow Cytometry analyses of integrin composition on the surface of prostate cancer cells revealed no integrin composition change in knockdown strain compared to parental. We also notice highly expression of integrin alpha2beta1 and alpha6beta4 in C4-2 and PC3 cells. Analyses of signaling pathways demonstrated no significant changes in p-FAK, p-Erk and p-Akt, suggesting not through beta1 downstream signal regulation. Immunoprecipitation of ADAM9 demonstrated the highly associated with integrin beta4 but not beta1. Intra-cardiac injection of prostate cancer cell line, PC3-pSM2C, PC3-siADAM9 demonstrated 100% metastasis activities in PC3-pSM2C, and no any metastasis in mice with PC3-siADAM9. In summary, we notice ADAM9 may associated with the activation/stabilization of integrin complex. Knockdown of ADAM9 demonstrated decreased of cell migration on dish and metastasis when inoculated in mice, suggests hemidesmosome-ADAM9 interaction may involved in cancer migration and metastasis potential.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 425. doi:10.1158/1538-7445.AM2011-425
Abstract 4259: Preclinical anti-tumor study of henatinib, a novel and selective inhibitor of VEGFR-2 in phase I clinical trials
Authors: Quan Haitian , Chengying Xie , Xu Yongping , Liguang Lou 
Published: July 2012

Abstract
Inhibition of VEGF/VEGFR-2 signaling represents a promising therapeutic approach to solid malignancies. Here, we demonstrated that henatinib, a selective VEGFR-2/KDR inhibitor, exhibited potent anti-angiogenic and anti-tumor activity. Henatinib inhibited the activity of VEGFR-2, c-kit, PDGFRα and PDGFRβ with IC50 values of 0.6 nM, 3.3 nM and 41.5 nM, respectively. Henatinib significantly inhibited VEGFR-2 phosphorylation and its downstream signal pathway in human umbilical vein endothelial cells (HUVECs), and consistently inhibited VEGF-stimulated HUVEC proliferation, migration and tubule formation, and micro-vessels spouting from matrigel-embedded rat aortic rings. In vivo, henatinib exhibited broad and potent anti-tumor activity, leading to regression or growth arrest of various established xenografts derived from human tumor cell lines. In summary, preclinical data indicate that henatinib is a novel and selective VEGFR-2 inhibitor with potent in vivo anti-tumor activity. Henatinib is currently in phase I clinical trials in China.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4259. doi:10.1158/1538-7445.AM2011-4259
Abstract 426: The molecular microenvironment critically affects the formation of isoDGR-dependent integrin binding sites in fibronectin
Authors: Curnis Flavio , Sacchi Angela , Longhi Renato , Corti Angelo 
Published: July 2012

Abstract
Fibronectin (FN) is an adhesive protein present in most body fluids and in the extracellular matrix of many tissues. This protein mediates a variety of cellular interactions with extracellular matrix and play important roles in haemostasis, thrombosis, inflammation, wound repair and angiogenesis. FN is constituted of three types of repeating homologous modules termed FN-I, FN-II and FN-III. Each module contains binding sites for molecules of the extracellular matrix and for cell adhesion receptors, such as integrins. Moreover, FN contains four NGR sites located in the: 5th type I, 2nd type II, 7th type I repeat, 9th type III repeats. We have previously shown that the NGR site of the 5th type I repeat (FN-I5) rapidly undergoes deamidation leading to formation of isoDGR. A deamidated FN fragment corresponding to this domain binds αvβ3, inhibits endothelial cell adhesion and proliferation and inhibits tumor growth in animal models. In the present study we have investigated the molecular mechanisms that regulate isoDGR formation in FN in vivo. We provide evidence to suggest that FN purified from plasma contains very low amounts of isoDGR (&lt;3%) despite its long half life (48h). In contrast, using anti-isoDGR antibodies, we observed that isoDGR is formed in significant amounts in small FN fragments injected in mice and left to circulate for 4 or 6 h (&gt;17% in 4 h). In vitro cell adhesion assays, antibody binding assays and integrin binding studies showed that FN deamidation can rapidly occur when FN is bound to microtiter plates, a condition known to cause conformational changes in this protein, but not with FN in solution. Rapid deamidation was observed to occur also with short fragments (FN-I5), either adsorbed on microtiter plates or in solution. These results suggest that the kinetics of NGR-to-isoDGR transition in plasma FN is slower than its clearance rate. Furthermore, the finding that conformational changes and/or protein fragmentation increase the kinetics of NGR-to-isoDGR transition suggest that changes in the molecular microenvironment of NGR sites, potentially occurring after FN deposition in tissues, could be critical for the formation of isoDGR integrin binding sites.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 426. doi:10.1158/1538-7445.AM2011-426
Abstract 4262: Regorafenib (BAY 73-4506): A broad spectrum tumor deactivator with high combinability potential and antimetastasis activity
Authors: Zopf Dieter , Scholz Arne , Fichtner Iduna , Becker Michael , Müller Tina , Kissel Maria 
Published: July 2012

Abstract
Regorafenib is an oral multi-kinase inhibitor which is in clinical development for the treatment of patients with metastatic and/or unresectable gastrointestinal stromal tumors who have failed imatinib and sunitinib therapy and patients with advanced colorectal tumors who have failed standard therapies.
Regorafenib is a tumor deactivation agent that addresses all three mechanisms of tumor growth and progression (angiogenesis, oncogenesis, and stromal interactions) by potently blocking multiple RTKs. Inhibition of angiogenic RTKs (e.g., VEGFR1-3, TIE2) by regorafenib results in breakdown of tumor vascular structure, which disrupts the tumor's oxygen and nutrient supply. Furthermore, regorafenib targets oncogenic RTKs (e.g., KIT, Ret), which control tumor growth, and stromal RTKs (e.g., PDGFR, FGFR), which are implicated not only in the establishment of tumor infrastructure but also in tumor progression.
Regorafenib was evaluated for additional tumor indications in several human cancer xenograft and syngeneic tumor preclinical models as single agent or in combination with standards of care or targeted agents in early clinical development. Regorafenib effectively inhibited tumor growth in a broad spectrum (e.g. liver, stomach, ovarian, breast and colon) of subcutaneous and orthotopic models of human xenograft and murine syngeneic tumors at an oral daily dose of 10mg/kg. Regorafenib inhibited various patient-derived oxaliplatin insensitive colorectal xenografts as single agent and in combination with concomitant irinotecan dosing. Finally, regorafenib was shown to exert potent antimetastasis activity in orthotopic syngeneic 4T1 and triple-negative MDA-MB 231 human xenograft breast cancer models by prevention of the formation of lung or lymph node metastasis, respectively.
In summary, by blocking multiple abnormal angiogenic and oncogenic signalling pathways, regorafenib deactivates tumors and prevents their continued growth and metastatic potential. In preclinical models regorafenib has shown a high potential as a combination partner with other therapeutic agents such as irinotecan, which may make it suitable as a future backbone for treatment of multiple cancer types.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4262. doi:10.1158/1538-7445.AM2011-4262