bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4073: Effects of metabolic and mitochondrial-targeted compounds on ovarian cancer cells
Authors: Chan Daniel , Miskimins Keith 
Published: July 2012

Abstract
Ovarian cancer has the highest mortality rate of all the gynecological cancers in the United States, and is highly resistant to current forms of treatment. Metformin, a type II diabetes drug, and phenethyl isothiocyanate (PEITC), a component of cruciferous vegetables, were examined for their effects on ovarian cancer cell growth and survival. Although the exact mechanism of both drugs is not known, both have been found to inhibit complexes within the electron transport chain. Metformin is also known to activate the AMPK-LKB1 pathway, possibly downstream of complex I inhibition. We examined the effects of these compounds in vitro to evaluate the potential of electron transport chain inhibitors as novel therapies for ovarian cancer. To assess cell growth and death, hemacytometry with trypan blue exclusion was used in the ovarian cancer cell lines: SKOV3, OVCAR3, CAOV3, and PA-1. Induction of apoptosis was measured by Western blotting for intact and cleaved poly-ADP ribose polymerase (PARP). Western blotting was also used to determine endogenous levels of enzymes responsible for clearing reactive oxygen species (ROS). Levels of mitochondrial ROS production were measured by flow cytometry and confocal microscopy using the fluorescent probe MitoSOX. Metformin treatment was found to induce cell death in PA-1, arrest growth in OVCAR3 and CAOV3, and slow growth in SKOV3. PEITC treatment induced cell death through apoptosis in all tested cell lines at low micromolar concentrations. Metformin's inhibitory effects were partially reversed when growth medium was supplemented with succinate to bypass complex I. Low expression levels of anti-oxidant enzymes were also found to correspond with higher sensitivity to metformin and PEITC. Additionally, levels of mitochondrial ROS increased with treatment. Metformin and PEITC both show potential as ovarian cancer therapies. Complex I inhibition likely contributes to metformin's anti-cancer effects, as succinate supplementation was able to reverse growth inhibition. Additional work is necessary to determine if the increase in mitochondrial ROS is caused by electron transport chain complex inhibition and whether it is essential to the anti-cancer effects observed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4073. doi:10.1158/1538-7445.AM2011-4073
Abstract 4079: Pilot study of copper chaperon ATOX1 in oncogenesis of colon cancer
Authors: Cai Huawei , Peng Fangyu 
Published: July 2012

Abstract
INTRODUCTION: Copper is an essential element for normal function of many cellular enzymes. Copper homeostasis is maintained by a delicate network of copper transporters, which include human copper transporter 1(hCtr1), ATP7A, ATP7B, and copper chaperons including ATOX1, CCS, and Cox17. It has been known that copper is required for cell proliferation and tumor angiogenesis. Human tumor xenografts in mice with increased uptake of radioactive copper could be localized with positron emission tomography. Copper hypermetabolism might play a role in oncogenesis of human cancers. Recently, it was reported that ATOX1 is a transcription factor involved in copper-stimulated cell proliferation. In this pilot study, we analyzed expression of ATOX in human colon cancer tissues compared with its expression in normal colon tissues. In addition, preliminary experiments were conducted to study potential role of ATOX1 in oncogenesis of colon cancer.
METHODS: Immunohistochemistry analysis was conducted to compare expression of ATOX1 in colon cancer tissues and normal colon tissues. A lentiviral vector encoding short-hairpin RNA (shRNA) specific for ATOX1 (Lenti-ATOX-shRNA) was constructed and used to transduce HCT-116 human colon cancer cells. Suppression of ATOX1 in HCT-116 cells transduced with Lenti-ATOX-shRNA (ATOX1-shRNA-HCT116) was confirmed by Western blot. MTT assay was conducted to assess effect of ATOX1 silencing on proliferation and sensitivity of ATOX1-shRNA-HCT-116 cells to copper, cisplatin and copper 8-hydroxyquinoline-2-carboxaldehyde thiosemicarbazide complex (CuHQTS), a new anticancer copper complex. The HCT-116 cells transduced by a lentivirus encoding a scramble shRNA (Scramble-shRNA-HCT116) were used as control.
RESULTS: Over-expression of ATOX1 is identified in all of human colon cancer tissue samples (N=10), compared with expression of ATOX1 in normal colon tissue samples (N=10). Suppression of ATOX1 with ATOX1-shRNA in HCT116 cells was confirmed by Western blot assay. However, the results of MTT assay revealed no significant effect of ATOX1 silencing on proliferation and sensitivity of ATOX1-shRNA HCT116 cells to copper chloride, cisplatin, and CuHQTS, compared with proliferation and sensitivity of Scramble-shRNA-HCT116 to these drugs.
CONCLUSIONS: ATOX1 holds potential as a new biomarker of colon cancer. Additional studies are necessary to determine the role of ATOX1 and other copper transporters in oncogenesis of colon cancer.
Key words: colon cancer, copper metabolism, copper chaperon, ATOX1
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4079. doi:10.1158/1538-7445.AM2011-4079
Abstract 4080: Metformin and rapamycin inhibit proliferation and alter glucose metabolism in endometrial and ovarian cancer cell lines
Authors: Zhou Chunxiao , Dickens Hallum , Robinson Jada , Gehrig Paola A. , Bae-Jump Victoria L. 
Published: July 2012

