bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1008: Concomitant HDAC and PI3K-AKT pathway inhibition as a new therapeutic strategy for prostate cancer.
Authors: Ku Sheng-Yu , Pili Roberto , Ellis Leigh 
Published: August 2014

Abstract
Background: Prostate cancer (PCa) is the most prevalent cancer in men in the United States. Prostate cancer patients that progress to a lethal phenotype are currently treated with chemotherapy, second generation androgen therapies and immunotherapy. Unfortunately, patient response is not often durable; therefore novel treatments are urgently needed. Histone deacetylases (HDACs) have shown to be up-regulated in PCa. Preclinical data indicates that HDAC inhibitors induce apoptosis in androgen receptor (AR)-positive cells. Unfortunately, HDACi display minimal clinical benefit. From this, we propose that combination of HDACi with novel targeted therapies will result in greater therapeutic efficacy. Methods: PC3, PC3AR and PtenCaP8 PCa cell lines treated with panobinostat (HDACi) and BEZ235 (PI3K-mTORC1 inhibitor) as single treatment or in combination for 48 hours. Cell death/apoptosis was assessed by loss of cell membrane integrity, phosphotidylserine exposure, cell cycle and caspase activation by flow cytometry. Expression levels of activated AKT were assessed by immunoblot. Results: Panobinostat induces cell death/apoptosis greater in PC3AR than parental PC3 cells by increasing subG1 population (47.8±9.3 vs. 11.1±2.8,), phosphotidylserine exposeure (41.4±3.0 vs. 21±7.2,) and caspase activation (57.3±0.9 vs. 12.0 ±4.1,) respectively. Moreover, PC3AR cells treated with panobinostat results in loss of AKT activation, but not in PC3 cells. Further, combination of panobinostat with BEZ235 increases greater cell apoptosis in PC3AR cells compared to panobinostat single agent (30.6±1.9 vs. 19.9±1.4) and in PtenCaP8 cells (42.0±6.5 vs. 29.4±2.2). Western blotting also shows that combination treatment leads to loss of AKT activation compared to panobinostat and BEZ235 as a single agent. Conclusions: Overall, our results suggest that inhibition of HDACs induces greater cell death associated with loss of AKT activation in AR-positive cells, but not in AR-null cells. Also, combination of HDAC inhibitor and PI3K-mTORC1 inhibitor has more effective cell cytotoxicity compared to single agent, suggesting that inhibition of HDACs and PI3K-mTORC1 will exhibit greater therapeutic efficacy. In future work, combination of panobinostat with BEZ235 will be investigated in preclinical animal models to propose this therapy combination for clinical trials in patients with lethal PCa.
Citation Format: Sheng-Yu Ku, Roberto Pili, Leigh Ellis. Concomitant HDAC and PI3K-AKT pathway inhibition as a new therapeutic strategy for prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1008. doi:10.1158/1538-7445.AM2013-1008
Abstract 1016: Combination low dose 5-azacytidine (AZA) and romidepsin (FK228) therapy re-sensitizes ovarian cancer cells to cisplatin.
Authors: Wilson Andrew , Sinaise Lanzi , Readus Jade M. , Park Michelle , Lalani Anum S. , Saskowski Jeanette , Khabele Dineo 
Published: August 2014

Abstract
Ovarian cancer is the deadliest gynecologic malignancy. Current options for treating platinum-resistant disease are limited by drug choices and toxicities. Epigenetic therapy is emerging as a strategy for reversing tumor resistance and a recent encouraging clinical trial in platinum-resistant ovarian cancer suggests a potential unique application in ovarian cancer. The epigenetic drugs histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) cause chromatin relaxation and multiple anti-tumor effects on cell growth, cell cycle, cell death and deregulation of DNA damage response and repair (DDR) pathways. Among HDACi we have tested in a panel of ovarian cancer cells, the depsipeptide FK228 exerts the most potent growth inhibitory effects in the majority of cells. Therefore, we aimed to determine whether the combination of FK228 and the DNMTi 5-azacytadine (AZA) can re-sensitize ovarian cancer cells to cisplatin more effectively than either agent alone. We found that FK228 synergized with low doses of the DNMTi 5-azacytadine (AZA) in SRB cell growth assays in vitro, and that low dose combinations of the drugs enhanced the growth inhibitory effects of cisplatin. Similar effects were observed when ovarian cancer cells were grown as xenografts in immunocompromised mice in vivo. Furthermore, a key DDR sensor, phosphorylated gamma-H2AX (pH2AX) activation was associated with the enhanced cytotoxic effects of the combination of the epigenetics and may be a marker of response. In conclusion, we have identified a novel combination of epigenetic drugs that can re-sensitize ovarian cancer cells to cisplatin treatment, at least in part through stimulation of pH2AX. Targeting DDR pathways in DDR-deficient ovarian cancer cells with low dose epigenetic drugs represents a promising strategy in ovarian cancer treatment.
