bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 135: Apoptotic cell death triggering in the prostate carcinoma cell line PC3 by the anoikis effector Bit1
Authors: Biliran Hector R. , Leleux Kelly E. , Eubanks Jolisha S. , Ireland Shubha K. 
Published: February 2011

Abstract
Highly aggressive cancer cells often are associated with resistance to caspase-dependent apoptosis, due, in part to loss in function or mutation in caspase effectors. Such apoptotic defects in caspase signaling pathway may provide a selective growth advantage for tumor cells and potentiate their aggressiveness and resistance to chemotherapeutic agents. Here, we test the responsiveness of the highly aggressive prostate cancer cell line PC3 cells to the apoptotic function of the novel, caspase-independent anoikis effector Bcl2 inhibitor of transcription (Bit1). Overexpression of the cytoplasmic localized Bit1 in PC3 cells results in significant induction of apoptosis as evidenced by the increased levels of histone-DNA fragments. Furthermore, PC3 cells transfected with the mitochondrial localized Bit1 exhibit significant apoptosis following loss of cell attachment as compared to vector treated cells, and such induction of anoikis is associated with increased levels of Bit1 in the cytosol. In contrast, both the control and Bit1 transfected PC3 cells show the same level of spontaneous apoptosis when grown attached to a culture dish. We also tested whether Bit1 alters the chemoresistant phenotype of PC3 cells. Consistent with the induction of anoikis sensitivity, overexpression of mitochondrial Bit1 also renders PC3 cells more sensitive to etoposide-induced apoptosis. Interestingly, the Bit1-mediated apoptosis in PC3 cells is correlated with increased NFkappa B activity as evidenced by increased nuclear translocation and transcription factor activity of the p65 subunit. Taken together, these findings indicate that activation of the caspase-independent Bit1 apoptotic pathway may serve as a preferred alternate approach in triggering apoptosis in aggressive prostate cancer cells. Bit1 may thus serve as a future therapeutic target for the treatment and alleviation of the chemoresistance characteristic of prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 135.
Abstract 1369: A novel anti-angiogenic vector with vascular disrupting activity as a promising treatment for metastatic cancer
Authors: Breitbart Eyal , Bangio Livant , Harats Dror , Greenberger Shoshana , Varda-Bloom Nira 
Published: February 2011

Abstract
A novel anti-angiogenic vector with vascular disrupting activity as a promising treatment for metastatic cancer
Breitbart E1, Greenberger S2, Varda-Bloom N2, Bangio L1, Harats D1
1VBL Therapeutics, Or Yehuda, Israel, 2Sheba Medical Center, Ramat Gan, Israel
Background: A major drawback of current approaches to cancer therapy is the lack of tissue-specific targeting. We have developed both tissue and condition-specific expression vascular targeting system (VTS) platform directed to areas in which angiogenesis is taking place, without perpetually harming the body's healthy tissues, to destroy these newly formed blood vessels of solid tumors. We have constructed VB-111 as a vascular disruptive (VDA) and anti-angiogenic agent.
Results: In vitro, VB-111 induced a dose dependent apoptotic death in HUVEC but not in non endothelial cells confirming its specificity. In a comprehensive set of in vivo studies employing the Lewis Lung metastasis mouse model, VB111 was safe and specific with activity only in the metastatic lesion themselves. VB-111 induced a dose dependent reduction of 90% in tumor burden of lung metastases with one injection and similar efficacy in other tumor models. Evaluation of the activity of Sutent in Lewis lung metastasis model showed better efficacy of VB-111 as compared to Sutent 40 or 80 mg/kg. Additive effect was reached when mice were treated with VB-111 and Doxorubicin 2.5mg/kg.
Conclusions: Collectively, our studies demonstrate that VB-111 is safe and specific. VB111 shows a dual action of anti-angiogenic and vascular disruptive agent. VB-111 has the potential to be utilized as a relatively broad-spectrum anticancer agent efficacious in different types of solid tumors. These findings have prompted us to proceed to clinical trials that are reported elsewhere.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1369.
Abstract 137: Targeting IAPs: NF-κB signaling pathways play a critical role in IAP antagonist induced apoptosis
Authors: Varfolomeev Eugene , Goncharov Tatiana , Vucic Domagoj 
Published: February 2011

