bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4410: Apoptosis in Ovarian Cancer Cells Induced by Polyclonal Antibodies to Secreted Frizzle-related Protein 2
Authors: Rossi Emma C. , Siamakpour-Reihani Sharerah , Ketelsen David , Van Le Linda , Patterson Cam , Klauber-DeMore Nancy 
Published: February 2011

Abstract
Objectives: We have previously discovered a novel angiogenesis factor, secreted frizzle-related protein 2 (SFRP2), that is strongly expressed in many human tumors including ovarian carcinoma. SFRP2 protects against endothelial cell apoptosis, and induces endothelial tube formation and migration. We hypothesize that in addition to its paracrine role in stimulating angiogenesis, SFRP2 also has a direct effect in tumor cells, and therefore blocking SFRP2 will induce ovarian cancer apoptosis.
Methods: Protein expression of SFRP2 in ovarian cancer cells: SKOV-3 and OVCA −3 ovarian cancer cells were cultured in McCoy's medium with 10% bovine serum albumin. Whole cell protein lysates were obtained and Western blot analysis was performed probing for SFRP2. Apoptosis assay: SKOV3 cells were plated in 96 well plates and allowed to attach overnight. Rabbit polyclonal antibody to SFRP2 (SFRP2 Ab) was run through a column with a saline buffer to remove the sodium azide preservative. Cells were treated with antibody in 1:10, 1:100, and 1:1000 concentrations. McCoy's culture medium with 1% saline was used as a negative control. Cells were incubated at 37°C for 48 hours. Apoptosis was measured by the activity of cleaved caspase-3 by using a caspase-specific fluorogenic substrate. Statistical analysis was performed with a two-tailed student's t-test.
Results: SKOV-3 and OVCA-3 ovarian cancer cells strongly express SFRP2 on Western Blot analysis. When SKOV-3 cells were treated with polyclonal antibody to SFRP2 (1:10) there was a 47% increase in apoptosis as compared with negative controls (control = 1509 RFU ± 50, SFRP2 Ab =2221 RFU ± 39, n=4 for both groups, p&lt;0.0001).
Conclusions: SFRP2 is a protein endogenously expressed by ovarian carcinoma. Blocking SFRP2 with a polyclonal antibody induces apoptosis in SKOV-3 ovarian cancer cell line, suggesting that this protein may be a potential target in the treatment of 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 4410.
Abstract 442: Down-regulation of MET/RON receptor tyrosine kinases in colon cancer cells under chronic hypoxia as a mechanism for resistance towards targeted therapy
Authors: Guin Sunny , Ma Qi , Padhye Snehal , Zhang Hong-Ying , Wang Ming-Hai 
Published: February 2011

Abstract
Hypoxia is a pathogenic factor observed in solid tumors, which plays a critical role in tumor malignancy and drug resistance. The MET and RON receptor tyrosine kinases belong to a unique proto-oncogene family and contribute to tumorigenic progression and malignant phenotypes in various epithelial cancers. To address their pathogenic significance under chronic hypoxic condition (1% O2, 5% CO2 for 5 days), functional analysis of MET and RON were conducted using colon cancer HCT116 and HT29 cells as models. Contrary to previous reports, we consistently observed that levels of MET and RON were significantly decreased over a period of 5 days under chronic hypoxic condition as documented by Western blot and cell-surface fluorescent analysis. The reduction was also accompanied with decreased in both spontaneous and ligand (HGF/MSP)-induced tyrosine phosphorylation manners, which affected the downstream signaling cascades. Moreover, we observed that hypoxia-induced HIF-1α expression (known as a positive regulator for both receptors) is unable to sustain MET or RON expression, suggesting that the receptor down-regulation is mediated through a HIF-1α-independent mechanism. RT-PCR analysis revealed that diminished MET and RON expression occurs at the mRNA transcription level. However, increase in protein degradation also contributed to the observed reduction. Functional studies further demonstrated that chronic hypoxia facilitates colon cancer cells to develop a unique pathogenic phenotype. This phenotype was featured by reduced cell migration, decreased cell proliferation, and lack of S phase in cell cycle profile. Tumor cells were also insensitive in response towards HGF or MSP-induced cell movement and replication. These cancer cells were resistant to cytotoxic effects induced by MET-RON duel small molecule inhibitors such as PHA665752 and compound I. As shown by cytotoxicity assay, the IC50 values of these inhibitors in cell survival were significantly increased in cancer cells under chronic hypoxic treatment compared to normoxic cells. In conclusion, our results demonstrate that under chronic hypoxia colon cancer cells developed a pathogenic phenotype characterized by diminished expression of MET and RON. Such a change contributes to the insensitivity of tumor cells towards cytotoxic activities of specifically targeted drugs. Thus, diminished expression of MET and RON under chronic hypoxia is a potential mechanism that affects the effectiveness of targeted therapy in the treatment colon 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 442.
Abstract 4423: Novel therapeutic potential in targeting the microtubules by nanoparticle albumin-bound paclitaxel in hepatocellular carcinoma
Authors: Zhou Qian , Ching Arthur K-K , Leung Wilson K-C , Szeto Carol , Ho Shuk-Mei , Holmes Chris C. , Yuan Yun-fei , Lai Paul B-S , Yeo Winnie , Wong Nathalie 
Published: February 2011