Citation Format: Andrew Wilson, Lanzi Sinaise, Jade M. Readus, Michelle Park, Anum S. Lalani, Jeanette Saskowski, Dineo Khabele. Combination low dose 5-azacytidine (AZA) and romidepsin (FK228) therapy re-sensitizes ovarian cancer cells to cisplatin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1016. doi:10.1158/1538-7445.AM2013-1016
Abstract 1023: Regulation of cell proliferation by GPR55/cannabinoid receptors using (R,R’)-4’-methoxy-1-naphthylfenoterol in rat C6 glioma cell line.
Authors: Paul Rajib K. , Wnorowski Artur , Indig Fred E. , Bernier Michel , Wainer Irving W. 
Published: August 2014

Abstract
(R,R’)-4’-Methoxy-1-naphthylfenoterol (MNF) is a potent inhibitor of the proliferation of rat C6 glioma cells with an IC(50) of 0.45 nM and initial in vivo data indicate that the compound may be potentially useful in the treatment of malignant gliomas. MNF is an agonist of the β(2)-adrenergic receptor and an antagonist of the GPR55 receptor. Previous studies have demonstrated that MNF inhibits proliferation in 1321N1 astrocytoma cells via the β(2)-adrenergic receptor and in HepG2 hetapocallular carcinoma cells via GPR55. In this study, the mechanism of the observed MNF effect in C6 cells was investigated using [(3)H]-thymidine incorporation, cell motility assay, and internalization of the fluorescent GPR55 ligand, Tocrifluor 1117 (T1117). The anti-mitogenic response of MNF was not affected by the β(2)-AR antagonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol (ICI 118,551). Cell treatment with synthetic agonists of cannabinoid receptors 1 and 2 (WIN-55212,2 and CP55940) led to growth inhibition, whereas pretreatment with AM251 (0.1-5 μM) dose-dependently blocked the anti-mitogenic responses of MNF. Both AM251 and the atypical cannabinoid O-1602 increased cell motility, which was blocked by MNF. Finally, there was marked inhibition in the cellular accumulation of T1117 in MNF-treated C6 glioma cells. These results indicate that MNF inhibits proliferation of C6 cells via GPR55/cannabinoid receptors and not via the β(2)-adrenergic receptor. This work was supported entirely by the Intramural Research Program of the NIA, NIH.
Citation Format: Rajib K. Paul, Artur Wnorowski, Fred E. Indig, Michel Bernier, Irving W. Wainer. Regulation of cell proliferation by GPR55/cannabinoid receptors using (R,R’)-4’-methoxy-1-naphthylfenoterol in rat C6 glioma cell line. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1023. doi:10.1158/1538-7445.AM2013-1023
Abstract 1037: Agents that target the PI3K/mTOR pathway decrease oxygen consumption, reduce tumor hypoxia and improve radiation response in solid tumors.
