bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 669: Sunitinib enhances TRAIL-induced apoptosis in preclinical colon cancer models
Authors: Mahalingam Devalingam , Bansal Sanjay , Medina Ernest , Kelly Kevin , Swords Ronan , Cool Robbert , de Jong Steven , Carew Jennifer S. , Giles Francis J. , Nawrocki Steffan T. 
Published: February 2011

Abstract
Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis that may have promise as an anticancer agent due to its selectivity toward tumor cells. However, resistance to TRAIL occurs frequently and is primarily due to defects in apoptosis signaling or activation of survival pathways. Sunitinib is an inhibitor of multiple receptor tyrosine kinases that promote cell survival and drug resistance. We hypothesized that disrupting pro-survival signaling cascades with suntinib would circumvent this mechanism of resistance and strongly enhance TRAIL-mediated apoptosis. We tested this hypothesis by investigating whether inhibition of survival signaling pathways with sunitinib could augment the anticancer activity of TRAIL in preclinical models of colon cancer.
Sunitinib significantly enhanced the anticancer activity of TRAIL in a panel of colon cancer cell lines as evidenced by increased caspase cleavage and DNA fragmentation. The TRAIL/sunitinib combination also promoted enhanced JNK activation and stimulated a decrease in the expression of XIAP, c-IAP2 and Bcl-xL, which correlated with apoptosis. siRNA-mediated knockdown of JNK reduced TRAIL/sunitinib-mediated apoptosis indicating that it is an important mediator of efficacy of this combination. We further investigated this combination regimen in HCT116 and HCT15 xenograft models treated with vehicle, TRAIL, sunitinib, or the combination. The TRAIL/sunitinib combination was very well tolerated and significantly reduced tumor burden in both models compared to either single agent treatment. The reduction in tumor volume correlated with increased apoptosis as measured by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and was associated with decreases in XIAP, c-IAP2 and Bcl-xL expression.
Our collective results suggest that sunitinib enhances TRAIL-mediated apoptosis by increasing JNK activation and downregulating multiple anti-apoptotic proteins. These findings are the first report of the therapeutic potential of the combination of sunitinib and TRAIL in preclinical models of 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 669.
Abstract 674: Cooperative induction of apoptosis through p53 signaling and mTOR inhibition in neuroblastoma
Authors: Barbieri Eveline , Chen Zaowen , Ludwig Andrew , Kim Eugene , Patterson Danielle , Sikorski Denae , Shohet Jason 
Published: February 2011

Abstract
The use of MDM2 inhibitors (e.g. Nutlin 3a) to stabilize p53 and induce apoptosis is an attractive therapeutic approach for neuroblastoma which is predominantly p53 wild-type at diagnosis and relapse. We sought to identify additional pathways to potentiate the p53 response. Mammalian target of rapamycin (mTOR) signaling pathway is active in neuroblastoma and mTOR inhibition has antiproliferative effects in vivo in neuroblastoma. It was recently demonstrated that two p53 target genes, Sestrin1 and Sestrin2, inhibit mTOR activity, linking genotoxic stress, p53 and the mTOR signaling pathway. We investigated the role of Sestrin1 and Sestrin2 in p53-mediated apoptosis in neuroblastoma and the interaction of mTOR and p53 pathways after their simultaneous blockade using the mTOR inhibitor, Temsirolimus and the MDM2 inhibitor, Nutlin 3a.
We show here that stabilization and activation of wt-p53 through MDM2 inhibition result in significant and rapid p53-dependent apoptosis. Using microarray analysis in primary tumor line and RT-PCR in several neuroblastoma lines, we demonstrate that the global transcriptional response is p53-dependent and that Sestrin1 and Sestrin2 are significantly up-regulated in response to Nutlin. With MTT and Tunnel assays we demonstrate a p53-dependent synergistic effect of combined Nutlin 3a and Temsirolimus treatment on cell growth and apoptosis. Flow cytometric analysis of the phospho-S6 ribosomal protein demonstrates a profound dephosphorylation of S6 in vitro when low dose Nutlin 3a is combined with Temsirolimus. Additional in vivo studies suggest that mTOR inhibition reduces tumor burden and proliferation of neuroblastoma xenografts in nude mice. We conclude that MDM2 inhibition and p53 driven Sestrin1 and Sestrin2 activation enhance the apoptotic response to mTOR inhibition. Thus the therapeutic strategy of combined MDM2 and mTOR inhibition may represent a clinically potent approach to de novo and relapsed neuroblastoma.
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 674.
Abstract 675: Effect of Progesterone on Antioxidant Activity in Cancer Cells
Authors: Nguyen Huyen , Syed Viqar 
Published: February 2011

