bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4455: Differential response to AS1411 in a pair of VHL-positive and VHL-negative renal carcinoma cell lines
Authors: Islam Ashraful , Jones David , McLaughlin Fiona , Bates Paula J. 
Published: February 2011

Abstract
AS1411 is a G-rich phosphodiester oligonucleotide that forms a stable G-quadruplex structure and functions as an aptamer to nucleolin. Preclinical studies have shown that AS1411 exhibits antiproliferative activity against a variety of cancer types, but has little effect on normal cells. In a Phase I clinical trial of AS1411 in 30 patients with advanced solid tumors, there were no serious adverse events associated with AS1411 treatment. Furthermore, there was evidence of clinical benefit, particularly in patients with metastatic renal cell carcinoma (RCC), including durable disease stabilization and objective responses. A phase II trial of AS1411 in metastatic RCC is now underway.
Renal cell carcinomas (RCC) are the most common form of kidney cancer and the majority of these (75%) have biallelic inactivation of the von Hippel-Lindau tumor suppressor gene (VHL) by mutation or less commonly by hypermethylation. The VHL gene product, pVHL, has multiple functions including ubiquitination of HIF transcription factors, regulation of endocytosis, and control of microtubule orientation. Here we investigated the effect of AS1411 on two previously established matched RCC cell lines with and without functional VHL: RCC4 cells which harbor a mutation in VHL and do not express functional VHL (VHL-negative), and RCC4/VHL which are stably transfected to express wild type VHL (VHL-positive). Using a variety of techniques (MTT assay, colony forming assay, and cell cycle analysis), we observed a clear difference in response to AS1411 between RCC4 and RCC4/VHL cells, with the VHL-negative line being much more sensitive to growth inhibition following AS1411 treatment. Cell cycle analysis showed that VHL-negative RCC4 cells treated with AS1411 accumulate predominantly in S phase after 72 h (as seen in other AS1411-responsive cell lines), followed by S and G2/M phase of cell cycle after 96 h treatment. In contrast, there was no perturbation of the cell cycle in the VHL-positive RCC4/VHL cells. Further studies are ongoing to determine if this is a general effect, dependent directly on pVHL, or if it is related to specific phenotypic differences between these two cell lines. In any case, the availability of two closely related cell lines with markedly different sensitivities to AS1411 should greatly facilitate our efforts to identify markers that may predict response to AS1411.
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 4455.
Abstract 4459: Apricoxib upregulates 15-PGDH and PGT in HNSCC
Authors: St. John Maie , Wang Guanyu , Luo Jie , Munaim Qahera , Lee Jay M. , Burrows Francis , Zaknoen Sara , Dubinett Steven M. 
Published: February 2011

Abstract
Head and neck squamous cell carcinoma (HNSCC), is the sixth most common cancer in the world. Patients with HNSCC are at considerable risk of mortality, with more than 300,000 deaths attributable to the disease per year. The five-year survival rate for patients with advanced head and neck cancer remains approximately 15-20 percent, emphasizing the importance of new therapeutic strategies. In spite of extensive research on EGFR and COX-2 inhibitors, their combined use for HNSCC is still in its developmental stage. We evaluated the efficacy of the newer COX-2 inhibitor, apricoxib, in HNSCC cell lines.
Here, we report that in comparison with celecoxib, apricoxib shows greater efficacy in vitro; and we define the mechanisms which may be responsible for this. Our studies show that apricoxib is effective in preventing tumor cell growth in 3-dimensional, and anchorage-independent growth assays; as well as decreasing the capacity for tumor cell migration. Treatment of HNSCC cells with apricoxib also causes greater up regulation of E-cadherin expression and down regulation of vimentin, as compared with celecoxib treatment. This has significant implications for targeted chemoprevention and anti-cancer therapy because E-cadherin expression has been implicated as a marker of sensitivity to EGFR TKI. In addition to PGE2 down regulation, indicating COX-2 inhibition, we also show that apricoxib treatment causes a marked up regulation of 15-PGDH (prostaglandin dehydrogenase) and PGT (prostaglandin transporter), both of which decrease PGE2. These effects are further amplified in 3-dimensional culture, indicating the import of the microenvironment in drug efficacy. This up regulation of 15-PGDH and PGT with apricoxib treatment may explain its increased efficacy over celecoxib in the assays we tested. As apricoxib affects other pathways of PGE2 degradation and uptake, there is ultimately less PGE2 to drive metastasis and tumor progression. These newly defined mechanisms for the increased efficacy of apricoxib have important implications for targeted chemoprevention and therapy.
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 4459.
Abstract 4462: Induction of apoptosis by 3-bromopyruvate involves endoplasmic reticulum (ER) stress and overcomes autophagy response in human hepatocellular carcinoma cell line Hep3B
Authors: Ganapathy-Kanniappan Shanmugasundaram , Geschwind Jean-Francois H. , Kunjithapatham Rani , Buijs Manon , Syed Labiq H. , Rao Pramod P. , Ota Shinichi , Kwak Byung Kook , Vali Mustafa 
Published: February 2011

