bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3672: Adrenocortical carcinoma cell lines are sensitive to compounds targeting the G2/M transition
Authors: Datrup Erica , Demeure Michael J. , Bussey Kimberly J. 
Published: February 2011

Abstract
Adrenocortical carcinoma (ACC) is an aggressive tumor of the adrenal cortex. It affects 1-2 per million and has a 5 year survival rate of 25-30% due to late detection and a lack of effective systemic therapy. Mitotane, an isomer of the insecticide DDT, is the only compound approved for the treatment of patients with ACC. It has a poor response rate (22% as a single agent) and a toxicity profile that often results in dose reduction or cessation of therapy altogether. New therapies are desperately needed.
Expression profiling of ACC by ourselves and others highlights the importance of the G2/M transition, the p53 pathway, and signaling of IGF2 through IGF1R. Using this knowledge, we profiled the in vitro chemosensitivity of the two ACC cell lines, H295R and SW-13, to compounds that target aspects of these pathways. Cells were plated, and drug added 24 hours later in a 3-fold serial dilution, with the exception of mitotane which was done as a 1.5-fold serial dilution. Viability was assessed by CellTiter Glo at 3 different time points. The cell lines show sensitivity to compounds that target the G2/M transition (VX-680 and BI-2536) and EGFR (erlotinib). The difference in response between H295R and SW-13 to LY294002 suggests the cell lines harbor a difference in the relative contributions of PI3K signaling versus Ras-Raf-MEK signaling downstream of IGF1R. Additionally, the response of both cell lines to erlotinib suggests that EGFR signaling may play a role in ACC. Neither cell line was particularly sensitive to MDM2 inhibition, indicating that this is not a good target to restore p53 pathway function. Finally, our results suggest that further testing of compounds that target G2/M is warranted, particularly PLK-1 inhibitors.In vitro chemosensitivity profiling in ACC cell linesCompoundMechanism of ActionTime PointAverage IC50 for SW-13 in uMAverage IC50 for H295R in uMMitotaneUnknown, but results in mitochondrial degeneration72 hours12.869.48 96 hours11.039.05 120 hours11.519.99Nutlin-3MDM2 inhibitor72 hours19.2415.81 96 hours16.8614.83 120 hours15.8114.00LY294002PI3K inhibitor72 hours4.3653.86 96 hours4.3122.73 120 hours4.8013.55ErlotinibEGF-R inhibitor72 hours2.73NA 96 hours2.562.29 120 hours2.662.34BI-2536PLK-1 inhibitor72 hours0.00590.35 96 hoursND0.11 120 hoursND0.12VX-680Aurora kinase inhibitor72 hours17.23ND 96 hours6.07ND 120 hours5.21ND
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 3672.
Abstract 3674: Inhibition of noncanonical NF-kappa B activation by (−)-DHMEQ in vitro and in adult T-cell leukemia cells
Authors: TAKEIRI Masatoshi , HORIE Ryoichi , UMEZAWA Kazuo 
Published: February 2011