Abstract
Progesterone (P4) has been implicated as a protective factor for epithelial ovarian and endometrial cancers, yet little is known about its mechanism of action. We previously reported that pregnancy-equivalent doses of P4 inhibited the growth of normal and malignant human ovarian surface epithelial (HOSE) and endometrial cells. Increased generation of reactive oxygen species (ROS) and an altered redox status have been observed in cancer cells. Here, we investigated if P4-induces cell death by modulating major antioxidant enzymes. The exposure of ovarian and endometrial cancer cell cultures to 10−6 M P4 induced time-dependent increases in early and late apoptotic cells and activation of caspase-3. A general caspase inhibitor Z-VAD effectively blocked the P4- induced cell death in a dose-dependent manner. Expression levels of glutathione peroxidase (GPX1), NAD(P)H:quinine oxidoreductase (NQO1) and copper and zinc SOD (CuZnSOD) were high in cancer cells. Treatment of cancer cells with progesterone at 10−8 M for a period of 72 h induced significant loss of GPX1, NQO1 and CuZnSOD protein expression. The inhibitory action of progesterone was blocked by the specific progesterone antagonist (miferpristone, 10−5 M), confirming P4 specificity. Further investigation on the regulation of antioxidant enzymes by P4 may provide new insights into P4's anticancer activities and facilitate the development of new strategies to use P4 as an anticancer 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 675.
Abstract 676: Induction of apoptosis via control of cell adhesion by peroxisome proliferator activated receptor-gamma agonist in human uterine leiomyoma cells
Authors: Cho Chi-Heum , Jung Sun-Wook , Shin So-Jin , Kwon Sang-Hoon , Cha Soon-Do 
Published: February 2011

Abstract
Objective : Peroxisome Proliferator-Activated Receptor (PPAR)-gamma ligands constitute important insulin sensitizers that have already been approved for the treatment of human metabolic disorders. It has been previously demonstrated that growth inhibition in human uterine leiomyoma cells mediated by caspase-dependent pathway and death receptor. The present study was designed to further understand the mechanism after uterine leiomyoma and normal myometrial cells were exposed to PPAR gamma agonist, Ciglitizone.
Methods : In order to confirm the unknown cellular and biochemical responses to ciglitizone treatment with three uterine leiomyoma and normal myometrial cells, DNA chip analysis were performed. Highly up-regulated genes were confirmed to ascertain effect of PPAR gamma agonist by RT-PCR and Western-blot analysis. To analyze mechanism of invasion and metastasis -associating gene regulation by PPAR-γ ligands, wound healing assay and soft agar assay were performed.
Results : DNA chip analysis revealed genes are related with cell adhesion and metastasis genes including plasminogen activating urokinase (PLAU), claudin 1, matrix metallopeptidase 1,2, and 9. Highly down-regulated genes had defense system against cell metastasis in common and was related with adhesion. Treatment with ciglitizone made decrease expression level of above cell adhesion related genes in dose dependent manner by RT-PCR and Western-blot analysis. Furthermore, treatment with ciglitizone in uterine leiomyoma cells decrease the invasion ability of leiomyoma cells and the formation of anchorage-independent colonies in soft agar.
Conclusions : These results suggest that PPAR-gamma could be considered as a therapeutic target for diverse disease states in which excessive angiogenesis is implicated, including cancer and uterine leiomyoma. This phenomenon has not been previously reported for PPAR-gamma agonist in uterine leiomyoma. Defining the role of PPARγ in uterine leiomyoma cells will be paramount for a rational design of combinatorial therapy schemes that takes advantage of the potent and well-tolerated PPARγ agonists.
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 676.
Abstract 684: Trifluoperazine modulates DNA damage-induced cell death in human lung cancer cells through inhibition of DNA repair, cell cycle delays, and augmentation of pro-apoptotic signaling
Authors: Zong Dali , Hååg Petra , Yakymovych Ihor , Lewensohn Rolf , Viktorsson Kristina 
Published: February 2011