Abstract
Background: Autophagy is a cellular response to adverse conditions that also plays a role in resistance to chemotherapy in cancer cells. Resistance renders systemic chemotherapy generally ineffective against human hepatocellular carcinoma (HCC). The HCC cell line Hep3B is deficient in key apoptotic regulators (p53, Fas) and shows differential apoptotic response to various chemotherapeutic agents. The antiglycolytic agent, 3-bromopyruvate (3-BrPA) is known to induce cell death in human HCC cell lines and has shown potent antitumor activity. In the current study we investigated the intracellular response of Hep3B cells to 3-BrPA treatment and compared it with another HCC cell line, SK-Hep1. Methods: We examined the intracellular effect of 3-BrPA by measuring endoplasmic reticulum (ER) stress using quantitative RT-PCR (qRT-PCR) and immunoblotting. The ultrastructural changes were observed by electron microscopy (EM). Apoptosis was evaluated by TUNEL assay and caspase-3 activation. Results: 3-BrPA treatment induced ER stress and inhibited protein synthesis in a dose and time dependent manner in both the HCC cell lines. EM revealed that 3-BrPA treatment resulted in the initiation of autophagy in Hep3B cells and apoptotic blebbing in SK-Hep1 cells. However, Hep3B cells overcame the initial autophagic response and finally progressed to apoptosis. Conclusions: SK-Hep1 cells upon 3-BrPA treatment underwent the classic pathway of apoptosis whereas Hep3B cells employed autophagy as a defense mechanism but failed to resist apoptosis. We conclude that 3-BrPA treatment promotes apoptosis in human HCC cell lines irrespective of their differential response associated with the status of key apoptotic regulators.
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 4462.
Abstract 4463: Thymoquinone, a potent phytochemical inhibits invasion and cell proliferation in a cell line derived from prostate cancer bone metastasis
Authors: Quadri Rehan S. , Hynes Paul G. , Yin Juan J. , Abou-Kheir Wassim G. , Kelly Kathleen 
Published: February 2011

Abstract
The majority of cancer related deaths in the United States result from metastatic malignancies in distant sites such as the brain, lungs, liver and bone. Androgen independent prostate cancer demonstrates a high affinity for metastatic colonization of the bone microenvironment, resulting in skeletal damage that can cause bone pain, hypercalcemia, pathological fracture and spinal cord-compression. Thymoquinone, an extract from the volatile oil of the black seed Nigella sativa has been shown to be a potent phytochemical, traditionally solubilized and administered nasally as an herbal remedy to combat a range of ailments. Thymoquinone functions in the electron transport chain as an electron shuttle, suggesting an anti-oxidant mechanism for its beneficial effects. In addition, thymoquinone exhibits anti-inflammatory and anti-neoplastic effects, inhibiting the growth of pancreatic, colon and prostate cancer cells in-vitro. In order to investigate the effects of thymoquinone on cells that had specifically adapted to growth in bone, we utilized a cell line derived directly from prostate bone metastases. Bone metastases were generated using a recently described ras over-expressing DU145 cell line (Yin et al., 2007). Bone metastases were subsequently isolated, and a cell line termed DU145 Bone 1 was established.
Thymoquinone treatment of DU145 Bone 1 cells resulted in significant dose dependent inhibition of cell proliferation and viability over 24, 48 and 72 hrs. Using an Annexin V/PI assay to investigate the rate of apoptosis, we found that thymoquinone treatment of DU145 Bone 1 cells induced apoptosis in a dose dependent manner. This increase in apoptosis correlated with the decrease in proliferative potential, suggesting that induction of apoptosis may be involved in inhibiting cell proliferation of DU145 Bone 1 cells following thymoquinone treatment. Finally, in an in-vitro transwell assay, thymoquinone treatment (10 to 50 nM) of DU145 Bone 1 cells resulted in near complete inhibition of cell invasion toward fetal calf serum.
In summary, we demonstrate that thymoquinone treatment of a metastatic cell line selected for growth in bone results in significant inhibition of cell proliferation, reduction in cell viability, induction of apoptosis and loss of in-vitro invasive potential. Further in-vivo studies will provide valuable insight into the therapeutic potential of thymoquinone for the treatment of bone metastasis.
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 4463.
Abstract 4466: Celastrol induces apoptosis through modulation of estrogen receptor in human breast cancer cells
Authors: Jang Soon Young , Ko Jesang 
Published: February 2011

