bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 71: Metformin inhibits lung cancer cell growth and angiogenesis in vitro and in vivo: Effect on IL6-Stat3 pathway
Authors: Lin Chien-Chung , Shen Mei-Chun , Su Wu-Chou 
Published: February 2011

Abstract
The usage of metformin as a first line treatment for type 2 diabetes associates with reduced cancer risk. Animal studies have shown that metformin inhibits breast cancer growth mainly via AMPK-mTOR pathway. Associated clinical trial is conducting. However, the application of metformin in other cancers and other mechanisms remain not clarified. In our previous study, we demonstrated the down-regulation of TSC1 (tuberous sclerosis 1) in lung cancer cells from malignant pleural effusion (MPE) and verified with qRT-PCR and immunohistochemistry. TSC1/TSC2 complex can suppress the mTOR pathway and receive input from LKB1-AMPK pathway and we found that metformin induced TSC1expression in vitro. Previous studies demonstrate that TNFα-sphingomyelinase and IL6-Stat3 contribute the formation of MPE via activating VEGF secretion. TNF-α can also induce IL6 secretion in many tumors. In our recent study, we first investigated the effect of metformin on proliferation of lung cancer cell. Lung cancer lines including PC14PE6/AS2 (AS2), A549 and CL 1-0 were treated with various dosage of metformin. After treatment for 96 hours, metformin inhibited proliferation of AS2, A549 and CL1-0 lung cancer cells dose-dependently. The IC50 of all cells are around 2.5-5 mM, measured by MTT assays. We also investigated the addictive cytotoxicity of metformin to cisplatin. Metformin co-incubation with cisplatin for 72 hr in AS2 cells displayed an increased cytotoxicity as compared to each agent alone. As for the association with angiogenesis, by analyzing the supernatant with ELISA assay, the VEGF secretion also decreased after treatment with metformin in AS2 and A549 cells. And Western blotting was conducted to access the effect on Stat3 and AMPK phosphorylation of metformin. In AS2 cell, not only the phosphorylation of AMPK increased after metformin treatment, the Stat3 phosphorylation was also suppressed. In addition, stimulation with TNF-α led to substantial secretion of IL6, which was inhibited by co-incubation with metformin. In vivo, the AS2 cells were injected i.p. into the unanesthetized nude mice and MQ-water or metformin (1mg) were injected 2 days later. Around 2 to 4 weeks, the mice developed peritoneal carcinomatosis and malignant ascites. In the metformin group, though the same number of mice developed peritoneal carcinomatosis and ascites, the amount of ascites and VEGF level are less than the control group. In conclusion, metformin inhibit lung cancer cell proliferation and angiogenesis in vitro and in vivo. And the IL6-Stat3-VEGF pathway may also involve in the anticancer effect of metformin.
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 71.
Abstract 712: Antitumor activity of SPINK1 monoclonal antibody in a subset of SPINK1 positive ETS-negative prostate cancer
Authors: Ateeq Bushra , Tomlins Scott A. , Laxman Bharathi , Cao Qi , Cao Xuhong , Jing Xiaojun , Pienta Kenneth J. , Varambally Sooryanarayana , Chinnaiyan Arul M. 