Abstract
Inhibition of apoptosis enhances the survival of cancer cells and facilitates their escape from immune surveillance and cytotoxic therapies. Inhibitor of apoptosis (IAP) proteins are anti-apoptotic regulators that block cell death in response to diverse stimuli. Because these proteins play an active role in promoting tumor maintenance, they are attractive targets for developing a novel class of cancer therapeutics. Through TRAF2 interactions, c-IAP1 and c-IAP2 are recruited to tumor necrosis factor receptor 1 (TNFR1)-associated protein complexes where they regulate receptor-mediated signaling. The ubiquitin E3 ligase activity of c-IAP1/2 regulates canonical and noncanonical NF-κB pathways by promoting ubiquitination of RIP1 and NIK. We have designed small-molecule IAP antagonists that bind with high affinities to select baculovirus IAP repeat (BIR) domains of IAPs resulting in a dramatic induction of c-IAP auto-ubiquitination and rapid proteasomal degradation. Neutralization of c-IAPs through knockdown or small-molecule IAP antagonists blunts TNF stimulated NF-κB activation and greatly sensitizes cells to TNF induced cell death. Investigation of death receptor signaling complexes revealed that FLIP plays an important role in IAP antagonist stimulated apoptotic pathways and that down-regulation of FLIP sensitizes otherwise resistant cells to IAP antagonist induced cell death. In addition, regulation of NF-kB signaling pathways by cellular IAPs represents a pivotal point in IAP antagonists induced cell death. The interplay between pro-survival and pro-apoptotic signaling involves multiple levels of coordination and the regulation of these processes can determine the fate of treated cells. Finally, our IAP antagonists inhibit tumor growth in vivo as single agents and in combination with a number of standard of care anti-tumor agents including death receptor agonists. Interestingly, while single-agent activity of IAP antagonists relies on TNF signaling, the synergistic activity of IAP antagonists with FasL or anti-DR5 antibody does not depend on TNF signaling but on XIAP antagonism. Understanding the significance of protein stability and death receptors mediated pathways for inhibition of apoptosis by IAP proteins is important for the design of potent IAP-directed compounds. These compounds can be used in the treatment of malignancies in which IAP expression contributes to tumor progression and resistance to conventional chemotherapeutic agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 137.
Abstract 1376: Antiangiogenic properties of the peptide CIGB-300
Authors: Farina Hernán G. , Acero Fernando Benavent , Perera Yasser , Rodríguez Arielis , Perea Silvio , Castro Boris Acevedo , Gomez Roberto , Alonso Daniel F. , Gomez Daniel E. 
Published: February 2011

Abstract
CK2 is a highly conserved protein serine/threonine kinase that is ubiquitously distributed in eukaryotes, constitutively active and has been implicated in multiple cellular functions, as well as in tumorigenesis and transformation. Elevated CK2 activity has been associated with the malignant transformation of several tissues and is associated with aggressive tumor behavior. Previously, we have described a peptide CIGB-300 (also named P15-Tat) targeting the acidic phophorylation domain of the CK2 substrates. Different groups around the world have tried to manipulate this biochemical event by targeting the ATP-binding site of CK2 or its gene transcription using antisense oligonucleotides. Otherwise, CIGB-300 peptide was developed following the innovative approach of targeting the phosphoaceptor site on the CK2 substrates rather than the enzyme per se. We demonstrated that CIGB-300 induced apoptosis on tumor cells and tumor regression when injected directly into solid tumors or by systemic administration in mice.
In this work we have evaluated the CIGB-300 peptide on the angiogenic process, both in vitro and in vivo. We have focused in the exploration of CIGB-300 properties to inhibit proliferation, tube formation and RNA pattern expression on endothelial cells (HUVEC). Likewise we used the chicken chorioallatoic membrane (CAM) assay as a model in vivo to asses the CIGB-300 activity on angiogenesis. Others authors have studied the role of different CK2 inhibitors on angiogenesis finding that CK2 is involved in endothelial cell proliferation, survival, migration and tube formation. Intraperitoneally administered CK2 inhibitors significantly reduced preretinal neovascularization in a mouse model of proliferative retinopathy. Solid tumors require the growth of new blood vessels (angiogenesis) to grow. Tumor angiogenesis utilizes at least some of the angiogenic signalling pathways that are required during vascular development. Tumor angiogenesis has become an important target for antitumor therapy, with most current therapies aimed at blocking the VEGF pathway. However, not all tumors are responsive to VEGF blockers, and some of them that are responsive initially may become resistant during the course of treatment, thus there is a need to explore other angiogenesis signalling pathways.
In this paper we have examined the antiangiogenic properties of CIGB-300 peptide in vitro and in vivo. The data suggests that CK2 is involved in angiogenic processes and CIGB-300 could act as promising antiangiogenic inhibitor.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1376.
Abstract 1378: Preclinical efficacy of the triple VEGFR inhibitor tivozanib (AV-951) in chimeric breast and lung tumor models
Authors: Zhou Yinghui , Zi Tong , Bressel Angela , Jesmer Kristen , Potz Darren , Monti Anthony , Brodeur Joelle , Rideout William , Chiu Maria Isabel , Robinson Murray O. , Heyer Joerg 
Published: February 2011