Abstract
Celastrol, a triterpene extracted from the Chinese medicine, is known to inhibit the growth of human prostate cancer cells. However, the anticancer activity of celastrol has not been reported in other cancer types. In this study, we investigated a negative role of celastrol in breast cancer development. We first examined the effects of celastrol on breast cancer cell growth. Results showed that celastrol inhibited estradiol-stimulated growth of MCF7 and T47D cells and increased apoptosis of breast cancer cells in a dose and time dependent manner. We also observed that celastrol decreased the expression of estrogen receptor (ER) at the both mRNA and protein levels in MCF7 and T47D human breast cancer cells. Results from the luciferase assay showed that the transcriptional activity of ER was decreased by the treatment with celastrol. Also, celastrol inhibited ER-mediated signaling and led to cell cycle arrest, which were confirmed by the expressions of cyclin D1 and progesterone receptor. We report that celastrol, an anticancer drug extracted from natural sources, induces apoptosis through modulation of estrogen receptor in human breast cancer cells and is a candidate for cancer chemotherapy in 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 4466.
Abstract 4468: A novel sulindac derivative (MDC-922) inhibits the growth of human colon cancer cell lines: A redox/polyamine-dependent effect
Authors: Caihua Zhu , Huang Liqun , Sun Yu , Xie Gang , Mackenzie Gerardo , Komninou Depina , Rigas Basil 
Published: February 2011

Abstract
Nonsteroidal anti-inflammatory drugs such as sulindac are promising chemoprevention agents against colon cancer. However, their weak potency and side effects limit their use for both chemoprevention and chemotherapy. Here we explored the effect of a novel sulindac derivative, MDC-922, on human cancer cells lines and explored its mechanism of action. MDC-922 inhibited the growth of human cancer cell lines originating from colon, pancreas and breast about 11- to 30-fold more potently than sulindac. It inhibited cell proliferation by up to 67% and significantly induced a G1/S phase cell cycle arrest. MDC-922 suppressed the levels of cell cycle regulating proteins including cyclin D1/D3 and CDK 4/6. The levels of intracellular reactive oxygen species (ROS), especially those of the mitochondrial superoxide anion were markedly elevated in response to MDC-922; ROS collapsed the mitochondrial membrane potential and triggered apoptosis, which was largely abrogated by the antioxidant N-acetyl cysteine. Interestingly, the expression of thioredoxin-1, a small redox protein which is essential for cell proliferation and survival, was rapidly downregulated (but not oxidized) by MDC-922, suggesting a unique ROS-inducing mechanism of MDC-922. Signaling pathways including cyclooxygenase (COX), nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways were modulated by MDC-922. Like sulindac, MDC-922 enhanced spermidine/spermine N1-acetyltransferase (SSAT) activity, reduced the cellular polyamine content and synergized with DFMO to inhibit cancer cell proliferation and induce apoptosis. Our results suggest that MDC-922 possesses promising anti-cancer properties and deserves further evaluation.
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 4468.
Abstract 4469: Antitumor activity of a single small molecule agent targeting Pi3K/mTor and HDAC
Authors: Bao Rudi , Lai Cheng-Jung , Wang Dagong , Qu Hui , Yin Ling , Zifcak Brian , Tao Xu , Wang Jing , Zhai Hai-Xiao , Xu Guang-Xin , Borek Mylissa , Atoyan Ruzanna , Samson Maria , Forrester Jeffrey , Dellarocca Steven , Cai Xiong , Qian Changgeng 
Published: February 2011