Published: February 2011

Abstract
We have identified SPINK1 outlier expression in an aggressive subset of TMPRSS2:ETS-negative prostate cancers (10% of all prostate cancers) by outlier meta-analysis (meta-COPA). We have further validated the mutual exclusivity of SPINK1 expression and ETS fusion status, demonstrated that SPINK1 outlier expression can be detected non-invasively in urine, and is a useful prognostic marker in prostate cancer (Tomlins et al., 2008 and Laxman et al., 2008). Here we examined the in vitro and in vivo effects of SPINK1 outlier expression. We demonstrate that exogenous SPINK1 recombinant protein stimulate cell proliferation in benign and cancerous prostate cells. Benign prostate epithelial cells RWPE treated with SPINK1 recombinant protein or conditioned medium (CM) from 22RV1 cells (SPINK1+) showed dramatic increase in cell invasion in Boyden chamber Matrigel invasion assay, which was attenuated in the presence of an anti-SPINK1 monoclonal antibody (mAb). We also showed that invasion of 22RV1 cells is attenuated with SPINK1 mAb, while SPINK1 mAb has no effect on the invasion of PC3 cells (SPINK1−) invasion. SiRNA knockdown of SPINK1 in 22RV1 cells attenuated invasion, which could be rescued by recombinant SPINK1 protein or 22RV1 CM. Stable knockdown of SPINK1 in 22RV1 cells using shRNA resulted in decreased cell proliferation, cell invasion and motility. Moreover, stable knockdown of SPINK1 in 22RV1-Luc cells showed reduced tumor burden in an in vivo xenograft model. The preclinical in vivo efficacy of SPINK1 mAb was evaluated in SPINK1 positive 22RV1-Luc xenograft model established in BalbC nu. nu mice. Antitumor activities were determined from the analyses of tumor growth inhibition, defined as the decrease in the mean tumor volume for SPINK1 mAb treated mice versus IgG mAb treated mice. Twice a week intra-peritoneal administration of SPINK1 mAb (10mg/kg) resulted in a 65% reduction of tumor burden. This study provides the rationale for the development of humanized anti-SPINK1 monoclonal antibodies for clinical targeting of the subset of patients with SPINK1 positive and ETS-negative 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 712.
Abstract 72: Metformin enhances tumor regression and reduces tumor burden in a preclinical paradigm modeling obesity's impact on postmenopausal breast cancer
Authors: Giles Erin D. , Anderson Steven M. , Schedin Pepper J. , Thor Ann D. , Johnson Ginger C. , Hedman Karla J. , Mahan M Chad , Houser Jordan L. , MacLean Paul S. 
Published: February 2011

Abstract
BACKGROUND: Obesity and type II diabetes have been linked to a higher risk of breast cancer in post-menopausal women. Patients treated with the anti-diabetic drug metformin (1,1-dimethylbiguanide hydrochloride) for type II diabetes or metabolic syndrome have shown a reduced risk of breast cancer, a greater pathologic complete response for neoadjuvant therapy and an improved breast cancer survival. The purpose of this study was to examine the effects of metformin on tumor promotion in a rodent model of obesity and postmenopausal breast cancer.
METHODS: Rats were injected with N-methylnitrosourea (MNU, 50 mg/kg) at 8 weeks of age to induce mammary tumors, and fed a high fat diet (from 5 weeks of age) to promote obesity. Obesity-resistant and obesity-prone rats were selected, based upon weight gain (between 10 and 14 weeks of age) and were matured under these conditions to produce adult, tumor-bearing lean and obese rats (24±1 vs 29±1 % body fat). Tumors were monitored by manual palpation at weekly intervals from the time of MNU administration. Obese animals were randomly assigned to either metformin treatment (2mg/mL in their drinking water, n=8) or control group (water only, n=6), after at least 1 tumor reached a volume &gt;1cm3. Rats were maintained on their respective treatments for the duration of the study. One week following the initiation of treatment, animals were ovariectomized (OVX) to mimic the post-menopausal state, and tumor palpations were continued for an additional 9 weeks.
RESULTS: Prior to OVX, control and metformin treated obese rats were similar in weight (413±21 vs 397±20 g) and tumor burden (3.3±1.2 vs 3.7±2.3 g). In response to OVX, tumor burden decreased in all animals, as predicted, based on the hormone responsiveness of MNU-induced tumors. Compared to untreated obese rats, the percent of pre-OVX tumor burden was lower in metformin-treated rats (weeks 1-3 post-OVX; 67±10 vs 26± 8%, p&lt;0.05). A tendency for metformin to attenuate the subsequent rebound in tumor burden was observed at week 7 (126±67 vs 41±35%, p=0.06), week 8 (170±112 vs 35±29%, p=0.06), and week 9 (249±165 vs 41±30%, p=0.09).
CONCLUSIONS: These preliminary observations indicate that metformin enhances OVX-induced tumor regression in obese rats and may reduce long term tumor growth and survival in these animals after the surgery. These findings suggest that metformin may have therapeutic benefits in obese, peri- or post-menopausal patients who are at risk for breast 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 72.