Abstract
All solid tumors are thought to require neo-vascularization. Therefore pharmacologic inhibition of angiogenesis may represent an important component for treating many therapeutically challenging tumor types. One attractive anti-angiogenesis agent is the ATP competitive small molecule VEGFR inhibitor tivozanib (AV-951). Tivozanib exhibits picomolar inhibitory activity against all three VEGF receptors, a multi-day T1/2 in humans, and demonstrates robust clinical activity in renal cell carcinoma, the signal tumor type for VEGF pathway inhibition. To test preclinical efficacy of tivozanib in other cancer types, we chose primary mouse tumor models due to their ability to capture the complex heterotypic interactions between tumor cells and the microenvironments. Our mouse tumor model strategy involves stepwise genetic manipulation of embryonic stem (ES) cells and chimera formation to enable direct tumor induction in tissues containing both normal and engineered cells. A HER2 driven breast model as well as an allelic series of lung cancer models containing EGFR, KRAS, or HER2 oncogenes demonstrated that resultant adenocarcinomas arose within surrounding normal tissue and exhibited features of advanced malignancies.
In this study, we tested the response of HER2 driven breast tumors as well as KRAS and EGFR driven lung tumors to the VEGFR inhibitor tivozanib in tumor bearing chimeric mice. We observed that although tivozanib treatment conferred significant survival benefit to the tumor bearing mice in all three models, it is not able to eradicate all tumor cells. Response to tivozanib in the breast model is much more heterogeneous than in the lung models, with some tumors exhibiting significant regression while others showing progression on treatment, either initially or after a period of response. In contrast, lung tumors showed more uniform response to tivozanib treatment initially, but tumors quickly grew back upon discontinuation of tivozanib treatment. These results indicate that both breast and lung cancer patients could potentially benefit from sustained anti-angiogenesis therapy, and combination of anti-angiogenesis with tumor targeting agents may be required for enduring efficacy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1378.
Abstract 1379: Impact of tumor blood flow modulation on sensitivity of 9L gliosarcoma xenografts to the bioreductive drug, AQ4N
Authors: Manley Eugene , Waxman David J. 
Published: February 2011