Abstract
Activation of the PI3K-Akt-mTOR signaling pathway plays a crucial role in cancer development and progression. Inhibition of this pathway has been investigated extensively as cancer therapy recently. However, primary or acquired resistance may present a major challenge to the success of inhibitors targeting this pathway due to the existence of redundant and compensatory pathways in cancer cells. In an effort to enhance anti-tumor activity and overcome these limitations, we have developed small-molecule compounds that are able to simultaneously inhibit both PI3K/mTOR and HDAC based on the rationale of synergistic effects of inhibition of these molecule targets in cancer cells. The lead compound exhibits potent inhibition of Pi3K subtypes and mTOR as well as HDAC. In cell proliferation assays, this compound displays potent anti-proliferation activity in cell lines from a variety of tumor types, including those cell lines with genetic mutations responsible for resistance to Pi3K inhibitors. In contrast to single-target PI3K inhibitors or PI3K/mTor dual inhibitors, this compound is able to simultaneously suppress both the Pi3K-Akt-mTOR and the MAPK signaling pathway due to epigenetic modifications via HDAC inhibition. This compound has a half-life of more than 10 hours in murine tumors, induces apoptosis and inhibits cell proliferation up to 48 hours following a single dose of the compound to tumor bearing animals. Efficacy studies in various tumor xenografts indicate that this compound has more potent antitumor activity than a leading Pi3K inhibitor and a dual Pi3K/mTor inhibitor, both of which are in clinical development, at doses causing no obvious side-effects to the tumor-bearing animals. This compound is under preclinical toxicology evaluation to support for further 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 4469.
Abstract 4470: The dual PI3K/mTOR inhibitor BEZ235 impairs gastric cancer growth in vitro and in vivo
Authors: Füreder Thorsten , Jaeger-Lansky Agnes , Hoeflmayer Doris , Kundtner Claudia , Wanek Thomas , Pflegerl Pamina , Wacheck Volker 
Published: February 2011

Abstract
Background
Gastric cancer is still a major health problem and the prognosis at advanced stage of disease with the current chemotherapeutic treatment strategies remains poor. Therefore novel treatment strategies and molecular targets for gastric cancer therapy are desperately needed. PI3K/mTOR pathway mutations, especially PTEN, PI3K3C and AKT mutations and pS6 overexpression, frequently occur in gastric cancer. Thus, we tested the activity of the dual PI3K and mTOR BEZ235 against gastric cancer in vitro and in vivo.
Materials and Methods
Three gastric cancer cell lines (N87, Mkn28 and MKN45) were treated with BEZ235 (20-80nM) and assessed for cell viability, cell death and cell cycle via celltiter blue and FACS analysis, respectively. PI3K/mTOR protein target modulation was measured by Western blotting. For in vivo studies athymic nude mice were inoculated with N87 or Mkn45 cells bilaterally and treated daily with 20 or 40mg/kg BEZ235.
Results
In vitro, treatment of gastric cancer cells with 20-80nM BEZ235 decreased cell growth in a dose dependent manner in all cell lines tested (up to −70%). This anti-proliferative activity was accompanied with a G1 cell cycle arrest of gastric cancer cells (up to 75%), whereas no significant levels of cell death were detected. On the molecular level, BEZ235 therapy resulted in a decrease of phosphorylation of AKT and S6 protein at 80nM. Notably, lower concentrations abolished mTOR downstream signalling but had no effect on AKT phosphorylation.
In vivo, treatment with 20 and 40mg/kg BEZ235 resulted in a significant anti-tumor effect in a N87 gastric cancer xenograft mouse model. Interestingly, BEZ235 therapy displayed no anti-tumor activity in the MKN45 gastric cancer xenograft mouse model. In both models, we observed similar results in terms of PI3K/mTOR pathway downregulation in xenografts.
Conclusion
BEZ235 has pronounced anti-tumor activity in gastric cancer cells at low nanomolar range, which is linked with PI3K/mTOR downregulation and G1 cell cycle arrest. In vivo, N87 gastric cancer cells responded to BEZ235 treatment, whereas MKN45 cells were resistant. Thus, in our models in vitro sensitivity of BEZ235 did not predict for in vivo activity. We are currently conducting a microPET mouse study in order to evaluate whether PET is a suitable tool to predict BEZ235 sensitivity in vivo and the results will be presented at the meeting.
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 4470.
Abstract 4471: Novel PI3K/mTOR dual inhibitor, NVP-BGT226, displays potent inhibitory activity against human head and neck cancer cell growth in vitro and in vivo
Authors: Chang Kwang-Yu , Chang Jang-Yang 
Published: February 2011

