bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 8: Identification of a non-canonical BH3 peptide that binds the BH3 pocket of Mcl-1
Authors: Placzek William J. , Sturlese Mattia , Wei Jun , Wu Bainan , Cellitti Jason , Pellecchia Maurizio 
Published: June 2012

Abstract
The identification of selective inhibitors of the anti-apoptotic Bcl-2 family remains a principal target for cancer drug development. With the recent recognition of Mcl-1 as the primary Bcl-2 family member expressed in solid tumors and its ability to enable therapeutic resistance, identification of peptides that specifically bind to Mcl-1 has become critical for the development of improved therapeutics. To identify novel peptides that bind to the BH3 cleft of Mcl-1, we screened a randomized twelve residue phage display library using a pan-active Bcl-2 small-molecule inhibitor. This screen identified a unique non-canonical BH3 sequence, rBH3, which selectively binds to Mcl-1 over Bcl-xL. NMR analysis of the rBH3 interaction with Mcl-1 shows that it binds to the BH3 binding groove and an alanine scan of the sequence highlights the key residues responsible for its binding. A search for proteins with the rBH3 motif has identified a number of interesting targets which have previously been associated with apoptosis regulation. Thus we believe that this sequence represents a unique, Mcl-1-specific peptide sequence that may identify a previously unknown family of Mcl-1 interacting proteins.
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 8. doi:10.1158/1538-7445.AM2011-8
Abstract 807: Hydrogen sulfide-releasing aspirin modulates xenobiotic metabolizing enzymes in vitro and in vivo
Authors: Street Cherease R. , Chattopadhyay Mitali , Kodela Ravinder , Boring Daniel , Crowell James A. , Kashfi Khosrow 
Published: June 2012

Abstract
Introduction: Xenobiotic metabolizing enzymes are classified as phase-I (oxidation/reduction) and phase-II (conjugation) enzymes; the balance between the phase-I carcinogen-activating enzymes and the phase-II detoxifying enzymes may be important in determining an individual's risk for cancer. Hydrogen sulfide-releasing aspirin (HS-ASA) is a new compound with significant anti-inflammatory properties. It consists of ASA covalently attached to 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione, which releases hydrogen sulfide. Our initial studies indicate that HS-ASA has chemopreventive properties. In the present study, we evaluated the effect of HS-ASA on xenobiotic metabolizing enzymes both in vitro and vivo.
Methods: HS-ASA was synthesized and purified by us with 1H-NMR verification. Cell lines: HT-29 human colon adenocarcinoma and Hepa 1c1c7 mouse liver adenocarcinoma. Cell growth inhibition: MTT. Levels of cytochrome P450 1A1 (CYP 1A1) a phase-1 enzyme and NAD(P)H:quinone oxireductase (NQO), glutathione S-transferase (GST) and UDP-glucuronyltransferase (UGT), phase-II enzymes by immunoblots. Enzyme activity: GST and thioredoxin reductase (Trx). In vivo: Male Wistar rats (N = 4/group) were treated via gavage either with vehicle or with HS-ASA 100 mg/kg/day. Weight of animals in each group was recorded every 3 days. After 21 days, animals were killed and liver microsomes and cytosols were prepared for phase-I and phase-II enzyme evaluation.
Results: HS-ASA inhibited the growth of HT-29 and Hepa 1c1c7 cells, with an IC50 of 2.5 ± 0.3 µM and 2.9 ± 0.4 µM, respectively. The IC50 for ASA in both cell lines was &gt;5,000 µM at 24h. The ratio ASA/HS-ASA is &gt;2000 in the HT-29 cells and &gt;1700 in Hepa 1c1c7 cells, suggesting that HS-ASA is at least 1700-2000-fold more potent than traditional ASA. In HT-29 cells, at 0.5xIC50, 1xIC50, and 2xIC50, HS-ASA increased GST activity by 2.5-, 7.2-, and 11-fold; and it inhibited Txr by 36 ± 3%, 67 ± 2% and 79 ± 2% respectively. In HT-29 cells, levels of CYP 1A1 were not significantly affected whereas levels of GST and UGT were increased dose-dependently by HS-ASA. In Hepa 1c1c7 cells, levels of NQO were also significantly increased. In vivo, HS-ASA: 1. had no effect on rat's weight; 2. increased hepatic GST activity by 3.4-fold and NQO by 1.4-fold; 3. immunoblots showed significant increases in GST and NQO protein levels but no changes in CYP 1A1 protein levels.
Conclusions: HS-ASA co-induces multiple phase-II metabolizing enzymes and thus may be regarded as a monofunctional inducer. This represents one mechanism by which HS-ASA exhibits chemopreventive properties.
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 807. doi:10.1158/1538-7445.AM2011-807
Abstract 813: Deletion of vitamin D receptor in prostate epithelial cells increases proliferation, reduces apoptosis, and enhances early carcinogenesis in the TgAPT121 mouse model of prostate cancer
Authors: Kovalenko Pavlo L. , Clinton Steven K. , Fleet James C. 
Published: June 2012