Abstract
Objectives: A well-established phenomenon of tumor cells is a shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis, termed the “Warburg” effect. Glycolysis is a much less efficient mechanism of producing ATP, suggesting that cancer cells may have an inherently high need for rapidly metabolized glucose. Glucose metabolism and growth control are tightly linked in proliferating cells and involve signaling pathways such as the PI3K/Akt/mTOR pathway. Metformin and rapamycin both exert their anti-tumorigenic effects through inhibition of the PI3K/Akt/mTOR pathway. Thus, our goal was to investigate the mechanism of action of metformin and rapamycin on proliferation and glucose metabolism in vitro using both endometrial and ovarian cancer cell lines
Methods: The endometrial cancer cell lines, ECC-1 and Ishikawa, and the ovarian cancer cell lines, CAOV-3 and SKOV-3, were used in these studies. Cell proliferation was assessed after exposure to metformin and rapamycin, and viable cell densities were determined by measuring conversion of the metabolic dye, MTT. Western immunoblotting was performed to determine the expression of the glucose transporters, GLUT1 and GLUT4, and phosphorylated glycogen synthase kinase-3 alpha and beta (GSK-α and GSK-β). Expression of phosphorylated S6, a downstream target of the mTOR pathway, was also evaluated by Western immunoblotting.
Results: Metformin and rapamycin both potently inhibited growth in a dose-dependent manner in the endometrial and ovarian cancer cell lines (IC50 of 1-10 mM for metformin and IC50 of 5-18 nM for rapamycin). Metformin and rapamycin also stimulated expression of the glucose transporters, GLUT1 and GLUT4, and increased phosphorylation of GSK-α and GSK-β among the endometrial and ovarian cancer cell lines. In parallel, S6 phosphorylation was decreased after treatment with metformin and rapamycin.
Conclusions: Metformin and rapamycin are both potent inhibitors of cell proliferation and potentially alter glucose metabolism in endometrial and ovarian cancer cells. These findings suggest that metformin and rapamycin may have two interrelated anti-tumorigenic benefits – inhibition of the PI3K/Akt/mTOR pathway and disruption of glucose uptake and utilization by tumor cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4080. doi:10.1158/1538-7445.AM2011-4080
Abstract 4083: Reduced carbohydrates in resistant aggressive tumors, The RECHARGE Trial: A safety and feasibility nutritional study in ten patients
Authors: Fine Eugene J. , Segal-Isaacson C.J. , Feinman Richard D. , Tomuta Nora , Romano Maria , Bontempo Maria , Sparano Joseph A. 
Published: July 2012