Abstract 723: Beyond temsirolimus: Discovery of PKI-587 a highly efficacious dual PI3K/mTOR inhibitor
Authors: Venkatesan Aranapakam M. , Dehnhardt Christoph M. , Santos Efren Delos , Chen Zecheng , Santos Osvaldo Dos , Ayral-Kaloustian Semiramis , Mallon Robert , Hollander Irwin , Feldberg Larry , Lucas Judy , Yu Ker , Brooijmans Natasja , Bard Joel , Gibbons James , Abraham Robert T. , Mansour Tarek S. 
Published: February 2011

Abstract
Temsirolimus, a rapamycin analog, is a selective mTor inhibitor that has been successfully used in the clinic for the treatment of renal cancer. mTOR integrates signals from multiple upstream growth and survival regulatory pathways including the LKB1/AMPK and PI3K (Phosphatidylinositol-3-kinase)/Akt pathways. Among these, Phosphatidylinositol-3-kinase (PI3-K) is a lipid kinase which phophorylates phosphatidylinositol diphosphate (PIP-2) to phosphatidylinositol triphosphate. This pathway regulates cell proliferation, growth, survival, and apoptosis. The aberrant activation of PI3K-α and its downstream effectors including Akt and mTOR, has been linked to the initiation and maintenance of numerous tumor phenotypes. During tumorigenesis, PI3K/Akt/mTOR pathway activation occurs through various mechanisms, including loss of PTEN (the phosphatase that regulates PI3K signaling), over-expression or activation of certain receptor tyrosine kinases (e.g. EGFR, HER-2), interaction with activated Ras, overexpression of the PI3K-α gene (PIKC3A), or mutations in PIKC3A that cause elevated PI3K kinase activity. Deregulated PI3K/Akt/mTOR pathway signaling has been implicated in poor prognosis and low survival rate in patients with various lymphatic tumors, glioblastomas, melanomas as well as breast, prostate, lung, colon, and ovarian cancers. Numerous pre-clinical and clinical studies indicate that PI3K-α plays a key role in the biology of human cancer. Hence, it is likely that a small molecule inhibitor of both PI3K and mTOR will have clinical utility.
Our project team has identified small molecules that potently inhibit the PI3K/mTor pathway. The current clinical candidate, PKI-587 (whose structure will be disclosed) is a pan PI3K (class I)/mTOR inhibitor. PKI-587 decreases tumor cell survival and proliferation in vitro. Additionally, PKI-587 has shown compelling efficacy in multiple human tumor nude mouse xenograft models such as MDA 361 (Breast), U87 (Glioma), H1975, A549 (NSCLC) in nude mice when administered as a single agent. The design of this novel potent inhibitor, synthesis, structure-activity relationships, PK and in vivo efficacy data will be presented.
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 723.
Abstract 724: Selective β2-adrenergic receptor agonists inhibit the proliferation of 1321N1 astrocytoma cells
Authors: Wainer Irving W. , Toll Lawrence , Jimenez Lucita , Polgar Willma , Green Carol , Gow Jason , O'Loughlin Kathleen , Bernier Michel 
Published: February 2011

Abstract
Selective β2-adrenergic receptor agonists inhibit the proliferation of 1321N1 astrocytoma cells
Lawrence Toll1, Lucita Jimenez1, Willma Polgar1, Carol Green1, Jason Gow1, Kathleen O'Loughlin1, Michel Bernier2, Irving W. Wainer2
1 SRI International, Menlo Park, CA
2 Intramural Research Program, National Institute of Aging, Baltimore, MD
We have reported the synthesis of fenoterol analogs and the characterization of these compounds as selective β2-adrenergic receptor (β2-AR) agonists, which have a broad range of abilities to stimulate cAMP accumulation in β2-AR transfected HEK cells, EC50cAMP. We now report the effect of a series of these compounds on the growth of 1321N1 astrocytoma cells (Table). In the 1321N1 cells, β2-AR stimulation by fenoterol analogs potently inhibited [3H]-thymidine incorporation with IC50 values that correlated with the EC50cAMP values. The effects were blocked by the β2-AR antagonist propranolol and mimicked by the adenylate cyclase activator forskolin. (R,R)-Fenoterol induced G1 arrest with an associated decrease in the proportion of cells in G2 and S phase and modulated the levels of proteins involved in cell division. The results indicate that selective β2-AR agonists may exert unanticipated antitumor effects against neural-derived neoplasms that express the β2-AR.Table.Functional activities of fenoterol analogs. Stimulation of cAMP accumulation was determined in intact HEK cells transfected with the β2-AR. Fenoterol analogs do not inhibit mitogenesis in HEK cells. Inhibition of [3H]-thymidine incorporation was conducted in 1321N1 cells in which the β2-AR is natively expressed. Results expressed as mean ± SD, n = 4.CompoundStimulation of cAMP AccumulationMitogenesis Inhibition EC50 (nM)% StimulationIC50 (nM)Isoproterenol0.20 ± 0.091000.05 ± 0.01(R,R)-fenoterol0.30 ± 0.09123.30 ± 8.790.14 ± 0.07(R,R)-4-methoxyfenoterol0.30 ± 0.23135.70 ± 11.030.17 ± 0.02(R,R)-ethylfenoterol2.80 ± 0.90125.40 ± 5.741.44 ± 0.27(R,R)-1-naphthylfenoterol12.5 ± 3.50129.20± 23.61.57 ± 0.34(R,R)-2-naphthylfenoterol0.40 ± 0.1290.30 ± 9.811.91 ± 0.57(R,R)-4-methoxy-1-naphthyl fenoterol3.90 ± 1.80105.90 ± 11.063.98 ± 0.28
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 724.
