bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4238: Azadirachta indica leaf extract inhibits mammary carcinogenesis by altering key signaling pathways
Authors: Agullo Pamela A. , Arumugam Arunkumar , Parada Jacqueline , Gamez Monica , Boopalan Thiyagarajan , Delgado Alejandro , Lakshmanaswamy Rajkumar 
Published: June 2012

Abstract
It is estimated that 20-60% of cancer patients utilize some form of alternative medicine. Plant products play a major role in complimentary medicine. Azadirachta indica tree commonly known as neem has been known for centuries to possess medicinal properties like immunomodulatory, anti-inflammatory, antimutagenic, and anticarcinogenic. We have previously shown that A. indica leaf extract has potent anticarcinogenic capabilities in N-methyl-N-nitrosurea (MNU)-induced mammary cancer model. The aim of our study is to explore the molecular pathways through which A. indica induces mammary tumor regression. Seven week old female Lewis rats were administered MNU. On the appearance of the first palpable tumor the rats were divided into groups receiving different doses of ethanolic A. indica leaf extract (ALE): group 1 control, no treatment; group 2 0.125mg/day; group 3: 0.250mg/day; group 4: 0.500mg/day; group 5: 1mg/day. Treatment was daily for 4 weeks intraperitoneally. The animals were euthanized 12 weeks after the termination of treatment and mammary tumor tissue samples were snap frozen and also fixed in formalin. To analyze key gene expression changes we performed pathway focused PCR microarrays for apoptosis, PI3-Kinase, and angiogenesis signaling pathways. Our results show that ALE induces tumor regression, decreases tumor volume, and inhibits mammary tumor growth by altering specific molecular pathways, linked to the stimulation (Bax, caspases) and inhibition (Bcl-2, CDC42)of apoptosis, up-regulation of tumor suppressor genes (PTEN), down-regulation of proto-oncogene Jun, and inhibition of cell survival (Foxg1, BTK, Akt). ALE treatment down-regulated genes fundamental to migration, adhesion and proliferation of tumor cells (EFNA1, Hif1a). Timp1 (TIMP family matrix metalloproteinase inhibitor) and cyclin D1 expression exhibited a clear dose response. Our data indicates that ALE treatment inhibits mammary tumor development by altering apoptosis, PI3-Kinase and angiogenesis pathways. In conclusion, ALE could be used as a novel complimentary agent that offers anticarcinogenic effects against breast cancer and could also be used along with the current standard treatment options.
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 4238. doi:10.1158/1538-7445.AM2011-4238
Abstract 4244: TTAC-0001, fully human anti-VEGFR2/KDR neutralizing antibody blocks tumor angiogenesis and tumor growth
Authors: Lee Weon Sup , Pyun Bo-Jeong , Kim Sung-Woo , Shim Sang Ryeol , Yoo Hyeon-Mi , Oh Keunhee , Lee Dong-Sup , Yoo Ji-Young , Yun Chae-Ok , Kwon Young-Guen , Lee Sang Hoon , Yoo Jin-San 
Published: June 2012

Abstract
Angiogenesis, the recruitment of new blood vessels is a crucial mechanism required for both tumor growth and metastasis. Vascular endothelial growth factor (VEGF) and its receptors, particularly VEGF receptor 2 (VEGFR2, or kinase insert domain-containing receptor, KDR), play a critical role in tumor-associated angiogenesis. Monoclonal antibodies (mAb), due to their high specificity towards a given target, represent a unique class of novel therapeutics as angiogenesis inhibitors. We developed TTAC-0001, anti-KDR antibody from a fully human naïve single chain variable fragment (ScFv) phage library. Interestingly, TTAC-0001 displayed cross reactivity against murine homologue, Flk-1, which allows us to evaluate the anti-tumor efficacy in various in vivo models. TTAC-0001 inhibits VEGF-mediated proliferation and migration. In HUVEC, TTAC-0001 inhibited the phosphorylation of VEGFR2/KDR and ERK mediated by VEGF. TTAC-0001 inhibited VEGF-mediated sprouting endothelial cells from rat aortic rings and showed a potent anti-angiogenic activity in VEGF-mediated matrigel model in nude mice. Further in vivo anti-tumor efficacy of TTAC-0001 was seen in the xenografts of A549 (lung) and HCT116 (colorectal) human cancer. These changes were accompanied by the inhibition of microvessel density and induction of apoptosis in the tumors. In summary, our data indicates that TTAC-0001 blocks the binding of VEGF to VEGFR2/KDR and inhibits VEGFR-induced angiogenesis. Therefore, this data strongly supports for the further development of TTAC-0001 as an anti-cancer agent (This study was supported by grants of the Korea Healthcare technology R&D Project, Ministry for Health & Welfare Affairs (A092255 and A040016) and Advanced Medi-cluster R&D Project, Daejeon TechnoPark, Republic of Korea).
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 4244. doi:10.1158/1538-7445.AM2011-4244
Abstract 4327: Fasting enhances the response of Gl26-glioma to radiation and multiple chemotherapies
Authors: Safdie Fernando , Brandhorst Sebastian , Wei Min , Wang Weijun , Lee Changhan , Hwang Saewon , Chen Thomas , Longo Valter D. 
Published: June 2012