Abstract
Hepatocellular carcinoma (HCC) shows low responses to most conventional chemotherapies. To facilitate target identifications for novel therapeutic developments, we deployed gene expression profiling on 43 paired HCC tumors and adjacent non-tumoral liver. Coupled with ontology analysis, the major functional process suggested in the malignant transformation of HCC was microtubule-related cellular assembly. We further examined the potential use of microtubule targeting Taxane drugs, including Paclitaxel and Docetaxel, and compared findings to the results obtained from Doxorubicin, a common chemotherapeutic agent used in the treatment of a number of neoplasms. Recent studies showed that drug delivery by nanoparticles have enhanced efficacy with reduced side effects. In this regard, the nanoparticle albumin-bound (nab)-Paclitaxel was also examined. In a panel of HCC cell lines studied, a high sensitivity towards Taxane drugs was generally found, although the effect from nab-Paclitaxel was most profound. The nab-Paclitaxel showed an effective IC50 dose at 15-fold lower than Paclitaxel alone or the derivative analogue Docetaxel, and approx.450-fold less compared to Doxorubicin. Flow cytometric analysis confirmed a cell cycle blockade at the G2/M phase and increased apoptosis following treatment with nab-Paclitaxel. In-vivo animal study also showed that nab-Paclitaxel readily inhibited xenograft growth with less toxicity compared to other anti-microtubule drugs and Doxorubicin. Silencing of a major microtubule regulatory gene STMN1 suggested a distinct synergistic effect in the combined treatment with nab-Paclitaxel. Our findings in this study would suggest the microtubule organizations to represent a promising target for treatment developments in HCC.
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 4423.
Abstract 4425: Oral efficacy and preclinical ADME evaluation of CKD-516, a novel tubulin polymerization inhibitor
Authors: Kim Soo Jin , Kim Se-Mi , Choi Jae-Hoon , Lee Do Hyung , Lee Dong Wook , Park Gyu-Tae , Lim In-Taek , Jeon Deok-Jin , Lee Seonwoo , Kim Dal-Hyun , Lee Kyung Joo , Lee Sungsook , Hong Chung Il 
Published: February 2011