Authors: Cerniglia George J. , Daurio Natalie , Gallagher-Colombo Shannon M. , Busch Theresa M. , Tuttle Stephen W. , Koch Cameron J. , Lin Alexander , Koumenis Constantinos , Maity Amit 
Published: August 2014

Abstract
Hypoxia/anoxia is a well-characterized component of the solid tumor microenvironment and has profound consequences for patient outcome. In particular, clinical data indicate that patients with certain types of tumors treated with radiotherapy have a significantly better outcome if the tumors are less hypoxic. Therefore, we are interested in finding agents that can improve tumor oxygenation. In this study, we investigated the effects of two drugs on tumor oxygenation, NVP-BEZ235 (Novartis), a dual PI3K/mTOR inhibitor, and nelfinavir, an HIV protease inhibitor that inhibits PI3K signaling. Treatment of mice bearing SQ20B head and neck squamous cell carcinoma xenografts with either drug led to a decrease in tumor hypoxia as measured by binding of the 2-nitroimidazole EF3. In vitro O2 consumption measurements of cells grown in tissue culture using a Clark electrode showed that both drugs led to decreased O2 consumption. This result was confirmed using a XF Extracellular Flux Analyzer (Seahorse Bioscience). Using this technique, we found that incubation with NVP-BEZ235 caused a 30- 50% decrease in the oxygen consumption rate (OCR). O2 consumption was stimulated by addition of the uncoupling agent CCCP in both controls and NVP-BEZ235-treated cells, which indicates that they were not killed by NVP-BEZ235 treatment. Similar results were obtained with nelfinavir. In order to identify whether components of the PI3K/mTOR pathway could contribute to the decrease in O2 consumption, we used siRNA directed against either mTOR or the p110alpha subunit of PI3K. Knockdown of either protein led to a decrease in O2 consumption. Studies are ongoing to determine whether the mitochondria are a direct target of NVP-BEZ235 or nelfinavir and if so, which mitochondrial respiratory complex might be affected. In summary, we show that NVP-BEZ235 and nelfinavir, both of which inhibit PI3K signaling, decrease O2 consumption and ameliorate tumor hypoxia. We have found both of these agents to increase radiation response in vivo in animal models, and nelfinavir is currently being used in combination with radiotherapy in clinical trials. These findings offer insight as to how these agents act as radiation response modifiers.
Citation Format: George J. Cerniglia, Natalie Daurio, Shannon M. Gallagher-Colombo, Theresa M. Busch, Stephen W. Tuttle, Cameron J. Koch, Alexander Lin, Constantinos Koumenis, Amit Maity. Agents that target the PI3K/mTOR pathway decrease oxygen consumption, reduce tumor hypoxia and improve radiation response in solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1037. doi:10.1158/1538-7445.AM2013-1037
Abstract 1040: The effect of Irinotecan in k-Ras wild and mutant type colon cancer cell lines.
Authors: Park Joo Sung , Jeon Jung Guk , Kang Myoung Hee , Jang You Jin , Lee Sun Il , Byun Jae Ho , Kim Jun Suk , Oh Sang Cheul 
Published: August 2014

Abstract
Irinotecan(IRI) prevents DNA from unwinding by inhibition of topoisomerase1. Its main use is in colon cancer, in particular, in combination with other chemotherapy agents. Recent studies, those with
Irinotecan treatment has a synergistic effect appears. However, there is no study on the effect of the Irinotecan mono-treatment. In addition their roles and the underlying mechanism in anti-tumorigenic function of solid tumor, especially kras wild and mutant type colon cancer, are not yet known. Bax protein is a key mediator of apoptosis and might be related to chemosensitivity. In this work, we evaluated the anti-tumorigenic action of these Irinotecan anti-cancer agent with especially k-ras wild and mutant type colon cancer cell lines, and investigated their apoptosis-inducing effects as the potential mechanism in this process.
The results show that the growth inhibitory effects of 5-fuorouracil (5-FU), Oxaliplatin(OX) produced a dose- and time dependent fashion in k-ras wild(HT29, Colo205) and mutant type(HCT116, DLD-1) colon cancer cell lines. Otherwise, Irinotecan(IRI) produced a cell growth of k-ras wild type cell lines were resistant versus that shown in the sensitive k-ras mutant type cell lines. Cell cycle analysis by FACS indicated that IRI-treated cell lines showed an increase in the proportion of cells in sub-G1 phase, compared to untreated cells. Exposure of colon cancer cells to IRI also resulted in the increase in the percentage of annexin V- positive and PI-negative cells. The results by multiple in vitro experimental model, showed that IRI induce these k-ras mutant type colon cancer cells to undergo apoptosis with increased the Bax protein and a release of cytochrome C from mitochondria, the activation of caspase9, the cleavage of PARP. But Bax protein was inactivation in k-ras wild type colon cancer cell lines. Importantly, inhibition of ERK kinase activity demonstrated that IRI-induced apoptotic pathway was regulated by the ERK signaling cascade. These data indicate that Anti-cancer agent, Irinotecan, promotes Bax mediate apoptosis of colon cancer cell lines by sequential activation of the ERK signaling pathway followed by the up-regulation of intrinsic pathway of caspase 9.