Abstract
Malignant gliomas like anaplastic astrocytoma and glioblastoma mutliforme (GBM) are among the most commonly diagnosed malignant adult brain tumors. GBM is highly invasive and angiogenic and causes mortality rates higher than any other brain tumor, resulting in a median survival for GBM patients that is ∼12 to 15 months. Treatment of GBM is multimodal, usually initiated by surgical resection, followed by the adjuvant therapy of radiation and chemotherapy. Temozolomide is the current standard of care for patients with newly diagnosed gliomas and is well tolerated. Temozolomide has been shown to delay tumor-progression and prolong patient survival. As the treatment of GBM remains elusive, the improvement of existing therapies becomes important.
The beneficial effects of dietary restriction (DR) on reducing age-dependent diseases, such as cancer, are well established. However, DR is expected to require weeks or even months for efficacy in human patients, which eventually would prove ineffective for cancer patients with fast progressing disease status.
We have previously reported that fasting, an intense but brief form of DR differentially protects normal, as opposed to various cancer cells, against the toxicity of high-dose chemotherapy in in-vitro and in-vivo in a neuroblastoma-bearing mice model by causing major changes including the reduction of glucose, and IGF-I. We termed this phenomenon Differential Stress Resistance (DSR).
We show that mimicking plasma-fasting conditions in-vitro sensitizes Gl26-glioma cells to chemotherapy treatment by Temozolomide and causes enhanced cell death of the starved glioma cells. We than applied this model of sensitization of cancer cells under fasting conditions to an intracranial and a subcutaneous glioma-tumor model in-vivo. We demonstrate that short term fasting enhances chemo- and radiotherapy in the in-vivo model and prolongs survival of tumor bearing mice even when compared to Temozolomide treated animals.
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 4327. doi:10.1158/1538-7445.AM2011-4327
Abstract 433: Altered expression of lumican in prostate cancer is identified by microarray analysis
Authors: Wang Yi , De Velasco Marco A. , Okazaki Erina , Izumi Ayaka , Tanka Motoyoshi , Yamamoto Yutaka , Hatanaka Yuji , Yoshimura Kazuhiro , Nozawa Masahiro , Rosser Charles , Goodison Steve , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotugu 
Published: June 2012

