bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 542: TGF-β inhibitors enhance chemotherapeutic efficacy via abrogation of autocrine and paracrine signaling in a triple negative breast cancer model
Authors: Biswas Tanuka , Sun LuZhe 
Published: June 2012

Abstract
Triple negative breast cancer (TNBC) accounts for approximately 15-20% of total invasive breast cancers. This subtype of cancer is often correlated with poor prognosis, visceral metastases and relapse. Molecular characterization reveals that these tumors are negative for hormone receptors and they often develop chemo resistance. Tumor microenvironment, among other factors, has emerged as a definite player in the progression of breast cancer and may also confer chemo resistance. In the current study, we demonstrate that MDA-MB-231 cells show greater resistance to paclitaxel in heterotypic culture with RMF/EG-hTERT (reduction mammary fibroblast with enhanced GFP) as compared to homotypic culture. Further, we show that RMF/EG-hTERT cells can enhance the motility of MDA-MB-231 cells in trans well migration assays, which could be attenuated by the TGF-β inhibitor sRIII (soluble receptor type III). TGF-β signaling was shown to activate pro-survival pathways like PI3K/Akt and MAPK/ERK pathways in mammary fibroblasts suggesting that they may mediate the paracrine tumor-promoting activity of TGF-β.
Autocrine TGF-β signaling has been shown to promote EMT and cancer stem cell-like features in TNBC cells and appears to be a potential therapeutic target. We show that paclitaxel in combination with sRIII was more effective in inhibiting the growth of MDA-MB-231 cells than either agent alone. The combination of a TGF-β inhibitor with paclitaxel was also more effective in inhibiting tumor sphere formation than either agent alone.
Our future research will be focused on the mechanisms of autocrine and paracrine TGF-β signaling in mediating chemo resistance and the tumor-promoting activity of mammary stromal cells. Our research will reveal the potential use of TGF-β inhibitors as novel therapeutics in combination with chemotherapy.
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 542. doi:10.1158/1538-7445.AM2011-542
Abstract 5427: Andrographolide is a novel inhibitor of interleukin-6 and suppresses prostate tumor growth
Authors: Chun Jae Yeon , Tummala Ramakumar , Nadiminty Nagalakshmi , Lou Wei , Liu Chengfei , Yang Joy , Evans Christopher P. , Gao Allen C. 
Published: June 2012

Abstract
INTRODUCTION AND OBJECTIVES: Elevated interleukin-6 (IL-6), a major mediator of the inflammatory response, has been implicated in androgen receptor (AR) activation, cellular growth and differentiation, plays important roles in the development and progression of prostate cancer, and is a potential target in cancer therapy.
METHODS: In an attempt to identify potential inhibitors of IL-6, DU145 human prostate cancer cells that express IL-6 autocrine loop were treated with compounds from the Natural compound library (TimTec LLC, Newark, DE) for 24 hours. The Natural compound Library consisted of 440 natural compounds with minimal purity of 95%. The media were collected and used for measurement of IL-6 protein by ELISA. Compounds that decreased the levels of IL-6 protein by 50% were selected for further characterization.
RESULTS: We found that andrographolide, a diterpenoid lactone isolated from a traditional Chinese and Indian medicinal plant Andrographis paniculata, could inhibit IL-6 expression and suppress IL-6-mediated signals. Andrographolide inhibits IL-6 expression at both mRNA and protein levels in a dose-dependent manner. Andrographolide suppresses both IL-6 autocrine- and paracrine-loop induced cell signaling including Stat3 and Erk phosphorylation. Furthermore, andrographolide inhibits cell viability and induces apoptotic cell death in both androgen-stimulated and castration-resistant human prostate cancer cells without causing significant toxicity to normal immortalized prostate epithelial cells. Moreover, treatment of andrographolide in mice bearing castration-resistant DU145 human prostate tumors that express constitutive IL-6 autocrine loop significantly suppresses tumor growth.
CONCLUSIONS: Taken together, these results demonstrate that andrographolide could be developed as a therapeutic agent to treat both androgen-stimulated and castration-resistant prostate cancer possibly by suppressing IL-6 expression and IL-6-induced signaling.
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 5427. doi:10.1158/1538-7445.AM2011-5427
Abstract 5435: The potential of ginseng for cancer chemoprevention
Authors: Wang Chong-Zhi , Calway Tyler D. , Yuan Chun-Su 
Published: June 2012