Abstract
[Objective and Rationale]Noncanonical NF-kappa B consisting of RelB and p52 is especially important for the maturation of B-lymphocytes and autoimmune diseases. In one hand, we have designed and synthesized a novel NF-kappa B inhibitor (−)-DHMEQ. It showed potent anti-inflammatory and anti cancer effects in animal models without any toxicity. We have reported (−)-DHMEQ covalently binds to the specific Cys residue of each NF-kappa B component and that it inhibits the DNA binding of canonical NF-kappa B components. However, the effects on noncanonical NF-kappa B has not been studied at the molecular level. In the present research we have studied theinhibitory effect of (−)-DHMEQ on noncanonical NF-kappa B in vitro and in cultured lymphoma cells in which noncanonical NF-kappa B is constitutively activated. [Experimental Design and Results]We prepared recombinant noncanonical NF-kappa B proteins, RelB and p52. (−)-DHMEQ was shown to covalently bind to Cys144 of RelB but not to p52 in MLADI-TOF/MS and mutation analysis. Either RelB or p52 does not form homodimer. Then, we prepared HeLa cells over–expressing full length RelB and p52. (−)-DHMEQ inhibited the NF-kappa B activity in RelB(wild type)/p52 cells but not in RelB(C144S)/p52 expressing cells in EMSA. Thus (−)-DHMEQ was shown to target Cys 144 of RelB in cultured cells to inhibit noncanonical NF-kappa B-DNA binding. It also inhibited RelB/p52 binding to DNA in vitro. Then, we looked for the cell line in which noncanonical NF-kappa B is constitutively activated using anti-RelB in EMSA. MT-1 cells are HTLV-1 transformed T-cells and often used for the adult T-cell leukemia (ATL) model. We found that the highly activated NF-kappa B is mainly consisting with noncanonical one in MT-1 cells. (−)-DHMEQ effectively inhibited the noncanonical NF-kappa B activity in MT-1 cells. [Conclusion] (−)-DHMEQ binds to RelB and effectively inhibited RelB/p52-DNA binding. We have found noncanonical NF-kappa B is highly activated ATL-like MT-1 cells, which was inhibited by (−)-DHMEQ. (−)-DHMEQ may be useful for the treatment of ATL and other diseases induced by noncanonical NF-kappaB activation.
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 3674.
Abstract 3678: Reducing non-specific toxicity of cisplatin in head and neck cancer by targeted therapy using cisplatin-heparin-folic acid nanoparticles
Authors: Peng Xianghong , Wang Yiqing , Huang Donghai , Wang Yuxiang , Chen Zuo Georgia , Nie Shuming , Shin Dong M. 
Published: February 2011

Abstract
Cisplatin(DDP) is a platinum-based chemotherapy drug which was widely used to treat various types of cancer including Head and Neck Squamous Cell Carcinoma (HNSCC). However, very little DDP reaches the tumor tissue due to poor specificity and it induces dose-limiting toxicities. The delivery of DDP selectively into a tumor mass has the potential to minimize toxicity to normal tissues and to improve the antitumor efficiency. We have developed novel nanoparticles by conjugating folic acid to modified heparin, then loaded cisplatin (DDP) into the targeted nanoparticles via the exchange of reaction of Pt from the chloride to the carboxylates on the nanoparticles. Uptake and biodistribution of DDP delivered by the nanoparticles or the free DDP form in vitro and in vivo was quantified by inductively coupled plasma-mass spectrometry (ICP-MS). We showed that DDP-Heparin-Folic Acid (FA) Nanoparticles are specifically internalized by FR-expressing HNSCC KB cells in vitro (17 fold higher than free DDP). Systemic delivery of DDP-Heparin-FA nanoparticles (2.5 mg/kg; 4 times treatment at 3 days intervals) into nude mice bearing KB cell tumors (6 mice/group) lead to selective accumulation of the DDP in subcutaneous tumor lesions (74 ppb/mg tissue for HFDDP, 16.5 ppb/mg tissue for DDP, P&lt;0.05), and have significant antitumor activity. Furthermore, mice receiving DDP-Heparin-FA nanoparticles showed no significant body weight loss or damage to liver or spleen, whereas mice that received free DDP had significant weight loss and massive organ damage. Our results suggest that DDP-Heparin-FA nanoparticles have the potential to be used for delivery of this highly toxic chemotherapeutic agent with reduced side effects in HNSCC. (This research was supported by the National Cancer Institute award 5 P50 CA128613)
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 3678.
Abstract 3680: The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane
Authors: Berndt Norbert , Yang Hua , Trinczek Bernard , Zhang Ziming , Wu Bainan , Lawrence Nicholas J. , Pellechia Maurizio , Schonbrunn Ernst , Cheng Jin Q. , Sebti Said M. 
Published: February 2011