Abstract
Prostate cancer is one of the principal medical problems facing men worldwide; fortunately mortality rates from prostate cancer have been decreasing in many developed countries, as a result of improved treatments and early detection. Developing biomarkers that correlate to prostate cancer will facilitate the delivery and development of treatment therapies for patients. To accomplish this we performed a comprehensive genome-wide microarray analysis of genes differentially up- or down-regulated in PSACre;PtenloxP/loxP mutant mice and examined novel differentially expressed genes in to identify novel genes that could potentially serve as biomarkers for disease tumor characterization. Total RNAs were collected form the prostate glands of tumor bearing PSACre;PtenloxP/loxP mutant and wild type mice. cDNAs were generated and were then hybridized onto Affymetrix microarray chips and analyzed with Agilent's Gene Spring software. Microarray analysis revealed that lumican was significantly upregulated in Pten mutant mice compared to wildtype controls. qRT-PCR validation was performed and correlated to the microarray data. Immunohistochemical staining was performed on mouse prostates at various stages of the disease process. Two staining patterns were observed and tabulated, 1) prostate epithelium and 2) stroma. Mouse epithelial cell tended to stain negative in normal glands. Expression increased in moderate and poorly differentiated tumor. The highest expression patterns were observed in the prostates from castrate resistant tumors. More notable was the increased an intense staining seen in the stromal component, especially in the thickened basement membranes cancerous glands. We also examined the expression patterns of lumican in 10 cases of human prostate cancer and benign prostatic hyperplasia (BPH). Epithelial expression in human was moderate to high in benign prostatic hyperplasia, Gleason score 6, 9 and metastatic tumors and moderate in Gleason score 7 tumors. Stromal staining was low in BPH and gradually increased to moderate as the Gleason score increased and high in metastatic lesions. The staining pattern of lumican was very similar to that of vimentin in both human and mouse tissues. Our data has shown that lumican may be differentially expressed in various stages of prostate cancer, however, larger number of clinical need to be evaluated to establish a clear correlation to clinicopathological features.
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 433. doi:10.1158/1538-7445.AM2011-433
Abstract 4334: Targeting p53 null neuroblastomas through RLIP76
Authors: Vatsyayan Rit , Singhal Jyotsana , Yadav Sushma , Nagaprashantha Lokesh Dalasanur , Singhal Sharad S. , Awasthi Sanjay 
Published: June 2012

Abstract
The search for p53-independent mechanism of cancer cell killing is highly relevant to pediatric neuroblastomas, where successful therapy is limited by its transformation into p53 mutant and a highly drug-resistant neoplasm. Our studies on the drug-resistant p53 mutant as compared with drug-resistant p53 wild-type neuroblastoma revealed a novel mechanism for resistance to apoptosis: a direct role of p53 in regulating the cellular concentration of pro-apoptotic alkenals by functioning as a specific and saturable allosteric inhibitor of the alkenal-glutathione-conjugate transporter, RLIP76. The RLIP76-p53 complex was demonstrated both by using immuno-precipitation analyses of purified proteins as well as by immuno-fluorescence analysis. Drug transport studies revealed that p53 inhibited both basal and PKCα stimulated transport of glutathione-conjugates of 4HNE (GS-HNE) and cisplatin. Drug resistance was significantly greater for p53 mutant as compared with p53 wild-type neuroblastoma cell lines, but both were susceptible to depletion of RLIP76 by antisense alone. In addition, inhibition of RLIP76 significantly enhanced the cytotoxicity of cisplatin. Taken together, these studies provide powerful evidence for a novel mechanism for drug and apoptosis resistance in p53 mutant neuroblastoma, based on a model of regulation of p53 induced apoptosis by RLIP76, where p53 is a saturable and specific allosteric inhibitor of RLIP76, and p53 loss results in over-expression of RLIP76; thus, in the absence of p53, the drug and glutathione-conjugate transport activities of RLIP76 are enhanced. Most importantly, our findings strongly indicate RLIP76 as a novel target for therapy of drug-resistant and p53 mutant neuroblastoma. (Supported in part by NIH grant CA 77495 (SA), CA 155350, Cancer Research Foundation of North Texas, and Institute for Cancer Research & the Joe & Jessie Crump Fund for Medical Education (SSS))
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 4334. doi:10.1158/1538-7445.AM2011-4334
Abstract 4336: Oncolytic reovirus as a novel therapy for neuroblastoma
Authors: Kellar Amelia , Redding Nicole , Blote Karen , Shi Qiao , Spurrell Jason , Beaudry Paul , Morris Don 
Published: June 2012