Abstract 728: Development of pharmacophore-based RET inhibitors for thyroid cancer therapy
Authors: Huang Jui-wen , Ko Ching-Huai , Chen Ting-Shou , Lee On , Tseng Hsiang-Wen , Tsai Yuan-Jang , Liu Chih-Peng , Chen Yen-Chun , Wang Ling-Mei , Hwang Chrong-Shiong 
Published: February 2011

Abstract
The new therapeutic option is pivotal due to the restricted efficacy of current treatments (surgery, radioactive iodine treatment, and chemotherapy) in progressive thyroid carcinomas. Gain-of-function mutations of the receptor tyrosine kinase RET have been identified as driving oncogenic events in subsets of papillary and medullary thyroid cancers (PTC and MTC), but targeted therapy for RET-driven cancers is currently clinically unavailable. Some mulit-kinase inhibitors, such as sunitinib and vandetanib, which have shown efficacy against other neoplastic diseases, are being evaluated in clinical trials for thyroid cancer therapy. However, the anti-VEGFR activities of these mulit-kinase inhibitors have been considered to lead cardiotoxicity in some patients. Moreover, Ret mutation-associated resistance have been reported by some RET inhibitors in preclinical data. The “in silico model” was applied to design the specific RET target compounds through mapping the pharmacophore of RET ATP-binding pocket. Some novel scaffold compounds which fit the pharmacophore model were selected form ITRI library, and their anti-RET activities were evaluated by kinase assay. The in vitro anti-cell proliferation activities of the compounds to the TT cells (MTC specific cells) were demonstrated by MTT assay. From the screening of ITRI library, ITRI-305 showed the impressive anti-RET (IC50 ∼ 90 nM) and anti-cell proliferation (IC50 at low micro molar) activities and the activities are compatible to those of sunitinib and vandetanib. ITRI-305 also shows good solubility and favorable oral PK profiles. The xenograft study of TT cells with ITRI-305 is proceeding. In conclusion, a novel scaffold RET inhibitor, ITRI-305, with less potent VEGFR activity (anti-VEFGR IC50 ∼ 1 μM) is developed to overcome the cardiotoxicity and resistance problems which is caused by conventional RET inhibitors.
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 728.
Abstract 729: Mechanism of action of a p53-derived peptide that targets a novel death pathway inducing selective necrosis in cancer cells
Authors: Bowne Wilbur B. , Yazdi Ehsan S. , Sookraj Kelley A. , Fenelus Maly , Adler Victor , Zenilman Michael E. , Michl Josef , Pincus Matthew R. 