Abstract
Background: Many aggressive cancers share a glycolytic phenotype associated with increased 18F-2-fluoro, 2-deoxyglucose (FDG) positron emission tomography (PET) uptake. Carbohydrate restricted (CR) diets, by inhibiting insulin secretion, enlist plausible but unproven mechanisms to limit cancer growth.
Objectives: We evaluated safety/feasibility of a CR diet in patients with advanced FDG-avid cancers using a change in exit vs. baseline FDG uptake as a surrogate measure of tumor response using prospective EORTC criteria.
Methods: Patients with advanced, incurable cancers and FDG-positive scans were recruited. Eligibility required ECOG performance status of 0-2, normal hepatic, renal, and gastrointestinal function, no diabetes or recent weight loss (&gt; 5% within 3 months), and a body mass index of &gt;20 kg/M2. A supervised CR diet (5% of total kCal) was monitored weekly for macronutrient intake, body weight, serum electrolytes, betahydroxybutyrate concentrations [BHB]. An exit four-week PET scan was obtained.
Results: Ten subjects with advanced cancer completed &gt; 26 days of the diet without associated adverse effects. Mean daily caloric intake decreased (35 + 6) % vs. Harris-Benedict formula's predicted energy requirements, and median/mean weight loss were 4.1% (range 0.0-6.1%.) and (4.1 + 0.7) %, respectively. One patient had advanced but indolent disease (14 years without chemotherapy). Among nine patients with pre-trial progressive disease (Table 1), 4 continued to progress on PET, and 5 did not. Non-progression (n=5) vs. continued progession (n=4) correlated (p=0.02) with three fold higher dietary ketosis but not with reduced energy intake (p=0.65).
Conclusions: Preliminary data suggest safety/feasibility of carbohydrate restriction in patients with advanced cancer, and that ketosis correlated with disease stabilization, supporting further evaluation of CR as a complementary approach in conjunction with standard therapies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4083. doi:10.1158/1538-7445.AM2011-4083
Abstract 4091: The oral iron chelator, deferasirox, induces apoptosis in myeloid leukemia cells through caspase-dependent activation
Authors: Kim Jung-Lim , Kang Han-Na , Kang Myoung Hee , Kim Jun Suk , Oh Sang-Cheul , Choi Chul-Won , Yoo Young-A 
Published: July 2012

Abstract
Iron plays a central role in the regulation of many cellular function. Recently several studies suggest that iron chelator, deferoxamine acts as an anti-cancer drug on various cancers. deferasirox(DFS) is a new oral iron chelator. Some of the papers has recently been reported that effect antiproliferative on leukemia cell by DFS but the effects of DFS on myeloid leukemia cells have not been clearly elucidated.
We measured the sensitivity of human leukemic cell lines (HL-60 and KG-1) to DFS using MTT assay. The proliferation of cells treated with DFS at various concentrations for various time was decreased in a dose-and time-dependent manner. Cell cycle analysis for subG1 fraction also detected the increased cell death in the cells treated with DFS. To determine whether DFS-mediated cell death was due to apoptosis in HL-60 and KG-1 cell lines, percentages of apoptotic cell were measured by staining with FITC-conjugated annexin V and PI. The percentage of apoptotic cells was significantly increased by DFS stimulation. Results by Western blotting and colorimetric assay indicated that DFS promotes apoptosis of human leukemic cells by both activating caspase-3 and -9 and inducing PARP cleavage. Furthermore, pretreated of leukemic cells with caspase inhibitor (z-V) significantly inhibited the DFS-induced apoptosis. In the in vivo model, treatment of leukemic tumor-bearing athymic nude mouse with DFS was showed significant decrease in tumor growth compared with treatment with DMSO.
These results demonstrate that a new oral iron-chelating agent, DFS, promotes apoptosis of myeloid leukemia cells via activating caspase 3/9, suggesting that DFS might be beneficial for iron-overloaded patients with myeloid leukemia, not only from iron chelation but also from reduction of leukemia cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4091. doi:10.1158/1538-7445.AM2011-4091
Abstract 4099: F-box protein 10, an NF-κB-dependent anti-apoptotic protein, regulates TRAIL-induced apoptosis through modulating c-Fos/c-FLIP pathway
Authors: Ge Rongbin , Wang Zongwei , Zeng Qing , Xu Xiaoyin , Olumi Aria 
Published: July 2012