Abstract
Background: Neuroblastoma (NB), a tumour of neurocrest progenitor cells of the sympathetic nervous system, is the most common extracranial pediatric tumour and accounts for approximately 15 percent of childhood cancer mortality. Even with surgery, radiation therapy, aggressive cytotoxic chemotherapy including autologous stem cell transplantation and more recently immunotherapy, high risk neuroblastoma has only a 30 percent predicted survival rate. Reovirus, a double-stranded RNA virus, has been shown to be effective against a myriad of cancers through its ability to preferentially lyse cancer cells with aberrant Ras pathway signaling. In this study, we investigate the potential of reovirus (serotype 3, strain Dearing) as a novel treatment for neuroblastoma and neuroblastoma tumour initiating cells (nbTIC).
Experimental Design/Results: Reovirus induces dramatic cytotoxic effects at a multiplicity of infection (MOI) of 40 within 48h as assessed by WST-1 viability assays for the IMR-32, IMR-5, SK-N-AS, SK-N-SH, LAN-1, LAN-5, and SHEP human neuroblastoma cell lines in vitro. Interestingly the human neuroblastoma tumor-initiating cell lines, NB-12, NB88 and NB122 (kind gift from Dr David Kaplan) were also found to be very sensitive to reovirus-induced cytotoxicity, suggesting a role for reovirus treatment of refractory neuroblastoma. In order to further study reovirus, immunotherapy and neuroblastoma, a syngeneic, immunocompetent murine model (Neuro2a, A/J neuroblastoma model) was utilized to test reovirus-induced cytotoxicity and RV-directed immunotherapy of Neuro2A in vitro and in vivo. Preliminary data suggest that the Neuro2a cells are exquisitely sensitive to reovirus in vitro. Updated results will be presented.
Conclusion: These preclinical results suggest that reovirus holds promise as a novel therapeutic for neuroblastoma and that it warrants further investigation in early phase clinical trials.
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 4336. doi:10.1158/1538-7445.AM2011-4336
Abstract 4338: The effect of opposing roles of NF-kB on TRAIL-R2 expression in TRAIL cytotoxicity in neuroblastoma cells
Authors: Jung Hye Lim , Lee Myoung Woo , Kim Hye Ryung , Kim Dae Sung , Kim Hye Jin , Lee Soo Hyun , Chueh Hee Won , Yoo Keon Hee , Sung Ki Woong , Koo Hong Hoe 
Published: June 2012

Abstract
TNF-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in most, but not all, cancer cells. The molecular factors regulating the sensitivity to TRAIL are still incompletely understood. The transcription factor nuclear factor-kappa B (NF-kB) has been implicated, but its exact role is controversial. In this study, we have investigated the role of NF-kB on enhancement of TRAIL cytotoxicity in neuroblastoma cells. IkB kinase (IKK) inhibitor decreased basal NF-kB activity and marginally induced cell death in neuroblastoma cell line SK-NMC. Pretreatment with IKK inhibitor synergistically increased TRAIL-mediated apoptosis via up-regulation of TRAIL- receptor2 (TRAIL-R2) expression in response to the decrease in basal NF-kB activity, indicating that basal NF-kB activity blocks TRAIL-R2 expression in SK-NMC cells. In addition, pretreatment with Cisplatin, a platinum analog and an alkylating agent widely used in neuroblstomas, showed increase in NF-kB activity and induction of apoptotic cell death in SK-NMC cells. Pretreatment with Cisplatin significantly increased TRAIL-mediated apoptosis via up-regulation of TRAIL-R2 expression through induction of NF-kB, suggesting that induced NF-kB is involved in TRAIL-R2 expression up-regulated by Cisplatin. IKK inhibitor or Cisplatin followed by TRAIL treatment increased caspase-8, -9, and -3 activation. Mcl-1 cleavage and Bid truncation. Our results implicate that basal NF-kB activity is involved in TRAIL resistance but induced NF-kB plays a role in TRAIL sensitivity, and suggest that the enhanced sensitivity of SK-NMC cells to TRAIL is associated with an increase in TRAIL-R2 expression.
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 4338. doi:10.1158/1538-7445.AM2011-4338
Abstract 4339: Evaluation of polyamine inhibitors in N/S/I-type neuroblastoma and hypoxia
Authors: Bachmann Andre S. , Borsics Tamas 
Published: June 2012