Citation Format: Joo Sung Park, Jung Guk Jeon, Myoung Hee Kang, You Jin Jang, Sun Il Lee, Jae Ho Byun, Jun Suk Kim, Sang Cheul Oh. The effect of Irinotecan in k-Ras wild and mutant type colon cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1040. doi:10.1158/1538-7445.AM2013-1040
Abstract 1047: AKT inhibitor MK-2206 induces necrotic cell death of uterine leiomyoma cells in vitro and reduces tumor volume in vivo.
Authors: Sefton Elizabeth , Qiang Wenan , Serna Vanida , Kurita Takeshi , Kim Julie 
Published: August 2014

Abstract
Uterine leiomyomas (UL), benign tumors of the myometrium, are the number one indication for hysterectomies in the U.S. due to a lack of effective therapy. ULs show increased phosphorylation of the pro-survival protein AKT compared to normal myometrium indicating that AKT signaling is increased in UL. However, substantial data directly linking AKT to UL cell survival is lacking. We hypothesized that AKT promotes UL cell survival and that it is a viable drug target for inhibiting UL growth. We utilized the AKT inhibitor MK-2206 (MK), currently in phase II trials, on cultured primary human UL cells. MK-2206 effectively reduced phosphorylation of AKT and PRAS40, an AKT substrate. MK-2206 did not affect cell proliferation but caused cell death. We observed a lack of apoptosis in dead UL cells by Annexin V staining. Additionally, MK-2206 was able to induce UL cell death in the presence of pan-caspase inhibitor, Z-VAD-FMK, indicating that MK-2206 mediated cell death is caspase independent and non-apoptotic. Given that caspases did not modulate cell death, we explored necrosis. MK-2206 induced HMGB1 cytoplasmic localization and mitochondrial disruption indicating possible leiomyoma necrosis. We next explored programmed necrosis, a form of non-apoptotic cell death mediated by RIP kinases (RIPK). However, MK-2206 was able to induce cell death in the presence of RIPK inhibitors, necrostatin-1 and necrosulfonamide, indicating that programmed necrosis is not the mechanism of MK-2206 mediated UL cell death. We are actively exploring alternate necrotic cell death pathways as the mechanisms of MK-2206 induced UL cell death. Lastly, in-vivo MK-2206 treatments reduced tumor volume of human UL cells implanted under the kidney capsule of NSG mice. Xenograft sections from mice treated with MK-2206-2206 contained dying cells in the absence of cleaved caspase 3 supporting the in-vitro results. This is the first report of non-apoptotic cell death in UL and the first time that AKT has been targeted in-vivo for UL therapy. Our data provides molecular evidence for the involvement of AKT in UL cell survival and suggest that AKT inhibition by MK-2206 may be a viable option for the future treatment of UL. This work was funded by NIH P01HD057877.
Citation Format: Elizabeth Sefton, Wenan Qiang, Vanida Serna, Takeshi Kurita, Julie Kim. AKT inhibitor MK-2206 induces necrotic cell death of uterine leiomyoma cells in vitro and reduces tumor volume in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1047. doi:10.1158/1538-7445.AM2013-1047
Abstract 1065: IL-6 and IGF-1 receptor signal in stemness expression of HBV-related hepatocellular carcinoma .