Abstract
Background: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) holds great promise as a potential anti-cancer agent, but some tumors develop resistance to TRAIL. AP-1 family member, c-Fos, is an important modulator of apoptosis. Although F-box protein 10 (FBXL10) has been implicated to regulate an AP-1 family protein, significance and mechanism of FBXL10 in apoptosis has not been investigated.
Methods: In this study, different types of TRAIL-sensitive cells (A498, PC3, MBA-MD-231) and TRAIL-resistant cells (LNCaP, PC3TR) were used, and a quantitative analysis of apoptosis was performed by using MTS and caspase-3, PARP activity assay and flow cytometry assay of annexin V- and propidium iodide-stained cells. RNAi, Chromatin immunoprecipitation (ChIP), EMSA, hydrodynamic-based transfection, oligonucleotide decoy technologies were performed to analyze the molecular interaction between FBXL10, c-Fos and NF-κB. The anti-apoptotic role of FBXL10 in vivo was analyzed by Lexatumumab (an agonistic human monoclonal antibody against TRAIL-R2) intravenous injection into mice carrying xenograft prostate cancers. All statistical tests were two-sided.
Results: We found that FBXL10 was suppressed and c-Fos was upregulated in TRAIL sensitive cancer cells and xenografts after treatment with TRAIL. However, in TRAIL resistant cancer cells and xenografts, FBXL10 and c-Fos were not affected. Expression of FBXL11, a FBXL10 homologous protein and c-Jun, was not affected by TRAIL. Silencing of FBXL10 sensitized resistant cells to TRAIL. Conversely, over-expression of FBXL10 repressed TRAIL-induced apoptosis. To behave as an anti-apoptotic molecule, we found that FBXL10 directly binds and represses c-Fos promoter in vitro and in vivo. In addition, FBXL10 regulates c-FLIP, another anti−apoptotic molecule, by a c-Fos dependent pathway. We also found that expression of FBXL10 is NF-κB – dependent, and TRAIL or proteasome inhibitors down-regulate FBXL10 via inhibiting NF-κB signaling. Using ChIP, EMSA assays and oligonucleotide decoy technologies, we found that NF-κB -p65 directly binds the FBXL10 promoter in vivo and in vitro, and promotes expression of FBXL10.
Conclusions: Differentiating molecular mechanisms between TRAIL sensitive and TRAIL resistant cancer cells will improve the efficacy of apoptotic therapies for cancer patients. In this study, we demonstrate a novel functional role for FBXL10 as an anti-apoptotic molecule, and describe a new apoptotic mediated pathway that involves NF-κB/FBXL10/c-Fos/c-FLIP. Therefore, silencing FBXL10 can help overcome resistant cancer cells for pro-apoptotic therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4099. doi:10.1158/1538-7445.AM2011-4099
Abstract 4102: Differing molecular mechanisms involved in the sensitization of human renal cancer cells to TRAIL-induced apoptosis
Authors: Brooks Alan D. , Thompson Candace R. , Pompei Richard J. , Booth Nancy , Gustafson Kirk R. , Henrich Curtis J. , McMahon James B. , Sayers Thomas J. 
Published: July 2012

Abstract
We have previously shown that the proteasome inhibitor bortezomib (Velcade/PS-341) specifically sensitized certain human renal carcinoma (RCC) lines to apoptosis induced by the TNF family-member TRAIL. A high-throughput screen conducted by the Molecular Targets Laboratory identified several promising new TRAIL sensitizers. One of these novel TRAIL sensitizers was the natural product withanolide E. Withanolide E, in contrast to bortezomib, had no activity as a proteasome inhibitor. Also withanolide E could sensitize some human RCC to TRAIL that were resistant to the effects of bortezomib. Furthermore sensitizing concentrations of bortezomib were also cytostatic to the RCC, whereas those of withanolide E were not. Bortezomib treatment of RCC resulted in the appearance of various proteins associated with a stress response, yet these proteins were not elevated by withanolide E treatment. By contrast the antioxidant n-acetyl cysteine completely blocked the TRAIL-sensitizing effects of withanolide E but not those of bortezomib. This suggests that changes in cellular redox are important for the sensitizing effects of withanolide E but not those of bortezomib. In order to study the molecular basis for increased TRAIL-mediated apoptosis, we investigated proximal apoptosis signaling events at the death-inducing signaling complex (DISC). Both bortezomib and withanolide E treatments resulted in an enhanced activation of the apoptosis signaling enzyme caspase-8 following exposure of the RCC to TRAIL. However, immunoprecipitation of the DISC revealed that bortezomib treatment resulted in a 4-5 fold increase in the amount of DISC formed. By contrast withanolide E treatment did not significantly alter the amount of the DISC, but reduced levels of the antiapoptotic DISC component c-FLIP. Therefore, both compounds amplified the apoptotic signal from the DISC via distinct molecular mechanisms of action.
Funded in part by HHSN261200800001E
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4102. doi:10.1158/1538-7445.AM2011-4102
Abstract 4104: TRAIL-induced p38 activation is regulated by MEKK4 with positive feedback manner
Authors: Sun Bo K. , Kim Joo-Hang , Oh Seeun , Kim So Y. , Choi Hye J. , Lee Yong J. , Song Jae J. 
Published: July 2012