Abstract
Background: Neuroblastoma (NB) is the most common extracranial childhood tumor and is derived from neural crest cells of the sympathetic nervous system. There is currently no curative treatment for children with relapsed/refractory NB, and for these children the 5-year survival rate is &lt;10%. As such, new therapeutic approaches with alternative modes of action are needed for treatment. Since MYCN controls a number of genes including ornithine decarboxylase (ODC), we proposed that ODC should be considered as a novel target for MYC-driven tumors such as NB (Oncogene, 2005, 24:5606-18; Int J Cancer, 2010, 126:2012-24). Our previous research identified two polyamine inhibitors, DFMO and SAM486A, as effective agents for the treatment of NB (Cancer Res, 2008, 68:9825-31; Mol Cancer Ther, 2009, 8:2067-75). Methods: We utilized in vitro MTS cell viability testing to assess the differential effects of DFMO and SAM486A in three specific NB cell sub-populations (neuroblastic (N), Schwann cell-like/adherent (S), and an intermediate (I) morphology types) in the presence or absence of functional tumor suppressor p53. A hypoxia chamber, Western blot analysis, and microscopy were applied to analyze the effect of polyamine inhibitors in a hypoxic environment. Results: While weak apoptosis was induced by DFMO in all three cell types with non-functional p53, SAM486A was most potent in N-type NB cells with functional p53. Interestingly, the potency of SAM486A in p53 wt cells under hypoxic conditions was significantly reduced. Conclusion: Our data provide evidence that the p53 status, NB cell sub-type and the presence/absence of oxygen in the tumor cell environment are crucial factors and determine the overall sensitivity of individual polyamine inhibitors. These new insights are important as polyamine metabolism-targeted NB therapy with DFMO has now entered the clinical stage.
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 4339. doi:10.1158/1538-7445.AM2011-4339
Abstract 4341: Bortezomib primes neuroblastoma cells for TRAIL- triggered apoptosis by linking the death receptor to the mitochondrial pathway
Authors: Naumann Ivonne , Kappler Roland , von Schweinitz Dietrich , Debatin Klaus-Michael , Fulda Simone 
Published: June 2012

Abstract
In contrast to remarkable improvements in the survival and cure rates that have been encountered for many childhood malignancies, the prognosis of children with advanced stage neuroblastoma remains poor.
Searching for novel strategies to modulate apoptosis in neuroblastoma we investigated the potential of the proteasome inhibitor Bortezomib to modulate TRAIL-induced apoptosis in neuroblastoma cell lines, primary neuroblastoma cultures and in an in vivo model of neuroblastoma.
Here, we provide first evidence that Bortezomib at subtoxic concentrations synergistically cooperates with TRAIL to induce apoptosis (combination index 0.5). In addition, Bortezomib acts in concert with TRAIL to reduce colony formation of neuroblastoma cells, demonstrating an effect also on longterm survival. Mechanistic studies reveal that Bortezomib profoundly enhances TRAIL-induced cleavage of Bid into tBid, accumulation of tBid in the cytosol and its insertion into mitochondrial membranes, pointing to a concerted effect on Bid cleavage (TRAIL) and stabilization of tBid (Bortezomib), which links the death receptor to the mitochondrial pathway. Additionally, Bortezomib increases expression of p53 and Noxa. All these changes lead to increased activation of Bax and Bak, loss of the mitochondrial membrane potential, cytochrome c release, caspase activation and caspase-dependent apoptosis upon treatment with Bortezomib and TRAIL. Knockdown of either Bid, Noxa or p53 significantly delays the kinetic of Bortezomib- and TRAIL-induced apoptosis, whereas it does not confer longterm protection. By comparison, overexpression of Bcl-2, which simultaneously antagonizes tBid, Noxa and p53, significantly inhibits Bortezomib- and TRAIL-induced apoptosis and even rescues clonogenic survival. Of note, Bortezomib and TRAIL act in concert to trigger apoptosis in several patients’ derived primary neuroblastoma cultures, underscoring the clinical relevance. Importantly, Bortezomib cooperates with TRAIL to suppress tumor growth in an in vivo model of neuroblastoma.
In conclusion, these findings demonstrate for the first time that Bortezomib at subtoxic concentrations represents a promising new approach to prime neuroblastoma cells towards TRAIL-induced apoptosis by linking the death receptor to the mitochondrial pathway. Thus, this study provides the rational for future (pre)clinical evaluation of the combination strategy with Bortezomib and TRAIL in neuroblastoma.
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 4341. doi:10.1158/1538-7445.AM2011-4341