Abstract
CKD-516 is a potent anticancer agent that inhibits microtubule assembly and disrupts tumor vasculature (VDA). CKD-516 is an amino acid prodrug of S516 releasing S516 in vivo. Previously we reported the discovery and its antitumor efficacy of CKD-516 as well as various in vitro studies (Abstract 5561, 2009 AACR). As a continuation of the investigation, a detailed ADME evaluation of CKD-516 in both rats and dogs and its potential as an oral agent is described in this report.
Following intravenous administration to rats and dogs, CKD-516 rapidly became the active metabolite S516 in plasma and the half-lives of S516 were 1.5 hrs in rats, and 8 hrs in dogs. Protein binding was high with an unbound fraction less than or equal to 20% in all species tested. In distribution studies in rats dosed intravenously, S516 was mainly distributed in thymus, lung and stomach and had a short half-life less than 2 hrs in all tissues tested. In rats, the excretion of CKD-516 in urine, bile and feces amounted to 0.22%, 8.22% and 4.92%, respectively.
S516 was found to have comparable metabolic stabilities both in dog and human liver microsomes where there was no difference between male and female microsomes. However, the rate of metabolism in rats from male and female liver microsomes were markedly different.
In general, S516 is expected to have low drug-drug interaction with IC50 values of &gt;10 μM against most CYP450 enzymes but had a moderate inhibition against CYP450 1A2 and 2C8.
The intestinal absorption of CKD-516 was predicted to be moderate to high as the apparent permeabilities (×106 cm/sec) of CKD-516 and its active metabolite S516 in Caco-2 permeability assay were 15.1 and 35.4, respectively. Thus, CKD-516 was found to have an acceptable oral bioavailability in rats, supporting its potential efficacy as an oral agent.
In vivo antitumor experiments were performed in the HCT116 human tumor xenograft model. When the established tumor reached the size of 150 mm3, CKD-516 was administered to mice orally. Groups of animals were received CKD-516 with doses of 10 mg/kg or 20 mg/kg (Q4d × 5). The treated group showed a tumor growth suppression (IR = 50∼60%). Drug related toxicity and body weight decrease were not detected at doses tested.
In summary, a complete ADME characterization of CKD-516, a novel tubulin polymerization inhibitor and VDA, both in vitro and in vivo was described. Moreover, CKD-516 was found to have a good potential as an oral agent.
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 4425.
Abstract 4431: A novel derivative of the Cdk inhibitor roscovitine that induces apoptosis in CLL and overcomes stromal cell-mediated protection
Authors: Chen Rong , Chen Yuling , Green Simon R. , Wierda William G. , Plunkett William 
Published: February 2011

Abstract
Cmpd 5 is a derivative of R-roscovitine (CYC-202, seliciclib) with increased potency that selectively inhibits Cdk2, Cdk5 and Cdk9. In chronic lymphocytic leukemia (CLL) a disease that is addicted to the over-expression of anti-apoptotic proteins for survival, inhibition of Cdk9 by Cmpd 5 reduced phosphorylation of the C-terminal domain of RNA polymerase II and blocked transcription. These actions depleted the intrinsically short-lived anti-apoptotic protein Mcl-1, and induced apoptosis in CLL cells in vitro. Cmpd 5 was about 30 times more potent than its parent compound R-roscovitine with an IC50 of 0.86 µM after a 24-hr incubation. Although cell death was initiated after a 4-hr incubation in a time course study of Cmpd 5-induced apoptosis, the maximum cell death was not reached until 10-12 hr. In addition, it was known that co-culture of CLL cells with the marrow and lymphoid stromal cells may be responsible for resistance to fludarabine therapy. We evaluated Cmpd 5 in overcoming such stromal cell-mediated protection. Cmpd 5 killed the CLL cells similarly in the presence or absence of the human stromal cell line StromaNKtert without toxicity to the stromal cells, whereas the stromal cells clearly protected the CLL cells from the toxicity of fludarabine. Since Mcl-1 is the major target of Cmpd 5 in CLL, and the action of Cmpd 5 relies on the intrinsically rapid turn-over rate of Mcl-1, we compared the protein levels and the half-life of Mcl-1 in CLL cells in the presence or absence of the stromal cell layer. After an overnight incubation of CLL cells with the StromaNKtert cells, there was a 3-4 fold induction of Mcl-1 transcript and protein. However, there was no difference in the Cmpd 5-induced decay rate of either the Mcl-1 mRNA or protein, indicating that stromal cells did not alter the stability of Mcl-1. Therefore, the elevated Mcl-1 level likely indicated increased biosynthesis, rather than enhanced stability. Thus, the activation of the survival pathways and induction of the biosynthesis of Mcl-1 by the stromal cells may protect CLL cells from fludarabine-induced apoptosis but loss of the short-lived anti-apoptotic proteins was not affected, explaining the lack of stromal cell protection for CLL cells from Cmpd 5. Similar time-dependence of cell death induction as well as stromal cell response was also observed with other inhibitors of transcription including flavopiridol, R-roscovitine and Actinomycin D, implying a class effect. Taken together, our data suggested that Cmpd 5 is a promising candidate for clinical development for CLL.
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 4431.
Abstract 4446: Targeted proteasome inhibition by Velcade induces apoptosis in human mesothelioma and breast cancer cell lines
Authors: Wang Ying , Rishi Arun K. , Puliappadamba Vineshkumar T. , Sharma Sunita , Yang Huanjie , Tarca Adi , Dou Q. Ping , Lonardo Fulvio , Ruckdeschel John C. , Pass Harvey I. , Wali Anil 
Published: February 2011