Abstract
The bioreductive drug AQ4N is reduced enzymatically under hypoxic conditions to yield AQ4, a cytotoxic metabolite and topoisomerase II inhibitor. This study tests the hypothesis that the two electron reductase DT-diaphorase (NQO1) contributes to AQ4N reduction and that modulation of tumor hypoxia increases AQ4N activity in vivo. A panel of human and rodent tumor cells was assayed for AQ4N sensitivity under normoxic and hypoxic conditions (0.1% O2 for 24 hr), followed by 3 days culture under normoxia without drug. 9L rat gliosarcoma and H460 lung carcinoma, but not 10 other tumor cell lines, exhibited substantially higher (≥ 8 fold) AQ4N sensitivity under hypoxic culture conditions. Investigation of the impact of the DT-diaphorase inhibitors dicumarol and flavone-8-acetic acid on AQ4N cytotoxicity and examination of the cell line dependence of DT-diaphorase protein expression indicated that this enzyme does not contribute to AQ4N cytotoxicity. Next, we investigated whether AQ4N chemosensitivity could be increased by modulating tumor hypoxia in s.c. 9L and H460 tumors implanted in immunodeficient mice. In mice treated with the vasodilator hydralazine, tumor hypoxia was significantly increased in 9L, but not H460 tumors, as determined by pimonidazole staining. Hydralazine also decreased tumor perfusion to a greater extent in 9L tumors than H460 tumors, as judged by uptake of Hoechst 33342. However, hydralazine-induced 9L tumor hypoxia did not increase AQ4N mediated tumor growth delay, in either scid or nude mouse models. Furthermore, combination of AQ4N treatment with inhibition of VEGF receptor-dependent angiogenesis, which increases tumor hypoxia in 9L xenografts, did not augment anti-tumor activity beyond that of VEGF receptor inhibition alone. These findings suggest that the enhancement of AQ4N cytotoxicity in these tumors requires a level of tumor hypoxia that is more extensive or prolonged that can be achieved using these vasodilators and anti-angiogenic agents. Supported in part by NIH grant CA49248 (to D.J.W.).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1379.
Abstract 1382: The sea cucumber-derived anti-cancer triterpenoid, Frondoside A blocks angiogenesis
Authors: Collin Peter D. , Adrian Thomas E. 
Published: February 2011

Abstract
We have previously shown that an extract (B1000) of the epithelial layer of the Atlantic sea cucumber, Cucumaria frondosa inhibited cancer cell proliferation. A pure triterpenoid glycoside, Frondoside A was purified from this extract, and has shown potent growth inhibitory effects, both in vitro and in vivo in pancreatic, colon, prostate, and breast cancer cells but no effect on normal cells. The present studies were aimed at investigating the effects of Frondoside A on angiogenesis. The parent sea cucumber extract, B1000, has marked anti-angiogenic effects in the chick chorioallantoic membrane (CAM) assay. B1000 virtually eliminated vasculature in this model (B1000 mean score of 3.8±0.1; hydrocortisone/heparin positive control: 3.2±0.1, P&lt;0.001, where a score of 3 = almost complete inhibition of vasculature and 4 = complete inhibition). The anti-angiogenic effects of B1000 were confirmed in the endothelial tube formation assay employing human umbilical vein endothelial cells (HUVEC) on matrigel coated slides. B1000 also inhibited migration of C8161 melanoma cells and RA116 synovial fibroblasts in a membrane invasion culture system. Based on these data, we investigated the effect of pure Frondoside A on the ability of HUVEC cells to differentiate into capillary-like structures. At a concentration of 1µM, Frondoside A virtually abolished endothelial tube formation (88±6% inhibition, P&lt;0.0001) and was more than ten-fold more potent than the Suramin positive control in this assay (74±3% inhibition at 10µM). This was not due to cytotoxicity, since the HUVEC cells were viable in the culture, however, they failed to form the tube-like structures seen in control.
These findings indicate that Frondoside A has anti-angiogenic effects in addition to its cancer growth-inhibitory effects. B1000 and Frondoside A may be valuable in the prevention or treatment of solid tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1382.
Abstract 1383: The effect of a novel angiogenesis inhibitor (TM) on the efficacy of HSV-1 oncolytic virus
Authors: Kaka Azeem , Pradarelli Jason C. , Alvarez-Breckenridge Christopher , Yoo Ji Young , Pan Quintin , Chiocca E. Antonio , Old Matthew , Teknos Ted , Kaur Balveen 
Published: February 2011