Abstract
Trifluoperazine modulates DNA damage-induced cell death in human lung cancer cells through inhibition of DNA repair, cell cycle delays, and augmentation of pro-apoptotic signaling
Resistance of human tumors to DNA damaging chemotherapy poses severe limitations to the efficacy of current available treatment. Small molecule compounds of the phenothiazine class, such as trifluoperazine (TFP), have documented chemosensitizing activities. We exposed human non-small cell lung cancer (NSCLC) cell lines to the DNA damaging drug bleomycin in the presence or absence of TFP, and studied potential differences with regard to DNA repair and cell death signaling. A colony formation assay showed that TFP significantly enhanced the cytotoxic potential of bleomycin, at doses achievable clinically. Bleomycin treatment resulted in a reversible arrest at the G2-M phase of the cell cycle. Notably, TFP delayed the repair of bleomycin-induced DNA double strand breaks (DSBs), causing higher residual levels of γH2AX 24 h after treatment. Despite the presence of unrepaired DNA DSBs, cells co-treated with bleomycin and TFP overcame the G2-M checkpoint arrest, as evidenced by the reappearance of the mitosis marker histone H3 phospho-Ser10 and reduction in CFSE fluorescence. This process, which is reminiscent of checkpoint adaptation, was associated with increased micronucleation and secondary arrest in G2-M phase during subsequent rounds of the cell cycle. Furthermore, the onset of secondary checkpoint arrest in cells co-treated with bleomycin and TFP coincided with the activation of pro-apoptotic Bak and Bax, and was followed by activation of caspase-3, which occurred preferentially in cells in the G2-M phase. In conclusion, we demonstrate here that the chemosensitizing effect of TFP in NSCLC cells involves interference with DNA DSBs repair, resulting in secondary G-M checkpoint arrest after initial checkpoint adaptation, and concomitant increases in pro-apoptotic signaling.
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 684.
Abstract 687: Structure-based design, discovery, and pharmacological profiling of human AP endonuclease (APE1) inhibitors for cancer therapy
Authors: Mohammed Mohammed Z. , Vyjayanti Vaddadi N. , Laughton Charles , Dekker Lodewijk , Fischer Peter M. , Wilson David M. , Madhusudan Srinivasan 
Published: February 2011

Abstract
Potentially cytotoxic AP site is an obligatory intermediate in base excision repair that is repaired by APE1. In the previous study we used fluorescence-based high through-put screening of a chemical library, biochemical and cellular investigations to identify compounds that selectively inhibited the DNA repair domain of APE1. To identify drug-like leads, we recently adopted an industry-standard high through-put virtual screening strategy. Sybyl8.0 molecular modelling software suite was used to build inhibitor templates based on first generation inhibitors. Similarity searching strategies, using ROCS2.3, were then applied to extract pharmacophorically related subsets of compounds from a chemically diverse database of 2546389 compounds resulting in 2535 potential hits. These 2535 compounds were then 3D-encoded, and subjected to docking against the active site of the APE1 model, using algorithm-based programme GOLD2.7. Predicted ligand poses were ranked on the basis of two scoring functions (GOLD score and CHEMO score). The top hits were examined for favourable pharmaceutical properties and underwent detailed biochemical analyses. Several novel inhibitors of APE1 have been identified. Further modelling and biochemical studies in polymorphic variants of APE1, showed that many APE1 inhibitors preferentially bound to the D148E polymorph compared to the wild type. APE1 inhibitors potentiated the cytoxicity of chemotherapeutic agents in melanoma, glioma, breast cancer and pancreatic cancer cell line models implying therapeutic applications in these tumour types.
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 687.
Abstract 69: Functional metabolomic profiling of human melanocyte and melanoma cells during hypoxic adaptation
Authors: Richardson Adam D. , Scott David A. , Filipp Fabian V. , Knutzen Christine A. , Chiang Gary G. , Ronai Ze'ev A. , Osterman Andrei L. , Smith Jeffrey W. 
Published: February 2011

Abstract
Adaptation to hypoxia is an important part of the cellular progression from normal melanocyte to malignant melanoma. This adaptation can be comprised of short-term remodeling of the cellular metabolic network and/or the permanent, gene-driven development of a new metabolic program. In either case, low oxygen conditions require a unique metabolic program for continued survival and proliferation. However, beyond a general shift from respiration to glycolysis, the details of this permissive metabolic program in melanoma are generally unknown. In order to better understand the changes to both the metabolome and metabolic flux in this system, we applied functional metabolomic profiling to seven human melanoma cell lines and to two human melanocyte cell lines under both hypoxic and normoxic conditions. The melanoma panel consists of four cell lines driven by B-raf mutations (WM35, UACC903, WM793 and LU1205), two containing N-ras mutations (MEL501 and WM1346) and one p53 mutant (MeWo). These cells, along with the two melanocyte lines, were grown in media containing a 1:1 mixture of natural and [U-13C]-labeled glucose for 24 hours in either 1% oxygen or atmospheric conditions. We then employed GCMS, NMR and biochemical experiments to map flux through five metabolic hubs and quantify the abundance of 28 key metabolites for each cell line and condition. These maps of central carbon metabolism encompass glycolysis, the pentose phosphate pathway, fatty acid biosynthesis, the glutamate-glutamine-proline network, and glycine/serine de novo synthesis, along with a number of other important metabolites. Analyzing these data with unbiased hierarchical clustering and Ingenuity Pathway Analysis, we discovered a metabolite-derived signature for hypoxic adaptation in melanocytes. Furthermore, we found that certain hypoxic responses are unique to either the B-raf or N-ras of the cell line subset. Interestingly, the hypoxic response of the mutant p53 cell line is more like that of the B-raf mutant cell lines than the B-raf and N-ras sets are to each other. The information gained from this functional metabolomic profiling advances our ability to identify hypoxia-adapted melanomas and develop metabolism-based therapeutic interventions.
This work was supported by P01 CA128814-01 from the National Cancer Institute.
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 69.
Abstract 690: Estrogen receptor beta (ERβ) enhances the chemosensitivity of breast cancer cells by altering DNA damage response signaling
Authors: Thomas Christoforos , Lindberg Karolina , Strom Anders , Damdimopoulos Tassos , Gustafsson Jan-Ake 
Published: February 2011