Abstract
The clinical management of cancer invariably involves diverse conventional modalities, including surgery, radiation, and chemotherapy. However, the complexity of human cancer requires some alternative management to improve the therapeutic efficacy of conventional treatment and/or the quality of life of cancer patients. Medicinal botanicals have recently gained more attention for cancer management. Numerous effective anticancer drugs have been developed from botanicals, and identifying new herbal sources to develop ideal chemoprevention remains an essential step in advancing the treatment of colorectal cancer. In this study, potential roles of ginseng herbs, especially American ginseng and notoginseng, in cancer chemoprevention are evaluated. The major pharmacologically active constituents of ginsengs are ginsenosides, which can be mainly classified into protopanaxadiol and protopanaxatriol groups. The recognized active anticancer compounds from American ginseng and notoginseng are ginsenosides Rg3, Rh2, and protopanaxadiol. The structure-activity relationship between their chemical structures and pharmacological activities is discussed. Sugar molecules within a ginsenoside have a high impact on cancer cells. Anticancer activities increase with the decrease of sugar number. In addition, we observed that various steaming temperatures and time treatments of the ginseng herbs can change their ginsenoside profiles and enhance their anticancer activities. This heat treatment process may increase the efficacy of ginseng in cancer chemoprevention. (This work was supported in part by the NIH/NCCAM grants AT003255, AT004418 and AT005362).
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 5435. doi:10.1158/1538-7445.AM2011-5435
Abstract 5438: The ex vivo approach of testing drug activity with clinical leukemia specimens
Authors: Lu Jiwei , Zhang Dongqing , Chen Li , Wang Licui , Chen Shi , Shu Lili , Chen Taiping 
Published: June 2012

Abstract
There is an urgent need to establish better preclinical evaluation platforms for anticancer drug development. To understand the therapeutic potential for leukemia patients, we establish an ex vivo platform for anti-leukemia compounds on freshly isolated leukemia blast cells. The primary leukemia cells were isolated from patients’ fresh bone marrow samples with Human Mononuclear Isolation Medium HISTOPAQUE-1077(Sigma-Aldrich) and subjected to different concentrations of testing anti-leukemia compounds. Then, the treated specimens were detected with annexin V/7-AAD and PI/FACS assays by flow cytometry to measure apoptosis and cell cycle. We have examined 54 cases (7 of ALL, 26 of AML, 21 of undetermined) of leukemia patients’ fresh bone marrow samples with 5 compounds. The leukemia blast cells displayed a dose-dependent drug reactivity which could be estimated through IC50. Combined with the patients’ clinical information, we found that patients showed distinct sensitivity to anti-leukemia compounds, which may guide further research on drug discovery. Therefore, these data provide a foundation for the preclinical investigation of anti-leukemia compounds. The ex vivo system constitutes a more sensitive and quantitative platform for the therapeutic potential of anti-leukemia compounds.
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 5438. doi:10.1158/1538-7445.AM2011-5438
Abstract 5444: Real-time RT-PCR of terminal deoxynucleotidyl transferase (TdT) is a useful tool for identification of minimal leukemia in cerebrospinal fluid
Authors: Belgaumi Asim F. , Bu Rong , Hussain Azhar R. , Al-Obaisi Khadija A S , Al-Mahr Mohammed , Uddin Shahab , Al-Kuraya Khawla S. 
Published: June 2012