Abstract
Previously, we demonstrated that TRAIL-induced p38 activation was responsible for the increases of Akt catalytic and invasive activity. Interestingly, TRAIL induced dramatically Akt catalytic activation in TRAIL-sensitive cells, whereas TRAIL did not induce Akt catalytic activation in TRAIL-resistant cells, suggesting Akt catalytic activation during TRAIL-induced apoptosis is likely to be a compensatory mechanism of cells. Here, we further provide that MEKK4 is the upstream molecule of TRAIL-induced p38 activation, and its catalytic activity is repressed by caspase-8 inhibitor. This result suggests that the caspase-8 activation induced by TRAIL is indispensible for MEKK4 activation. The CIN85, an adaptor molecule with three SH3 domains also interacted with MEKK4 and dissociated from MEKK4 in the presence of p38 inhibitor, providing the possibility that p38 induced the recruitment of CIN85 to MEKK4 for its activation by positive feedback manner. For the examination of p38 with CIN85, in vitro kinase assay, site-directed mutagenesis, and siRNA technique were used whether CIN85 was phosphorylated by p38, and the exact site of phosphorylation, and for the study of biological significance of CIN85 during TRAIL-induced p38 activation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4104. doi:10.1158/1538-7445.AM2011-4104
Abstract 4176: The biology of circulating nucleic acid in non-small cell lung cancer and prognostic implication
Authors: Vinayanuwattikun Chanida , Sriurangpong Virote , Mutirangura Apiwat 
Published: July 2012

Abstract
Background: Increased amount of circulating nucleic acid in plasma or serum (CNAPS) of cancer patient had been confirmed in many studies. The source of CNAPS was still enigmatic however the correlation with prognostic outcome was confirmed in various types of cancer. These might be the effect of tumor-derived CNAPS, correlated with tumor burden; however the interaction of cancer and immune cell was not negligent.
Material and Method: Fifty-eight plasma of advanced non-small cell lung cancer (NSCLC) and 52 sex/age match healthy volunteer were studied. Total amount of CNAPS was measured. We further explored substantial biology proportion of CNAPS according to cell source by using epithelial-specific marker, methylated SHP-1 promoter 2 (mSHP1P2), and hematopoietic-specific marker, unmethylated SHP-1 promoter 2 (uSHP1P2). Clinicopathological parameters were included with these markers evaluation.
Result: Significantly increased amount of CNAPS in plasma of NSCLC compared with healthy volunteer. Median levels were 7.6 ngml-1 (range 1.3-49.8) and 4.6 ngml-1 (range 0.03-26.9) respectively (p = 0.002). The mSHP1P2 represented the increasing amount of tumor-derived CNAPS in NSCLC (p &lt; 0.001). Contrast to uSHP1P2 which was the predominant portion of CNAPS in healthy volunteer. The mSHP1P2 level was correlated with prognostic strategy in NSCLC. Moreover proportion of uSHP1P2 level was also increased among NSCLC and it was related with survival outcome. Comparison CNAPS, mSHP1P2 and uSHP1P2 with baseline demographic parameters by multivariate analysis, total amount of CNAPS was the only independent parameter for prognostic assessment. The level of &gt; 4.5 ngml-1 indicated shorter median PFS (2.6 months) and OS (4.7 months) while the level of &lt; 4.5 ngml-1 indicated longer median PFS (5.6 months) and OS (&gt;15 months) (p &lt; 0.001).
Conclusion: Total amount of CNAPS in NSCLC was the valuable prognostic implication confirmed by our study, the impact of both tumor and immune cell-derived portion.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4176. doi:10.1158/1538-7445.AM2011-4176