Abstract
Dysregulation of PI3K/AKT/mTOR signaling pathway is frequently observed in head and neck cancer, and often accounts for its tumorigenesis. To develop new treatment strategy in human head and neck cancer, we investigated the effect of a novel dual PI3K/mTOR inhibitor, NVP-BGT226, in head and neck cancer cell lines and one nasopharygeal cancer cell line (HONE-1) with its cisplatin-resistant variants. The growth inhibition assay revealed that NVP-BGT226 was active against all tested tumor cell lines with IC50 values ranged from 7.4 to 27.8 nM. In addition, cross-resistance of this compound to cisplatin-resistant cell lines was not observed. The expression level of p-AKT (S473), p-mTOR (S2481) was decreased in a dose- and time-dependent manner, with a concurrent downregulation in the level of p-4E-BP1 and p-S6P70K. Cell cycle analysis revealed that cells treated with NVP-BGT226 resulted in a dose- and time-dependent accumulation in the Go/G1 phase with concomitant loss in the S phase. The observation in annexin V assay showed an increment of double-staining cells in a time-dependent manner. Interestingly, the cleavage of caspase 3 and PARP was not noted. Further autophagy studies showed that NVP-BGT226 induced autophagy by the conversion of LC3-II from LC3-I. In addition, the accumulation of autophagosome by acridine orange staining was detected. Moreover, the treatment of cells by 3MA 1.25μM blocked the autophasome formation. Collectively, these data indicated that the growth inhibition effect induced by NVP-BGT226 was manipulated through the induction of autophagy. Notably, oral feeding of NVP-BGT226 5 mg/kg daily for 21 days showed potent activity against tumor growth in FaDu xenograft model. In conclusion, our studies suggested that NVP-BGT226 is a potent anti-cancer compound in head and neck cancer cells.
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 4471.
Abstract 4474: Dual inhibitors for PI3K and Erk induce growth inhibition of tumor cells
Authors: Seipelt Irene , Gerlach Matthias , Baasner Silke , Blumenstein Lars , Mueller Gilbert , Aicher Babette , Guenther Eckhard , Teifel Michael 
Published: February 2011

Abstract
The Ras/Raf/Mek/Erk and the PI3K-Akt signaling pathways are prime targets for drug discovery in proliferative diseases such as cancer. The results of research to date indicate that both the MAPK and the PI3K signaling pathways represent therapeutic intervention points for the clinical treatment of malignant tumors.
Our multi-parameter optimization program for kinase inhibitor selectivity, cellular efficacy, physico-chemical and in-vitro ADMET properties has led to the identification of a small molecular compound class with an uniquely advantageous dual kinase inhibition profile. These ATP competitive compounds inhibit Erk and PI3K in the nanomolar range and exert high selectivity against other serine threonine and tyrosine kinases. The anti-tumor efficacy of these dual kinase inhibitors was evaluated in diverse human tumor cell lines like HCT116, A549, MDA-MB 468, PC-3 and others. Physicochemical and in-vitro ADMET and safety parameters have been widely assessed. Furthermore in-vivo pharmacokinetic experiments showed plasma profiles expected to result in beneficial in-vivo anti-tumor efficacy.
Here we present the key characteristics of the compound class that led to the selection of AEZS-132 for in-vivo experiments with tumor bearing nude mice. The optimization of ADME and physicochemical properties such as solubility, permeability and metabolic stability by medicinal chemistry is ongoing.
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 4474.