Abstract
Accurate detection of central nervous system (CNS) involvement in children with newly diagnosed acute lymphoblastic leukemia (ALL) could have profound prognostic and therapeutic implications. The detection of cerebrospinal fluid (CSF) infiltration by leukemic cells as performed by morphological assessment is subjective and unable to detect low levels of involvement. Therefore, newer and more accurate techniques are required to more efficiently detect minimal leukemic cell involvement. For this reason, a quantitative, Real-time RT-PCR targeting the TdT molecule was developed and tested to allow an objective and sensitive methodology for detecting CNS leukemia. 35 diagnostic CSF samples were subjected to the qRT-PCR assay for TdT. Only 4/35 samples were positive by cytomorphological detection. Of these 4 samples, one sample was diagnosed with CNS disease (CNS 3) and three samples had lower numbers of leukemic blasts (CNS 2). When compared to morphology results, as the gold standard, we found 24 out of the 35 samples to be positive by qRT-PCR. 20 CSF samples that were negative by morphology had detectable TdT by RT-PCR, possibly indicating leukemic infiltration below the level of cytomorphological detection. Serial samples for the 4 CNS-positive patients were tested by qRT-PCR and showed persistent positivity with gradual reduction in quantity of TdT with chemotherapy administration. 11 samples had no detectable TdT by RT-PCR and were found to be negative by cytomorphological assessment as well. In patients with no cytomorphologically detected blasts, TdT positivity was not associated with the level of peripheral blood WBC count. This methodology provides an objective, quantitative and sensitive tool for the detection of leukemic blasts in the CSF. This allows us to detect molecular CNS involvement in CNS negative patients. Although the outcome for all CNS negative patients is good, this has been achieved with fairly intensive prophylactic CNS-directed therapy, reduction in CNS-directed therapy may be possible in molecularly negative patients.
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 5444. doi:10.1158/1538-7445.AM2011-5444
Abstract 5450: CYP2A6 and ERCC1 polymorphisms correlate with efficacy of S-1 plus cisplatin in metastatic gastric cancer patients
Authors: Park Sook Ryun , Kong Sun-Young , Nam Byung-Ho , Choi Il Ju , Kim Chan Gyoo , Lee Jong Yeul , Cho Soo-Jeong , Kim Young-Woo , Ryu Keun Won , Lee Jun Ho , Rhee Jiyoung , Park Young-Iee , Kim Noe Kyeong 
Published: June 2012

Abstract
Introduction: S-1 contains tegafur, which is converted to 5-fluorouracil by CYP2A6. We evaluated the association between polymorphisms of CYP2A6, ERCC1 and XRCC1 and treatment outcomes of metastatic gastric cancer (MGC) patients treated with S-1/cisplatin.
Methods: Among chemonaive MGC patients (n=108) who received S-1 40 mg/m2 b.i.d. on days 1-14 and cisplatin 60 mg/m2 on day 1 of a 3-week cycle, we analyzed the wild-type allele [W] (CYP2A6*1), four CYP2A6 variants [V] that abolish (CYP2A6*4) or reduce (CYP2A6*7, *9, *10) enzyme activity, and the polymorphisms of ERCC1 [8525C&gt;T (rs11615), 19442C&gt;A (rs3212986)] and XRCC1 [1196G&gt;A (rs25487)].
Results: Patients having fewer CYP2A6 variants had significantly better response rates (W/W vs W/V other than *1/*4 vs V/V or *1/*4 = 66.7% vs 58.3% vs 32.3%; P=0.008), time to progression (TTP) (median, 7.2 vs 6.1 vs 3.5 months, P=0.021), and overall survival (median, 23.2 vs 15.4 vs 12.0 months, P=0.004). ERCC1 19442C&gt;A was also associated with response rate (C/C, 46.7% vs C/A, 55.3% vs A/A, 87.5%) (P=0.048) and TTP (median, 4.4 vs 7.6 vs 7.9 months) (P=0.012). When we classified patients according to the number of risk genotypes of CYP2A6 (V/V or 1/*4) and ERCC1 19442C&gt;A (C/C), patients carrying two vs those carrying none showed an adjusted odds ratio of 0.113 (95% CI, 0.025-0.509) (P=0.004) for response and adjusted hazard ratios of 3.748 (95% CI, 1.900-7.393) (P=0.0001) for TTP and 2.961 (95% CI, 1.371-6.393) (P=0.006) for death.Conclusion: CYP2A6 and ERCC1 19442C&gt;A polymorphisms are important predictors for the efficacy of S-1/cisplatin in MGC patients.
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 5450. doi:10.1158/1538-7445.AM2011-5450
Abstract 5454: Drug effect analysis of methoxyamine through quantifying the drug on its therapeutic target
Authors: Li Lan , Xu Yan , Liu Lili , Gerson Stanton L. 
Published: June 2012