Abstract
Persistently activated hyper-phosphorylated Akt contributes to human oncogenesis and tumor resistance. TCN-P, the active metabolite of the Akt phosphorylation inhibitor triciribine (TCN), is in clinical trials in patients whose tumors contain hyper-phosphorylated Akt, but the mechanism by which TCN-P, inhibits Akt phosphorylation is not known. In this manuscript, we show that in vitro, TCN-P inhibits neither Akt kinase activity nor the phosphorylation of Akt S473 and T308 by mTOR or PDK1, respectively. However, in intact cells, immunofluorescence and subcellular fractionation experiments demonstrate that TCN inhibits EGF-stimulated Akt recruitment to the plasma membrane and subsequent phosphorylation of Akt on Ser473 and Thr308. Surface plasmon resonance (SPR) demonstrates that TCN-P, but not TCN, binds to full-length, non-phosphorylated (inactive) Akt. However, neither TCN-P nor TCN interacts with full-length, phosphorylated (active) Akt. Furthermore, TCN-P, but not TCN, binds Akt-derived pleckstrin homology (PH) domain with KD values of 690 nM and 1.4 µM as demonstrated by SPR and isothermal calorimetry (ITC), respectively. Consistent with these data, nuclear magnetic resonance (NMR) spectroscopy shows that TCN-P, but not TCN, binds to the PH domain engaging amino acid residues in the vicinity of the PIP3 binding pocket. Thus, SPR, NMR, as well as biochemical studies indicate that the anti-cancer drug TCN-P inhibits Akt function by binding to the PH domain of Akt, blocking its recruitment to the plasma membrane and subsequent phosphorylation, suggesting that this drug may be beneficial to patients whose tumors express persistently activated Akt.
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 3680.
Abstract 3682: Enhanced anticancer effect of 5-fluorouracil loaded into thermoresponsive conjugated linoleic acid-incorporated poloxamer hydrogel on metastastic colon cancer models
Authors: Bae Woo Kyun , Lee Ji Hee , Park Myong Suk , Hwang Jun Eul , Shim Hyun Jeong , Cho Sang Hee , Guo Ding-Ding , Cho Chong Su , Lee Sang Joon , Park In Kyu , Chung Ik Joo 
Published: February 2011

Abstract
Background: 5-Fluorouracil (5-FU) is a useful chemotherapeutic agent in the treatment of solid tumors. However, it is very short half-life in plasma circulation greatly limited the in vivo antitumor efficacy, and intravenous 5FU injection is unlikely to achieve optimal dose effectiveness within peritoneal cavity. Conjugated linoleic acid-coupled Pluronic F127 (Plu-CLA) is an effective drug delivery system with numerous advantages and has an anticancer activity. It was also shown that paclitaxel loaded in Plu-CLA demonstrated synergistic tumor suppression through robust cell cycle arrest and enhanced apoptosis in tumor compared to paclitaxel in poloxamer hydrogel. The aim of this work is to evaluate the therapeutic efficacy of Plu-CLA as a new intraperitoneal 5FU delivery system.
Methods: Cytotoxicity was evaluated by using CT-26 murine colon carcinoma cell. We established peritoneal metastasis models and hepatic metastasis models for colon cancer using BALB/c mice and firefly luciferase-expressing CT-26 (CT26/Fluc) cells. Tumor progression and response to therapy were monitored by bioluminescence imaging (BLI).
Results: MTT assay indicated that 5-FU loaded in Plu-CLA hydrogel (P-FU) could increase the cytotoxic activity of 5-FU in CT-26. P-FU significantly enhanced apoptosis compared with 5-FU control. It was found that Caspase 3 and p21 were up-regulated, whereas Bcl-2 was down-regulated. Moreover, growth of hepatic metastases in vivo was significantly reduced in mice treated with P-FU. Treatment with P-FU substantially delayed tumor growth of intraperitoneal metastasis greatly and tumor-bearing mice treated with P-FU showed a better survival tendency than the 5-FU alone.
Conclusion: These results were attributed to the synergistic effect of Plu-CLA. 5-FU administered in Plu-CLA hydrogel led to significant enhancement of tumor growth suppression and cellular apoptosis. Therefore, Plu-CLA could be a potential intraperitoneal carrier for hydrophilic 5-FU for the effective treatment of metastatic colon cancer.
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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 3682.
Abstract 3684: Developing STAT3 protein inhibitors as adjuvant therapeutics: Promising synergistic effects in human cancers
Authors: Fletcher Steven , Page Brent D. G. , Yue Piebin , Zhang Xiaolei , Sharmeen Sumaiya , Schimmer Aaron D. , Turkson James , Gunning Patrick T. 
Published: February 2011