Abstract
High vitamin D status has been proposed to prevent prostate cancer (PCa). In vitro, the active metabolite of vitamin D suppresses PCa cell growth and has a number of other anti-cancer actions in prostate epithelial cells (PEC) that are mediated through a vitamin D receptor (VDR)-dependent transcriptional mechanism. We examined the in vivo importance of VDR in normal PEC biology and in PCa development using mouse models. In the first study, 7 wk-old wild type mice and mice with PEC-specific deletion of VDR (PEC-VDR KO) were randomized to intact, castration, or castration + testosterone propionate (TP, 2.5 mg/kg BW for last 5 d) groups and mice were killed 12 d later. PEC proliferation (Ki-67) and apoptosis (TUNEL) were determined in the anterior prostate (AP). Castration reduced proliferation and increased apoptosis indices in the prostate while TP treatment reversed these effects. In PEC-VDR KO mice, TUNEL staining was significantly reduced (e.g. 50% lower after castration) and Ki-67 staining was significantly increased (e.g. 2-fold higher after castration + TP) compared to the controls. This suggests that loss of VDR signaling provides an environment in the prostate that may be permissive to events that enhance prostate carcinogenesis. We tested this hypothesis in the TgAPT121 transgenic mouse model of PCa. The TgAPT121 transgenic mice express a truncated SV40 Large T antigen (T121) in PEC. T121 expression inactivates the retinoblastoma (Rb) family of proteins causing epithelial cell hyperplasia, development of prostatic intraepithelial neoplasia (PIN) lesions by 12 wk of age, and microinvasive adenocarcinoma by 6 mo of age. TgAPT121 (APT;VDR WT) mice and TgAPT121 lacking both VDR alleles in PEC (APT;PEC-VDR KO) were generated and at 28 wks of age their prostates were removed and histologically graded. The total area covered by high grade PIN, adenocarcinoma, and microinvasive cancer was significantly higher in APT;PEC-VDR KO as was the number of foci per AP for each of these lesions (e.g. adenocarcinoma lesion foci 7.93% in APT;PEC-VDR KO versus 2.55% in APT;VDR WT, p&lt;0.01). PEC VDR deletion significantly increased the histological grade of carcinogenic lesions in APT;PEC-VDR KO (score = 17.47 vs. Control = 16.32, p&lt;0.05). This demonstrates that VDR signaling is critical for the anticancer effects of vitamin D and that signaling through the VDR delays transition of normal epithelium to PIN and early carcinoma.
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 813. doi:10.1158/1538-7445.AM2011-813
Abstract 817: Isothiocyanates inhibit proteasome activity and proliferation of multiple myeloma cells
Authors: Mi Lixin , Gan Nanqin , Chung Fung-Lung 
Published: June 2012

Abstract
Isothiocyanates (ITCs), including benzyl ITC (BITC), phenethyl ITC (PEITC), and sulforaphane, induce cell cycle arrest and apoptosis in a variety of cancer cells and animal models. Although studies show that reactive oxygen species (ROS) generation may be responsible, at least in part, for apoptosis induced by ITCs, our recent studies show that covalent binding to target proteins may actually be an important event triggering apoptosis (Cancer Res., 2007, JBC.,2008, and JBC., 2009). In this study, we report that BITC and PEITC significantly inhibit proteasome activity in a variety of cell types. Further studies show that ITCs inhibit both the 26S and 20S proteasome, presumably through direct binding, and that this inhibition is unrelated to either ROS generation or ITC-induced protein aggregation. The potency of ITC-induced proteasome inhibition correlates with the rapid accumulation of p53 (tumor suppressor) and IκB (NF-κB inhibitor). Finally, our results demonstrate that BITC and PEITC as stronger proteasome inhibitors significantly suppress growth of multiple myeloma cells through induction of cell cycle arrest at G2/M phase and apoptosis. These results suggest that proteasome, like tubulin, is a potential molecular target of ITCs, unraveling a novel mechanism by which ITCs may inhibit multiple myeloma cell growth. This study provides new leads for ITC compounds with therapeutic and preventative efficacies for multiple myeloma.
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 817. doi:10.1158/1538-7445.AM2011-817
Abstract 826: Potential Combination Therapy to Combat Endometrial Cancer
Authors: Daikoku Takiko , Jackson Lindsey , Dey Sudhansu K. 
Published: June 2012