Published: February 2011

Abstract
In a series of preliminary in vitro and in vivo studies we have shown that p53-derived peptides consisting of residues 12-26 and 17-26 from the murine double minute binding domain (MDM-2) possess anti-cancer activity. These peptides are linked to a trans-membrane penetrating sequence (penetratin) derived from the antennapedia homeodomain of Drosophila and are designated PNC-27 and PNC-28, respectively. We also found that the previously determined 3D structure of these PNC residues are directly superimposeable on the same residues bound to MDM-2, suggesting that these peptide may target MDM-2 in cancer cells. These peptide constructs appear to promote cancer cell death through a novel pathway that leads to necrosis rather than apoptosis while sparing their untransformed counterparts. In our initial experiments, the critical role of the MDM-2 oncoprotein as a potential target molecule for these PNC peptides was elucidated when a sequence specific MDM-2 antibody blocked PNC-27 activity on cancer cells. To further elucidate this anti-cancer mechanism we then tested parent molecule PNC-27 against selected cancer cell lines (Panc-02, pancreatic; HT1080, fibrosarcoma; and MCF-7, breast) plus respective untransformed counterparts (BMRPA1, BJ, and MCF-10) which were treated with PNC-27 and control peptide. Subsequently, treatment with fluorescent labeled peptide, immunoprecipitation (IP), confocal, and time-lapse electron microscopy (EM) was employed as well as transfection of untransformed cells with the MDM-2 gene to study the anti-cancer mechanism. PNC-27 did not cause elevation of pro-apoptotic proteins but induced rapid dose-dependent tumor cell death with release of lactate dehydrogenase (LDH). This specific anti-cancer mechanism, in part, may be due to observed increased expression of MDM-2 found in cancer cells compared to their normal cellular counterparts which is consistent with abrogation of MDM-2 and stabilization of p53 protein levels after PNC-27 treatment. Moreover, following IP of fluorescent labeled PNC-27 from treated cancer cells; labeled MDM-2 was detected. Furthermore, confocal microscopy and EM revealed co-localization of PNC-27 and MDM-2 along with cancer cell membrane pore formation, respectively. Remarkably, transfection of the MDM-2 gene resulted with increased expression of MDM-2 and now untransformed cell susceptibility to PNC-27. These results suggest a mechanism of PNC-27 binding to MDM-2 in the cancer cell membrane, leading to pore formation and membrane disruption; a p53-independent pathway consistent with rapid selective cancer cell necrosis.
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 729.
Abstract 731: 4-Amino-substituted 5-resorcinol-isoxazole derivatives, a novel class of Hsp90 inhibitor: Synthesis and evaluation of in vitro activity
Authors: Giannini Giuseppe , Cabri Walter , Brunetti Tiziana , Ciacci Andrea , Simoni Daniele , Baruchello Riccardo , Grisolia Giuseppina , Rullo Cinzia , Vesci Loredana , Castorina Massimo , Milazzo Ferdinando Maria , Carminati Paolo , Pisano Claudio 
Published: February 2011

Abstract
Hsp90 (heat shock protein 90) is a component of a molecular chaperone complex, involved in the folding, maturation and stabilisation of key signalling molecules which control cell proliferation, survival and transformation. It works by a modulation of a set of cancer-associated proteins, collectively referred to as “clients”. Inhibition of Hsp90 causes simultaneous destabilization and eventual degradation of client proteins that result in suppression of tumor growth. This observation led to the idea, among pharmaceutical chemists, to consider Hsp90 as a potential target for a new strategy in human cancer therapy. After pioneering studies with natural products (geldamycin and radicicol), many selective Hsp90 inhibitors from various institutions have entered in clinical trials. One of these classes of inhibitors is the 4,5-diaryl-isoxazole with a resorcinol in position 5 and a second substituted aryl in position 4. This scaffold was considered a prerequisite for the activity on Hsp90.
VER-52296/NVP-AUY922, currently in Phase II clinical trials, belongs to diaryl-isoxazole class.
In our project, we systematically investigated - with in silico pre-screening, in concert with structural information from X-ray protein crystallography - all possible modifications to make on the isoxazole scaffold. We have mainly focused our attention on the importance of an amide portion at the 4 position. Now we have identified a new class of synthetic small molecule Hsp90 inhibitors, characterized by a 4-amino-substituted 5-monoaryl-isoxazole (5-resorcinol-isoxazole) scaffold. We turned our attention to the 4 position of isoxazole where unexpectedly, we have found that compounds possessing a nitrogen atom directly attached to the isoxazole ring are endowed of activity against Hsp90 similar or even better than the diaryl analogues.
Here we describe design, synthesis and preliminary in vitro biological profile of a small library of these derivatives.
Examples from this series of compounds have activities ranging from low to high nM against Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay, and are active in human cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72.
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 731.