Abstract
Signal Transducer and Activator of Transcription 3 (Stat3) protein is a cytosolic transcription factor that relays signals from receptors in the plasma membrane directly to the nucleus, and is routinely hyper-activated in many human cancers and diseases. STAT3 induces anti-apoptotic gene expression programs (e.g. Bcl-xL) and the over-expression of cell cycle regulators (e.g. cyclin D1) that contribute significantly to the resistance of cancer to current chemotherapeutic strategies. Since most cancer drugs aim to initiate apoptosis, tumor cells containing activated STAT3 have an intrinsic resistance to current treatment strategies. It has therefore been postulated that STAT3 inhibitors could play a significant role in the future of adjuvant cancer therapies by sensitizing human tumors to traditional chemotherapy. By examining the protein-protein interaction interface and employing computational modeling, we have thus developed a series of small molecule inhibitors of the transcriptionally active STAT3-STAT3 homo-dimer complex. Lead inhibitors showed potent anti-STAT3 activity in vitro and in tumor cell lines, as well as in malignant cells taken from leukemia patients. More specifically, these compounds displayed single digit micromolar activity against breast, prostate, pancreatic and leukemia cell lines and showed negligible cytotoxic effects on healthy cells treated with high µM concentrations of compounds. Preliminary adjuvant studies with a series of clinically relevant therapeutics have shown impressive synergistic effects in leukemia cell lines, as well as in patient tumor cells.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 3684.
Abstract 3685: A strategy to identify therapeutic candidates for chronic lymphocytic leukemia from a library of FDA approved drugs
Authors: Shen Min , Zhang Yaqin , Wiestner Adrian U. , Ashlock Melissa A. , Austin Christopher P. , Auld Douglas S. 
Published: February 2011

Abstract
Chronic lymphocytic leukemia (CLL) is an adult lymphoid malignancy with a variable clinical course. There is considerable interest in the identification of new treatments, as most current approaches are not curative. While most patients respond to initial chemotherapy, relapsed disease is often resistant to the drugs commonly used in CLL and are left without limited therapeutic options. In this study, we used a luminescent cell viability assay based on ATP levels (CellTiter-Glo, Promega) to find compounds that were potent and efficacious in killing CLL cells. We employed an in-house process of quantitative high throughput screening (qHTS) to assess 8-9 concentrations of each member of a 2,816 compound library (including FDA-approved drugs and those known to be bio-active from commercial suppliers). Using qHTS we generated potency values on each compound in lymphocytes donated from each of six individuals with CLL and five unaffected individuals. We found 102 compounds efficacious against cells from all six individuals with CLL (“consensus” drugs) with seven of these showing no efficacy on lymphocytes from a majority of unaffected donors, suggesting some degree of specificity for the leukemic cells. Furthermore, to determine if we could save time and cost we screened the same library using CLL cells pooled from these individuals. We found that over 90% of the 102 drugs identified as efficacious on cells from individuals were also efficacious in the pooled experiment. Importantly, a near perfect correlation was observed in potency values between the single and pooled studies. The results of this “pooling” approach suggests it is rationale to apply pooling and qHTS when screening CLL cells against much larger collections (&gt;300,000 unapproved compounds) where novel compounds could be identified as starting points for drug discovery and development.
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 3685.
Abstract 3697: Evaluation of monocyte and granulocyte function with and without ex vivo pegylated liposomal doxorubicin (PLD) exposure in blood of healthy volunteers
Authors: Caron Whitney P. , La-Beck Ninh M. , Fong Alan M. , Liu Peng , Hanna Suzan K. , Ngo Tuongvy L. , Zamboni Beth A. , Gehrig Paola A. , Tarrant Teresa , Zamboni William C. 
Published: February 2011