Abstract
Endometrial cancer (EMC) is the most common gynecological malignancy causing approximately 7,000 deaths each year in the United States. The underlying causes of EMC are not clearly understood, and treatment options for patients with advanced stages are limited. The gene with the highest frequency of alteration in EMC is Phosphatase and tensin homolog (Pten). The loss of Pten results in increased PI3K activity with enhanced Akt activation. Increased levels of activated Akt (pAkt) stimulate both cyclooxygenase-2 (COX-2) and mammalian targets of rapamycin complex 1 (mTORC1) activity. Although these activities are also heightened in human EMC, it is not clear whether they are the critical players in cancer initiation and progression or whether they work interactively. Animal models that spontaneously develop cancers are powerful tools for studying mechanisms of cancer initiation and progression and for developing treatment strategies. We recently generated an EMC mouse model in which uterine Pten was conditionally deleted by crossing floxed Pten mice with progesterone receptor (PR)-Cre (PRcre/+) mice. All PtenloxP/loxP/PRcre/+ mice developed EMC by one month of age with invasion occurring by 3 months. Tumor phenotypes in these mice mimic many aspects of human EMC. Using this mouse model, we found that uteri of these mice show heightened levels of COX-2 and mTORC1 activities. These observations led us to examine whether inhibiting COX-2 and/or mTORC1 activities reduces the growth of EMC. PtenloxP/loxP/PR+/+ (control) and PtenloxP/loxP/PRcre/+ mice were treated with rapamycin (an inhibitor of mTORC1 signaling) and/or celecoxib (an inhibitor of COX-2 activity) by oral gavages every alternate day starting from 30 days of age for 29 days. We found that although treatment with rapamycin or celecoxib attenuated tumor growth, maximum reduction in tumor growth and progression was noted for PtenloxP/loxP/PRcre/+ females receiving both rapamycin and celecoxib. These results suggest that a combined treatment with celecoxib and rapamycin is an effective therapeutic strategy for combating EMC. This study was supported in parts by grants from NIH-P01-CA-77839 (S.K.D), Concern Foundation (T.D.) and Ohio Cancer Research Associates (T.D.).
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 826. doi:10.1158/1538-7445.AM2011-826
Abstract 837: Novel sulindac derivatives that inhibit colon cancer growth by a COX independent mechanism involving PDE5 inhibition and the suppression of nuclear β-catenin levels
Authors: Whitt Jason D. , Keeton Adam B. , Tinsley Heather N. , Gary Bernard D. , Li Nan , Mathew Bini , Reynolds Robert C. , Piazza Gary A. 
Published: June 2012