Authors: Chang Te-Sheng , Ling Thai-Yen , Wu Yu-Chih , Su Wei-Chi , Wu Jaw-Ching , Chi Ching-Chi , Chang Pey-Jium , Chang Jui-Hung , Yang Ya-Ting , Lee Kam-Fai , Liu Jun-Jen , Tung Shui-Yi , Huang Yen-Hua , Kuo Liang-Mou , Ho Hong-Nerng , Huang Yen-Hua 
Published: August 2014

Abstract
Expression of cancer stemness in hepatocellular carcinoma (HCC) is linked to drug resistance and tumor relapse which challenge the current therapy. However, mechanisms underlying the regulation of cancer stemness in HCC remain unclear. Effects of interleukin (IL)-6 and insulin-like growth factor I (IGF-I) on stemness expression in HCC were examined using OCT4/NANOG promoter luciferase reporter assays, RNA interference, secondary sphere formation, side population assay, and a xenograft animal model. Western blot analysis and immunohistochemical staining were used to detect the expression of OCT4/NANOG and phospho-IGF-I receptor (p-IGF-IR) in tissues. Levels of OCT4/NANOG and IGF-IR expressions were analyzed by real-time quantitative reverse transcriptase polymerase chain reaction (qPCR) and their association with tumor recurrence of hepatectomized HCC patients (n = 119) was determined using a Kaplan-Meier survival analysis. A high positive correlation between OCT4/NANOG and IGF-IR/p-IGF-IR expressions in human HCC tissues was observed. The concurrent expression of OCT4/NANOG/IGF-IR was mostly confined to HBV-related HCC (HBV-HCC) and was significantly associated with early tumor recurrence. Investigation of the underlying mechanism showed that IL-6 stimulated the autocrinal IGF-I/IGF-IR expression in a STAT dependent manner, and IGF-I/IGF-IR activation promoted the expression of stemness-related properties of Hep3B cells in both cell lines and xenograft murine models. IL-6 stimulated the expression of stemness-related properties in Hep3B cells, and inhibition of IGF-IR activation significantly suppressed the IL-6’s effects both in vitro and in vivo. Conclusions: Expression of OCT4/NANOG is regulated by IL-6-mediated IGF/IGF-IR signaling in HBV-HCC and is associated with the early recurrence of HCC.
Citation Format: Te-Sheng Chang, Thai-Yen Ling, Yu-Chih Wu, Wei-Chi Su, Jaw-Ching Wu, Ching-Chi Chi, Pey-Jium Chang, Jui-Hung Chang, Ya-Ting Yang, Kam-Fai Lee, Jun-Jen Liu, Shui-Yi Tung, Yen-Hua Huang, Liang-Mou Kuo, Hong-Nerng Ho, Yen-Hua Huang. IL-6 and IGF-1 receptor signal in stemness expression of HBV-related hepatocellular carcinoma . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1065. doi:10.1158/1538-7445.AM2013-1065
Abstract 108: Coffee prevents early events in tamoxifen-treated breast cancer patients and modulates hormone receptor status.
Authors: Simonsson Maria , Söderlind Viktoria , Henningson Maria , Hietala Maria , Rose Carsten , Ingvar Christian , Jernström Helena C. 
Published: August 2014

Abstract
Whether coffee modulates response to endocrine therapy in breast cancer patients is currently unknown. The CYP1A2 and CYP2C8 enzymes contribute to tamoxifen and caffeine metabolism. The aim was to investigate the impact of coffee consumption on tumor characteristics and disease-free survival in relation to breast cancer treatment and CYP1A2 and CYP2C8 genotypes. Questionnaires regarding lifestyle were completed preoperatively by 592 patients in Southern Sweden. CYP1A2*1F and CYP2C8*3 were genotyped. Clinical data and tumor characteristics were obtained from patients’ charts, population registries, and pathology reports. Coffee consumption was categorized as low (0-1 cups/day), moderate (2-4 cups/day), or high (5+cups/day). The proportion of estrogen receptor negative (ER-) tumors increased with increasing coffee consumption (Ptrend=0.042). Low consumption was associated with higher frequency of discordant receptor status (ER+PgR-) OR 2.61 (1.59-4.29) compared to higher consumption. Median follow-up time was 4.92 years. Tamoxifen-treated patients with low consumption had significantly increased risk for early events compared to patients who consumed two or more cups/day, adjusted HR 2.50 (1.20-5.26). Low coffee consumption was also associated with higher risk for distant metastases in tamoxifen-treated patients with ER+ tumors, adjusted HR 2.43 (1.00-5.88). Low consumption combined with at least one CYP1A2*1F C-allele or CYP2C8*3 was associated with a high risk for early events in tamoxifen-treated patients, adjusted HRs 3.49 (1.54-7.90) and 6.14 (2.46-15.34), respectively. In conclusion, a moderate to high coffee consumption of caffeinated coffee was associated with significantly lower risk for early breast cancer events in tamoxifen-treated patients. This may be due to modification of the hormone receptor status or altered CYP enzyme activity. If confirmed, new recommendations regarding coffee consumption during tamoxifen-treatment may be warranted.
Citation Format: Maria Simonsson, Viktoria Söderlind, Maria Henningson, Maria Hietala, Carsten Rose, Christian Ingvar, Helena C. Jernström. Coffee prevents early events in tamoxifen-treated breast cancer patients and modulates hormone receptor status. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 108. doi:10.1158/1538-7445.AM2013-108