Abstract
Oncolytic viruses (OVs) are modified viruses specifically designed to lyse cancerous cells while leaving surrounding tissue intact. Solid tumors such as glioma represent an excellent candidate for this novel cancer therapy. We are investigating barriers towards oncolytic viral therapy in vivo. The tumor microenvironment plays an inhibitory role in viral propagation and spread. In particular, the angiogenic and inflammatory response that follows OV inoculation have been demonstrated to significantly limit OV efficacy. The goal of our current project is to determine if the novel copper-chelating angiostatic/anti-inflammatory drug, tetrathiomolybdate (TM), represents a potential co-therapy that can be used in conjunction with OV to enhance overall efficacy in a glioma model. Based on previous findings from our laboratory, the anti-cancerous effects of oncolytic viruses can be significantly increased by pre-treatment with an angiostatic agent. Apart from supporting angiogenesis, copper found in serum has also been shown to inhibit wild-type HSV infection and replication. Due it its copper chelating properties, TM has been FDA approved for Wilson's disease and is currently under clinical investigation for efficacy as an angiostatic and antineoplastic agent. Here we tested if copper can inhibit OV mediated glioma cell killing. 1): We found a significant and dose dependant inhibitory effect of copper on the cytotoxic ability of OV against multiple glioma and head and neck SCC cells. 2): The inhibitory effects of copper were apparent even at physiologically relevant concentrations of copper (1 mg/L in serum). 3): Further we found that Cu mediated inhibition of OV killing of glioma cell could be rescued by TM mediated copper chelation. 4): Finally we have tested that TM does not interfere with viral replication or tumor cell killing properties in vitro. Given the potential angiostatic and anti-inflammatory properties of TM, these studies support further in vivo testing of TM in conjunction with oncolytic viral therapy. 5): We are currently testing therapeutic efficacy of combining TM and OV for anti-glioma efficacy in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1383.
Abstract 1391: Inhibition of Hsp90 induces BRCA1 degradation and hypersensitivity to ionizing radiation
Authors: Stecklein Shane R. , Harlan-Williams Lisa M. , Wang Wenjia , Eskew Jeffrey D. , Chaguturu Vamsee , Jensen Roy A. 
Published: February 2011

Abstract
Cells expressing high levels of breast cancer susceptibility gene 1 (BRCA1) are resistant to ionizing radiation and alkylative chemotherapeutic agents. Ablation of BRCA1 expression in vitro and in vivo can enhance and/or restore sensitivity to these agents.
BRCA1 is a nuclear phosphoprotein that is critical for resolving double-strand DNA (dsDNA) breaks. Thus, its overexpression likely confers an advantage to cancerous cells targeted by anti-neoplastic agents that induce this form of DNA damage. In vitro evidence suggests that ablating BRCA1 expression may present a novel mechanism to enhance or restore radio- and chemosensitivity in refractory cancers. Like BRCA1, high expression of heat shock protein 90 (Hsp90) has been associated with resistance to radiotherapy and chemotherapy, though the mechanism(s) behind this phenotype are poorly characterized. Hsp90 is a cytoplasmic chaperone that is upregulated or exists in a hyperfunctional state in many human malignancies. Previous studies have demonstrated that Hsp90 regulates the assembly of several molecules involved in the homology-directed repair of dsDNA breaks, including BRCA2/FANCD1, FANCA, MRE11/RAD50/NBS1 (MRN), and RAD51. Using in vitro culture of breast, ovarian, and colorectal cancer cell lines, we demonstrate that inhibition of Hsp90 by the pharmacologic agent 17-allylamino-17-demethoxygeldanamycin (17-AAG), which is currently in clinical evaluation, targets BRCA1 for ubiquitylation and proteasome-mediated degradation. Furthermore, inhibition of Hsp90 and the subsequent loss of BRCA1 expression are associated with decreased repair of ionizing radiation-induced DNA damage and increased tumor cell death. Using lentiviral shRNA expression, we also demonstrate that loss of BRCA1 is epistatic to the ability of 17-AAG to sensitize cells to the effects of ionizing radiation, consistent with the central role of BRCA1 in assembling the dsDNA break repair machinery.
These results suggest that inhibition of Hsp90 using an existing therapeutic agent (17-AAG) may be an effective mechanism to transiently inhibit BRCA1 expression and improve or restore radio- and/or chemosensitivity in breast and ovarian cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1391.