Abstract
Many colon cancers harbor APC mutations that prevent the proteosomal degradation of oncogenic β-catenin. Previous studies have found that certain nonsteroidal anti-inflammatory drugs (NSAIDs) have the ability to reduce nuclear levels of β-catenin and inhibit tumor cell growth through a cyclooxygenase (COX)-independent mechanism, which might be responsible for their cancer chemopreventive activity. A potential mechanism may involve cGMP phosphodiesterase (PDE) inhibition and the activation of protein kinase G (PKG). In this study we evaluated over 500 novel sulindac derivatives for colon tumor cell growth inhibitory activity. Select compounds were also evaluated for COX and cGMP PDE inhibitory activity to determine which activity is associated with colon tumor cell growth inhibition and ability to suppress nuclear β-catenin levels. A subset of derivatives was identified that displayed reduced COX-1 and COX-2 inhibitory activity, yet increased potency to inhibit the growth of several colon tumor cell lines (HT29, HCT116, SW480, and COLO741) with IC50 values of 2-10 µM compared with IC50 values of 80-110 µM for the parent compound, sulindac sulfide (SS). Certain derivatives also displayed increased potency to inhibit recombinant phosphodiesterase 5 (PDE5), which appears to be the isozyme responsible for the cGMP PDE inhibitory activity of SS. Treatment of colon tumor cells with such compounds also increased the phosphorylation of vasoactive stimulated protein (VASP), a known PKG substrate. Furthermore, nuclear levels of β-catenin decreased within the same time period as PKG activation, which is consistent with previous reports suggesting that PKG can phosphorylate β-catenin to induce proteosomal degradation. Together, these data indicate that sulindac can be chemically modified to eliminate COX inhibitory activity while enhancing its ability to inhibit colon tumor cell growth. We conclude that the suppression of nuclear β-catenin levels by SS is independent of COX inhibition and that novel derivatives can be developed with improved antineoplastic activity while reducing the toxicities associated with COX inhibition. Funding provided by NIH/NCI grants CA131378 and CA148817.
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 837. doi:10.1158/1538-7445.AM2011-837
Abstract 841: Inhibition of head and neck squamous cell carcinoma growth by combination treatment of erlotinib and celecoxib: Potential chemopreventive agents
Authors: Zhang Hongzheng , Nannapaneni Sreenivas , Chen Zhengjia , Saba Nabil , Khuri Fadlo R. , Chen Georgia (Zhuo) , Shin Dong M. 
Published: June 2012

Abstract
The interaction of epithelial growth factor receptor (EGFR) and cyclooxygenase 2 (COX-2) pathways plays an important role in tumorigenesis. Our recent Phase I chemoprevention trial of premalignant lesions including pathologically moderate or severe dysplasia and carcinoma in situ in oral cavity and larynx showed a 71% (5/7) estimated overall response rate after a 6-month-long combination treatment of Erlotinib and Celecoxib without significant toxicities (ASCO 2010 Abstract # 5535). The current preclinical study was designed to investigate the underlying mechanisms that contribute to the inhibitory effect on the disease progression by the combined treatment of Erlotinib and Celecoxib. Chemopreventive efficacy was determined using a head neck squamous cell carcinoma (HNSCC) xenograft model with Tu212 cell line. Animals received vehicle control (0.1% Tween 80 and 0.5% methylcellulose, n=6), Celecoxib at 50mg/kg body weight (n=6), Erlotinib at 75mg/kg body weight (n=7), or combination of Erlotinib and Celecoxib (n=8) with the same dose as the single agent by oral gavaging daily for 6 days before subcutaneous implantation of cancer cells. Animals were further treated daily for 5 days per week with a total of 4 weeks. The combination treatment significantly suppressed tumor growth compared with Erlotinib alone (p=0.01), Celecoxib alone (p&lt;0.0001) or the vehicle control (p&lt;0.0001). In vitro study was performed with Tu212 and Tu686 HNSCC cell lines. Cell cycle analysis revealed that G1 arrest was induced by either Erlotinib alone (59% and 67% for Tu212 and Tu686, respectively), or Celecoxib alone (50% and 58% for Tu212 and Tu686 cells, respectively). The combination treatment resulted in greater G1 arrest than either single agent alone (72% in Tu212 and 65% in Tu686 cells). Molecular analysis showed that the combined treatment augmented suppression of pERK, pAKT and pEGFR. In addition, Erlotinib suppressed mTOR pathway by diminishing pS6. These results support the findings in the phase I study. The study has progressed to Phase II clinical trial. In conclusion, augmented inhibition of pEGFR/pERK/pS6 pathways could contribute to the synergism by Erlotinib and Celecoxib in suppressing HNSCC tumor growth. (This study is supported by NIH grant U01 CA151802 and P50CA128613 to Dr. Shin and Georgia Cancer Coalition Distinguished Cancer Scholar award to Drs Shin and Chen. *: These authors had equal contribution.)
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 841. doi:10.1158/1538-7445.AM2011-841
Abstract 845: Heparin-like polysaccharides reduce osteolytic bone destruction and tumor growth in a mouse model of breast cancer bone metastasis
Authors: Pollari Sirkku , Käkönen Rami , Mohammad Khalid S. , Rissanen Jukka P. , Halleen Jussi , Wärri Anni , Nissinen Liisa , Pihlavisto Marjo , Marjamäki Anne , Perälä Merja , Guise Theresa , Kallioniemi Olli , Käkönen Sanna-Maria 
Published: June 2012