Abstract
Estrogen Receptor beta (ERβ) is a mediator of estrogen signaling that regulates growth in mammary gland and is involved in breast cancer. In response to DNA damage most tumor cells due to disruptions in the p53 pathway and consequent loss of G1 cell cycle arrest are entirely dependent in S and G2/M checkpoints to maintain genomic integrity. Inhibition of these checkpoints following DNA damage induces selective killing of p53-defective tumor cells. We show that expression of ERβ caused abrogation of Cdc25C-mediated G2/M checkpoint following cisplatin and doxorubicin exposure selectively in p53-deficient cells, resulting in mitotic catastrophe and decreased cancer cell survival. The loss of G2/M checkpoint observed was due to ERβ-mediated inhibition of the DNA damage-induced expression of brca1. ERβ by modulating DNA damage response signaling seems to selectively enhance the chemosensitivity of tumor cells. This suggests that co-operation of compounds that specifically induce the ERβ signaling with DNA damaging chemotherapeutic drugs may represent an attractive new cancer therapeutic strategy.
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 690.
Abstract 691: In vitro and in vivo characterization of selective orally available Parp-1 inhibitors with demonstrated antitumor efficacy in BRCA negative cancer models
Authors: Papeo Gianluca , Rainoldi Sonia , Gianellini Laura , Ciavolella Antonella , Leone Antonella , Lupi Rosita , Sola Francesco , Caprera Francesco , Paolucci Mauro , Thieffine Sandrine , Perego Rita , Albanese Clara , Casale Elena , Forte Barbara , Guanci Marco , Orsini Paolo , Posteri Helena , Scolaro Alessandra , Riccardi-Sirtori Federico , Zuccotto Fabio , Donati Daniele , Moll Jurgen , Montagnoli Alessia 
Published: February 2011

Abstract
Poly (ADP-ribose) polymerase 1 and 2 (Parp-1 and Parp-2) are nuclear enzymes responsible for signaling the presence of DNA damages by catalyzing the addition of ADP-ribose units to DNA, histones and various DNA repair enzymes, thus facilitating DNA repair. Parp-1 has been gaining increasing interest as a therapeutic target for cancer in combination with DNA damaging agents but also as single agent in particular tumor settings, such as BRCA mutated tumors. While Parp-1 knock out mice are viable and display only defects in DNA repair, double Parp-1 and Parp-2 knock-out are embryonic lethal indicating that the absence of Parp-1 and Parp-2 is less tolerated in normal cells. We confirmed this concept in vitro by RNAi of Parp-1 and Parp-2, showing that the inhibition of Parp-1 alone is enough to kill tumor cells but spares normal cells. Hence a selective Parp-1 inhibitor might have a better safety profile, particularly in view of a long treatment. Here we report the discovery and the in vitro and in vivo characterization of a novel class of potent, orally available Parp-1 selective small molecule inhibitors with no activity on other Parp isoforms such as Parp-2, −3 and −5a (tankyrase), which differentiates it from current clinical Parp inhibitors. The most potent compounds were further evaluated in vitro and in vivo. These compounds are highly potent in inhibiting DNA damage-induced Parp-1 activity in cells and exhibit selective anti-proliferative and pro-apoptotic activity in tumor cell lines harbouring defects in DNA repair. In vivo, the compounds show an excellent pharmacokinetic profile with almost complete oral bioavailability and demonstrate efficacy as a single agent in xenograft tumor models with DNA repair deficiencies superior to reference Parp inhibitors. These compounds are very well tolerated with no overt toxicity even after prolonged exposure and their mechanism of action is confirmed both in tumors and peripheral blood cells of treated mice.
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 691.