Abstract
Methoxyamine (MX) is the first DNA base-excision-repair (BER) inhibitor evaluated in humans. MX potentiates the cytotoxicity of alkylating and antimetabolic agents by condensing with DNA apurinic/pymidinic (AP) sites which are produced through the removal of alkylated or abnormal nucleobases from DNA backbone by DNA glycosylases. The formation of AP-MX complex blocks the BER pathway, and hence reverses tumor resistance to the chemotherapeutic agents. The further repair of MX-bound DNA by topoisomerase II results in ds-DNA breaks, and induces tumor cell death.
In this work, we developed and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantitative analysis of AP-MX complex released from MX-bound DNA by a multi-enzyme system. The enzyme-released AP-MX (i.e., deoxyribose-MX, or dR-MX) was first separated from the enzyme digestion matrix on a Hypercarb® column, and then quantitated by a triple quadrupole mass analyzer using multiple-reaction-monitoring (MRM) mode with a mass transition of m/z 164 &gt; 117. The calibration curve which corresponds to 3.55 to 227 AP-MX complexes/107 bases was established using AP-MX calibrators obtained by serial dilution of DNA oligomer containing known amount of AP-MX complex in blank calf thymus DNA. The method developed has been applied to AP-MX analysis of DNA extracts from T98G cells treated with temozolomide with MX, and blood samples from an ongoing Phase I study of methoxyamine and temozolomide in patient with advanced solid tumors. The dose, AP-MX complex, and time profiles have been obtained. This method provides a quantitative measure of methoxyamine at its proposed target sites.
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 5454. doi:10.1158/1538-7445.AM2011-5454
Abstract 5460: Dual efficacy of Lazaroid U-74389G liposomes in glioblastoma mouse model
Authors: Ibrahim Fady Makram , Cui Kemi , New Pamela , Wang Lulu , Zhao Hong , Wong Stephen , Chow Diana S-L 
Published: June 2012

Abstract
Purpose: Lazaroid U-74389G (LAZ) is a 21-aminosteroid that has radioprotective effect against radiation-induced lipid peroxidation. In-vitro antiproliferative effect was reported against Glioblastoma primary cell lines. The aim of this study was to use a liposomal formulation in a proof-of-concept efficacy study to evaluate LAZ radioprotective and antiproliferative effects in Glioblastoma mouse model.
Methods: LAZ PEGylated liposomes (Lipo G) were developed in our laboratory. Lipo G size was 80-90 nm with Zeta potential of -22mv. Glioblastoma cell line U87-Lexpressing firefly luciferase reporter gene (100,000 cells in 2 μL) was injected intracranially in each male SCID hairless outbred mouse. The mice were randomized among 4 treatment groups (n=8-9, each): brain model (M) without treatment (control), radiation of 2Gy once a week (M+R), Lipo G at 5 mg/kg dose IP twice a week (M+L) and radiation with Lipo G (M+R+L). The treatment lasted three weeks. The tumor size was monitored using non-invasive bioluminescence imaging (BLI), in each mouse, expressed as the relative BLI photon intensity on the second and third week to that of the first measurement. The mice were sacrificed at the end of the third week and the whole brain was harvested for immunohistochemistry examinations. Lipid peroxidation of brain tissues was quantified by measuring malondialdehyde (MDA) as a surrogate biomarker. The survival was evaluated using Kaplan Meier analysis at P = 0.05.
Results: The relative BLI intensity was 4002.03±1737.67, 2034±737.72, 1387.36±684.53 and 2498.89±2521.32 % for M, M+R, M+L and M+R+L, respectively. The tumor size of the M+L group was reduced by 65% compared to the control group. For the radiation treated groups (M+R and M+R+L), there was no significant difference in the tumor size suppression compared to the control group. MDA brain concentration in M+L and M+R+L groups was significantly less than that in M+R group (8.27±0.78 and 10.37±3.30 µM/gm vs. 23.09± 3.79 µM/gm). The survival mean was 22.67, 25.33, 25.22 and 27.13 days for M, M+R, M+R+L and M+L groups, respectively. The mean survival duration of LAZ treated groups (M+L and M+R+L) was significantly longer than that of the control group (27.13 and 25.22 day vs. 22.67 day, respectively).
Conclusion: LAZ liposomal formulations administered at 5 mg/kg dose delivered a therapeutic concentration of LAZ to the brain for the efficacy of suppressing Glioblastoma tumor growth (65% reduction). The liposomal LAZ also protected the brain tissue from radiation-induced lipid peroxidation by reducing MDA concentration (lipid peroxidation surrogate) to 50%.
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 5460. doi:10.1158/1538-7445.AM2011-5460
Abstract 5476: Small molecule activation of BAX-mediated apoptosis through direct engagement of the BAX trigger site
Authors: Gavathiotis Evripidis , Reyna Denis , Walensky Loren 
Published: June 2012