Abstract
Transforming growth factor β (TGF-β) is a key regulator of several steps in cancer metastasis, including the establishment of bone metastatic lesions. TGF-β is released from bone during osteoclastic bone resorption and it stimulates breast cancer cells to produce osteolytic factors such as interleukin 11 (IL-11). We conducted a cell-based siRNA screen and identified heparan sulfate 6-O-sulfotransferase 2 (HS6ST2) as a critical gene for TGF-β-induced IL-11 production in highly bone metastatic MDA-MB-231(SA) breast cancer cells. HS6ST2 attaches sulfate groups to glucosamine residues in heparin sulfate which is a member of the glycosaminoglycan family of carbohydrates. Our subsequent studies with highly sulfated heparin-like glycosaminoglycans (HLGAGs) with low anti-coagulant activity indicated that a high-molecular-weight E. coli K5-derived heparin-like polysaccharide (K5-NSOS) inhibited TGF-β-induced IL-11 production in MDA-MB-231(SA) cells. We then evaluated the therapeutic potential of K5-NSOS and a low-molecular-weight synthetic heparin (fragmin) in a mouse model of breast cancer bone metastasis. MDA-MB-231(SA) cells were inoculated into the left cardiac ventricle of athymic nude mice which were then administered with K5-NSOS, fragmin, or vehicle once daily for 4 weeks. Both HLGAGs increased body weight, decreased osteolytic lesion area, and reduced tumor burden in bone. Our in vitro studies showed that both K5-NSOS and fragmin inhibited adhesion of breast cancer cells to ICAM-1, and K5-NSOS also inhibited adhesion to E- and P-selectin. Furthermore, K5-NSOS inhibited bone resorption activity of human osteoclasts in vitro. Our data support and further clarify the critical role of heparan sulfate glycosaminoglycans in breast cancer metastasis and indicate that K5-NSOS is a potential antimetastatic and antiresorptive agent with low anticoagulant activity that could be further optimized as an anti-tumor agent.
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 845. doi:10.1158/1538-7445.AM2011-845
Abstract 847: Resolvin D1 stimulates efferocytosis through p50/p50-mediated suppression of tumor necrosis factor-α
Authors: Lee Ha-Na , Kundu Joydeb Kumar , Shin Jun-Wan , Cha Young-Nam , Surh Young-Joon 
Published: June 2012

Abstract
Phagocytosis of apoptotic neutrophils by macrophages, called efferocytosis, is critical to resolution of inflammation as this process prevents the exposure of surrounding tissues at the inflammatory site to the toxic contents of lytic cells. Docosahexaenoic acid-derived resolvin D1 (RvD1), endogenously generated during resolution of inflammation, is known to stimulate efferocytosis, but little is known about the mechanism of its action. In the present study, we found that lipopolysaccharide (LPS; 200 μg/ml) suppressed efferocytosis by murine macrophage-like RAW264.7 cells, and RvD1 (50 nM) restored the phagocytic ability of these cells by down-regulating TNF-α expression. The inhibitory effect of RvD1 on LPS-induced TNF-α expression was associated with enhanced nuclear localization of p50/p50 homodimer and concomitant reduction in the nuclear levels of p65/p50 heterodimer. RvD1 triggered extracellular signal-regulated kinase (ERK)- and Akt-mediated nuclear factor κB1 (NF-κB1) p105 degradation and subsequently translocation of p50/p50 homodimer to nucleus in RAW264.7 cells. In contrast, LPS-induced nuclear translocation and DNA binding of p65/p50 heterodimer were attenuated by RvD1 treatment through inhibition of IκBα degradation. siRNA knockdown of NF-κB p50 abolished RvD1-mediated suppression of TNF-α expression and resulted in impaired efferocytosis, suggesting that the replacement of p65/p50 with p50/p50 homodimer is an essential event for RvD1-mediated stimulation of efferocytosis. In a murine peritonitis model, intraperitoneal administration of RvD1 (300 ng) abrogated zymosan A (30 mg/kg)-induced TNF-α production, thereby reactivating efferocytosis. In addition, RvD1 significantly reduced polymorphonuclear leukocyte infiltration while it increased monocyte infiltration. Taken together, these findings indicate that RvD1 expedites resolution of inflammation via p50/p50-mediated repression of TNF-α production.
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 847. doi:10.1158/1538-7445.AM2011-847