Abstract
Thoracic malignancies and human breast cancers (HBC) continue to be aggressive solid tumors that are poor responders to the existing chemotherapeutic approaches. Malignant Pleural Mesothelioma (MPM) is an asbestos-related tumor of the thoracic pleura that lacks effective treatment options. Altered ubiquitin proteasome pathway is frequently encountered in many malignancies including HBC and MPM and thus serves as an important target for therapeutic intervention strategies. Although proteasome inhibitor Velcade (Bortezomib) has been under clinical investigation for a number of cancers, limited preclinical studies with this agent have thus far been conducted in HBC and MPM malignancies. Here, we studied the role of Velcade mediated changes in cellular, morphological, and molecular patterns in five MPM (H2595, H2373, H2452, H2461, and H2714) and two HBC (MDA MB-468, SKBR-3) cell lines. Our data revealed significant reduction in cell growth properties that were dose and time dependent. Velcade treatment resulted in G2M phase arrest, increased expression of cyclin-dependent kinase inhibitor p21 and pro-apoptotic protein Bax. Pretreatment of MPM cells with Velcade showed synergistic effect with cisplatin combination regimens. High-throughput gene expression profiling among Velcade treated and untreated MPM cells resulted in identification of novel transducers of apoptosis such as CARP-1, XAF1, and Troy proteins. Thus, Velcade targets cell cycle and apoptosis signaling to suppress MPM and HBC growth in part by activating novel transducers of apoptosis. This pilot study has paved way for further in-depth analysis of the downstream target molecules associated with presensitization of mesothelioma cells in finding effective therapeutic treatment options for both mesothelioma and recalcitrant breast 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 4446.
Abstract 4451: The effects of anthocyanins from the fruit of Vitis coignetiae Pulliat on NF-κB and NF-κB-regulated gene expressions in human lung cancer cells
Authors: Lee Won Sup , Kim Min Jeong , Yun Jeong Won , Lu Jing Nan , Kang Myung Hee , Kim Hun Gu , Kim Dong Chul , Kim Hae Gyeong , Lee Yun Koung , Jeong Jae-Hoon , Choi Yung Hyun , Kim GonSup , Ryu Chung Ho , Park Ok Jin , Shin Sung Chul 
Published: February 2011

Abstract
Vitis coignetiae Pulliat (Meoru in Korea) has been used as a remedy for inflammatory diseases and various cancers. We isolated anthocyanins from Meoru. We previously suggested that anthocyanins from fruits of Vitis coignetiae Pulliat (Meoru in Korea) should have anti-invasive effects through suppression of NF-κB activation. Here, we investigated their effects on NF-κB-regulated gene products and cellular responses in human lung cancer cells. The anthocyanins inhibited NF-κB activation in a dose-dependent manner. TNF-α augmented proliferation, migration and invasion of A549 cells. The anthocyanins inhibited the augmented proliferation, migration and invasion of the cancer cells by TNF-α. We also found that the anthocyanins suppressed NF-κB-regulated proteins involved in caner proliferation, metastasis and anti-apoptosis. The anthocyanins inhibit NF-κB activity by inhibiting IκBα phosphorylation. Taken together, this study suggested that the anthocyanins isolated from fruits of Vitis coignetiae Pulliat inhibit the NF-κB activation and downstream proteins, which may be a factor in their anticancer activities of fruit of Vitis coignetiae Pulliat.
Keywords: anthocyanins, Vitis coignetiae Pulliat, NF-κB, cancer
* This study was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family affairs, Republic of Korea (0820050)
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 4451.
Abstract 4456: Molecular events required for the induction of lethal iron deprivation in malignant hematopoietic cells via an antibody-avidin fusion protein specific for human transferrin receptor 1
Authors: Rodríguez José A. , López-Valdes Héctor E. , Helguera Gustavo F. , So Sokuntheavy , Luria-Pérez Rosendo , Daniels Tracy R. , Charles Andrew C. , Penichet Manuel L. 
Published: February 2011