Abstract
BCL-2 family proteins are key regulators of the mitochondrial apoptotic pathway in health and disease. Anti-apoptotic members such as BCL-2 and BCL-XL have been implicated in the initiation, progression, and chemoresistance of human cancer. The anti-apoptotic BCL-2/BCL-XL groove that binds and sequesters pro-apoptotic BH3 death helices has been successfully targeted by small molecules and peptides. Such compounds induce tumor cell apoptosis and are being advanced in clinical trials as promising next-generation cancer therapeutics. We recently localized a distinct BH3 binding groove on pro-apoptotic BAX and demonstrated that engagement of the novel site by a triggering BIM BH3 helix directly activates BAX (Gavathiotis et al. Nature, 2008), unleashing a succession of key conformational changes that culminates in the formation of a toxic mitochondrial pore (Gavathiotis et al. Mol Cell, 2010). Here we applied these new structural insights in a computational screen to identify small molecules capable of directly engaging the BAX trigger site for therapeutic induction of BAX-mediated apoptosis in human cancer. We confirmed by NMR analysis that a series of identified small molecules indeed bound to the BAX trigger site and in fluorescence polarization assays were strikingly selective for the BH3-binding groove of BAX as compared to that of anti-apoptotic targets. We demonstrate that molecular binding triggers dose-responsive BAX activation, as assessed by in vitro oligomerization, membrane permeabilization, and cell death assays. Importantly, the small molecule BAX activators induce apoptosis of cancer cells in a BAX-dependent manner, highlighting both the selectivity and pharmacologic potential of direct BAX activation as a novel strategy for cancer therapy.
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 5476. doi:10.1158/1538-7445.AM2011-5476
Abstract 5479: Mcl-1 is differentially regulated in acute myeloid leukemia cells treated with all trans retinoic acid and arsenic trioxide
Authors: Wang Rui , Waxman Samuel , Jing Yongkui 
Published: June 2012

Abstract
Both all trans retinoic acid (ATRA) and arsenic trioxide (ATO) induce complete remission in acute promyelocytic leukemia (APL) patients. Using the APL derived NB4 cell line containing the PML-RARα fusion protein it has been found that ATRA induced differentiation while ATO mainly induced apoptosis. Previously it has been reported that the antiapoptotic proteins Bcl-2 and Bfl-1/A1 were regulated during ATRA-induced differentiation process in APL cells. However, the regulation of Mcl-1, a major antiapoptotic protein required during myeloid granulocyte differentiation, has not been determined. Recently it has been shown that ERK phosphorylates Mcl-1 and regulates its stability. The regulation of Mcl-1 and p-ERK by ATRA and ATO were investigated in NB4 and its subclone R4 cells, HL-60 and its subclone HL-60/Res cells. Both NB4 and R4 cells contain PML-RARα while HL-60 and HL-60/Res cells contain RARα. However, the ATRA binding domain in PML-RARα and RARα is mutant in R4 and HL-60/Res cells, respectively. The levels of Mcl-1 were induced by ATRA in both NB4 and HL-60 cells, but not in R4 cells nor HL-60/Res cells. The induction of Mcl-1 in NB4 and HL-60 cells correlated with the induction of differentiation and the increased level of p-ERK. Unlike ATRA treatment, ATO treatment decreased the levels of Mcl-1 in both NB4 and R4 cells, but not in HL-60 nor in HL-60/Res cells, which correlated with the induction of apoptosis and down-regulation of p-ERK. Both NB4 and R4 cells contain PML-RARα which is degraded by ATO, suggesting that PML-RARα plays a role in ATO-mediated down-regulation of Mcl-1. To test the effect of PML-RARα on the regulation of Mcl-1 after ATO treatment, U937/PR9 cells with the inducible expression of PML-RARα were used. Expression of PML-RARα increased the levels of Mcl-1 and p-ERK. ATO treatment decreased the levels of both Mcl-1 and p-ERK. These data suggest that ATRA increases the level of Mcl-1 through activating ERK due to overcoming PML-RARα transcriptional repression and activating RARα while ATO decreases the level of Mcl-1 through inactivation of ERK due to inducing degradation of PML-RARα. The increased level of Mcl-1 after ATRA treatment protects against cell death and promotes differentiation while the decreased level of Mcl-1 after ATO-treatment sensitizes apoptosis induction.
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 5479. doi:10.1158/1538-7445.AM2011-5479