Abstract
Background: PLD is a nanoparticle approved for treatment of refractory ovarian cancer. The reticuloendothelial system (RES), which includes monocytes (MO), may have a key role in clearance (CL) of nanoparticle sized pegylated liposomes such as PLD, though factors affecting the CL of liposomes are unclear. Previously we reported that the CL of liposomes is associated with age and monocyte counts. This study's objective was to characterize the function of MO and granulocytes with and without ex vivo PLD exposure in the blood of healthy volunteers.
Methods: Blood samples were obtained from six (4 males, 2 females) healthy human volunteers, immediately placed on ice and processed. Blood samples were incubated with PLD 10 mcg/mL or 5% dextrose solution (control) for 1 hour (h) at 37°C with 5% CO2. After incubation, PHAGOTEST® and PHAGOBURST® (Orpegen Pharma) tests were performed to evaluate phagocytic activity and respiratory burst activity. PHAGOBURST® tests were performed after fMLP and PMA stimulation. Samples were analyzed using Dako CyAn Flow Cytometer with Summit software. Comparisons were made between samples with and without PLD exposure, gender, and age &gt;60 and &lt;60 years old (yo) based on previously reported trends.
Results: The mean + SD age of healthy volunteers was 45.9 + 14.9 yo. The mean fluorescence per cell, grouped by functional test and age, gender, and with or without PLD exposure are summarized in Table 1.Table 1.Mean Fluorescence Phagocytic ActivityRespiratory Burst Activity with fMLPRespiratory Burst Activity with PMA GranulocytesMonocytesGranulocytesMonocytesGranulocytesMonocytesAge &gt;60 (n=2)447.6323.383.757.7377.789.4Age &lt;60 (n=4)343.3213.5555.538.8663.6163.6p-value0.4590.240.0470.0480.6130.583 Male (n=4)370.2256.860.344.5587.9171.1Female (n=2)393.7236.674.146.4529.174.4p-value0.8940.9080.5290.8790.9320.449 Without PLD (n=6)414.2250.148.839.1542.1114.4With PLD (n=6)378.0250.164.945.1568.3138.9p-value0.6630.9990.2530.6290.9410.761
Conclusions: Differences in phagocytic and respiratory burst activity in granulocytes and MO of healthy volunteers were observed. There is variability in activity based on the type of assay used. There appears to be both age and gender differences in activity. A 1 h ex vivo exposure to PLD does not seem to significantly alter cell function. Future studies will characterize MO and granulocyte function, PLD uptake, and viability with and without PLD exposure in additional healthy subjects and ovarian and breast cancer patients.
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 3697.
Abstract 3699: Multi-walled carbon nanotubes induce apoptosis in normal human small airway epithelial cells through proteasome-mediated Mcl-1 protein degradation
Authors: Yuan Bao-Zhu , Chapman Joshua , Rojanasakul Yon , Castranova Vincent , Reynolds Steven H. 
Published: February 2011

Abstract
Engineered carbon nanotubes (CNTs) are emerging as the major building blocks in nanotechnology thanks to their unique physical and chemical properties. However, widespread application of CNTs, including single- and multi-walled (SWCNTs and MWCNT), has resulted in increased public concern regarding potential toxicities from occupational or environmental exposures to CNTs. Recently, both SWCNTs and MWCNTs have been observed to exhibit pulmonary toxicities. To better understand CNT-related pulmonary toxicities, the present in vitro study used normal human small airway epithelial cells (SAEC), which constitute a primary target of respiratory exposure to CNTs, as a model to investigate cell death effects of either SWCNTs or MWCNTs. We observed that, at 24 h after exposure, greater than 5 μg/cm2 MWCNT, but not SWCNT, induced a significant dose-dependent cell death in primary cultured SAEC cells as assayed by WST-1. The cell death was accompanied by DNA damage, as indicated by the appearance of sub G0/G1 cells in a flow cytometry assay, and protein cleavages for PARP, caspases 3, 7 and 9, as revealed by Western blotting. It was further observed that the pro-apotpotic activities of MWCNT were reduced by caspase specific inhibitors, demonstrating that MWCNT, but not SWCNT, can induce a caspase-dependent apoptosis in SAEC cells. To understand regulation of the MWCNT-induced apoptosis, we then examined expression of the anti-apoptotic Bcl-2 family proteins and found that only Mcl-1 was significantly reduced in protein level by MWCNT, but not SWCNT, and such reduction was blocked by proteasome inhibitor MG132. Furthermore, it was found that reduction of Mcl-1 protein expression through Mcl-1 siRNA enhanced sensitivity of SAEC cells to MWCNT-induced apoptosis, suggesting that proteasome-mediated Mcl-1 protein degradation contributes to MWCNT-induced apoptosis. This study reveals a difference in cell death effects on normal human SAEC cells between SWCNT and MWCNT. It also provides new insights into understanding of the MWCNT-induced pulmonary toxicity.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 3699.