Abstract
Iron is an essential nutrient for cell growth and division. The transferrin receptor 1 (TfR1 or CD71) is a major gateway for iron import, and as such is expressed on a variety of cells; it is over-expressed in a number of tumors including hematopoietic malignancies. We have previously shown that an antibody-avidin fusion protein (ch128.1Av) specific for TfR1 is toxic to cancer cells, capable of inducing lethal iron deprivation in some malignant B-cells such as IM-9, but not in others such as U266. Importantly, ch128.1Av induces iron deprivation without directly preventing the binding of transferrin (Tf) to TfR1. In an attempt to identify the molecular events behind the iron deprivation induced by ch128.1Av, we have found that like Tf, internalization of ch128.1Av bound to TfR1 is clathrin, dynamin, and temperature dependent. Additionally, recycling of TfR1-bound ch128.1Av at short timescales (30min) is also similar to that of Tf and does not significantly alter the rate of Tf uptake. Long-term incubation (&gt;6h) of IM-9 cells with ch128.1Av precludes their uptake of Tf and induces degradation of TfR1. This is not the case with U266 cells, in which Tf uptake remains unaffected and degradation of TfR1 is negligible in the presence of ch128.1Av. Clustering of cell surface TfR1 by ch128.1Av, given its multivalent nature, was previously thought to cause degradation of the receptor in sensitive cells such as IM-9. We now show that clustering of TfR1 occurs both in cells that are sensitive and resistant to treatment with the antibody (IM-9 and U266), indicating that clustering of TfR1 induced by ch128.1Av is not sufficient to induce receptor degradation and subsequent iron deprivation. Instead, resistance to treatment with ch128.1Av may be attributed to elements downstream of receptor binding/clustering; possibly related to those involved with TfR1 recycling and degradation. Further studies are needed to identify these resistance factors and potentially enhance the efficacy of ch128.1Av as well as other antibodies and/or small molecules that similarly target TfR1 for the treatment of hematologic malignancies.
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 4456.
Abstract 4472: NVP-BKM120, a pan class I PI3K inhibitor impairs microvascular permeability and tumor growth as detected by DCE-MRI and IFP measurements via radio-telemetry: Comparison with NVP-BEZ235
Authors: Schnell Christian R. , Arnal Samuel , Becquet Mike , Allegrini Peter , Voliva Charles , Cozens Robert , Garcia-Echeverria Carlos , Maira Sauveur Michel 
Published: February 2011

Abstract
Tumor blood vessels are distinctly abnormal in structure and function. When compared to normal vessels, they are enlarged and tortuous and leaky, poorly covered by pericytes and with a defective basement membrane. VEGF is a prominent cytokine responsible for the hyperpermeable state of tumor microvasculature to plasma macromolecules. The phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway functions downstream of VEGF and can activate the production of the free radical gas nitric oxide (NO) through the enzyme endothelial NO synthase (eNOS), a key player for the in vivo biological activity of VEGF.
In the present study, we investigated the effect of NVP-BKM120, a novel, synthetic low molecular mass compound, which potently inhibits class I PI3K activity, on vascular leakage in tumors and its impact on tumor progression in an orthotopic breast cancer model (BN472) in syngeneic rats. Effects on the vasculature were investigated in normal and tumor tissues with a variety of technologies: dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), tumor interstitial fluid pressure (IFP) measurements in conscious animals via radio-telemetry and a modified Miles assay, representing non invasive, minimally invasive and invasive methods, respectively. Tumor histology and western blots were used to confirm pathway inhibition.
For comparison, the effect of NVP-BEZ235, a potent pan class I PI3K and mTOR activity inhibitor, was assessed head-to-head in the same experiments.
BKM120 induced significant decreases in VEGF-induced vascular leakage in normal and tumor tissues. These effects were similar to those obtained following BEZ235 treatment. Western blot of total ear lysates from treated mice clearly demonstrated pathway inhibition. The inhibition of vessel permeability observed with BEZ235 and BKM120 correlated with their respective anti-tumor activities, IFP change and Ktrans (vascular permeability transfer constant measured by DCE-MRI) decrease.
In conclusion, our data demonstrate that in BN472 tumors, BKM120 significantly decreases tumor microvascular leakage similar to BEZ235 at equipotent antitumor dose. Changes in Ktrans may be a useful independent clinical surrogate biomarker for NVP-BKM120 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 4472.