bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-290: Tranilast inhibits breast cancer stem cells
Authors: Prud'homme Gerald J. , Glinka Yelena , Toulina Anna , Subramaniam Venkateswaran , Chakrabarti Rabindranath , Jothy Serge 
Published: February 2011

Abstract
Cancer stem cells (CSCs) have increased resistance to anti-cancer drugs, and may be responsible for chemotherapeutic failure. CSCs can be enriched from cancer cell lines by growth with anti-cancer drugs (e.g., doxorubicin, mitoxantrone), and form mammospheres in low-adherence, serum-free cultures. We are studying tranilast, a non-toxic orally active drug in clinical use for allergic diseases in Japan, but that we found also targets cancer cells. Previously, we reported that tranilast exerts multiple anti-cancer effects and protects against breast cancer metastasis. Our recent studies show that tranilast strongly inhibits breast CSCs in several assays, at pharmacologically relevant concentrations. We enriched CSCs from breast cancer cell lines by cell sorting for ALDH-1 positive cells (ALDEFLUOR+), or by growth in mitoxantrone-containing medium to select drug-surviving CSCs. In both cases, CSCs readily formed mammospheres in vitro. Tranilast inhibited mammosphere formation,’ and dissociated formed mammospheres. It was more effective than paclitaxel or etoposide. We recently identified molecular targets of this drug. We found it has aryl hydrocarbon receptor (AHR) agonist activity and this might explain its anti-cancer effects. The AHR is a receptor for toxins such as dioxin and polycyclic aromatic hydrocarbons. It is a transcription factor that exerts a number of ligand-dependent effects, such as cell-cycle arrest, reduced RB phosphorylation, and decreased cytokine and growth factor production. Unlike many AHR ligands, tranilast has very low toxicity (LD50 &gt; 1 gm/kg in rats), and is well tolerated by patients. In accord with a role for the AHR, breast CSCs expressed higher levels of this receptor than the main population of cancer cells, and the effects of tranilast were markedly diminished by an AHR antagonist (alpha-naphthoflavone). Moreover, we found tranilast inhibits some ATP-binding cassette (ABC) multiple drug resistance transporters, and it enhances the effects of other anti-cancer drugs. Our studies show that tranilast is a drug of low toxicity that has potential as an anti-CSC drug.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-290.
Abstract LB-300: Small molecule modulators of MET kinase for treatment of human malignancies
Authors: Wise Scott C. , Smith Bryan D. , Hood Molly M. , Kaufman Michael D. , Lu Wei-Ping , Flynn Daniel L. 
Published: February 2011

Abstract
MET kinase is involved in numerous cancers including lung, melanoma and gastric. MET can not only be the oncogenic driver of the cancer cell but also is a key player in the cells ability to metastasize and invade tissues distant from the primary tumor site. It has been shown that 2 out of 3 cancers involving MET leads to a poor prognosis for patient survival. Using Deciphera Pharmaceutical's approach to kinase inhibition, compounds have been designed which effectively inhibit wild type and mutant MET kinase forms. These inhibitors are selective, including sparing of close family members AXL and RON. This presentation will highlight the attributes and development status of these compounds for treatment of human malignancy. Deciphera's MET program has afforded potent inhibitors that achieve low nanomolar inhibition of wild type MET and secondary activating mutant forms. Data will be presented on DP-4693 and DP-4756.IC50MET Kinasep-MET MKN-45MKN-45 Proliferationp-MET EBC-1EBC-1 ProliferationA549 MigrationDP-46934nM13 nM44 nM10 nM3nM260 nMDP-47566nM6nM23 nM2nM5nM21 nM
DP-4693 and DP-4756 are selective, having as few as three kinases within 50 fold of MET potency. Inhibitor bound crystal structures will be shown which demonstrate the compounds mechanism of action. In addition, proliferation and MET phosphoprotein analysis performed with EBC-1 and MKN-45 cell lines have demonstrated excellent inhibitory profiles with potencies in the low nanomolar range. The compounds also inhibit HGF dependent cell motility in an A549 migration assay. In vivo evaluation of DP-4693 in an MKN-45 gastric cancer xenograft PK/PD model revealed complete target suppression at doses as low as 6 mpk. Futher studies will be presented highlighting the efficacy in both autocrine and paracrine (HGF-dependent) xenograft models.
Deciphera's MET inhibitors also show acceptable ADME properties and are orally bioavailable in rat and dog using simple vehicles. These inhibitors have also been evaluated in two week toxicology studies, exhibiting excellent tolerability up to doses of 300 mpk. Further studies are ongoing to enable Development Candidate selection for progression into clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-300.
Abstract LB-328: Granulocytic myeloid-derived suppressor cells that have suppressive function: CD15+/CD16low human granulocytes from advanced cancer patients
Authors: Choi Jahyang , Suh Beomseok , Ahn Yong-Oon , Kim Tae Min , Lee Se-Hoon , Heo Dae Seog 
Published: February 2011

Abstract
Objectives: Myeloid-derived suppressor cells (MDSCs) are a subpopulation of myeloid cells with suppressive function, found to be increased in various conditions such as chronic infection, trauma, and cancer. Unlike the murine MDSC defined as CD11b+/Gr-1+, there are no specific markers for human MDSC. We have investigated human granulocytes from advanced cancer patients to delineate a specific MDSC subpopulation with clinical implication.
Methods: To find changes of granulocyte markers, we collected whole blood of 53 advanced cancer patients and 20 healthy donors and analyzed them by flow cytometry. To investigate the growth suppressive activity of granulocytes, we purified them and tested growth inhibition activity by 3H thymidine assay.
Results: Through a study of 53 advanced cancer patients, we observed heterogeneity of CD15(+)CD16(+) granulocytes: CD15+/CD16lowand CD15+/CD16high. The number of CD15+/CD16low subsets is increased in advanced cancer patients, compared with healthy donors (p = 0.009). p-methoxyamphetamine (PMA) activated granulocytes (CD16low/CD66b++/CD15+) that have similar phenotype of MDSC from cancer patients suppressed both proliferation and cytotoxicity of normal T cells. T cell proliferation is highly suppressed by granulocytes isolated from advanced cancer patients with high proportion of CD15+/CD16low granulocytes among cancer patients. We also found that patients whose peripheral blood samples with lower levels of CD15+/CD16low populations had significantly longer survival times than those with higher levels of CD15+/CD16low populations. Patients with higher levels of CD15+/CD16low are associated with poor performance status (PS, p = 0.022) as well as shorter survival time (p = 0.0036). Because these phenotypic changes of granulocytes are also shown in the case of inflammation, we speculate that some factors in tumor-bearing hosts may activate granulocytes and induce their suppressive activity.
Conclusions: These data suggest that CD15+/CD16low granulocytes from cancer patients may have a role in progression of cancer by inhibiting tumor immunity. Monitoring of these cells also can be used as a marker of terminal cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-328.
Abstract LB-33: Selective inhibition of Histone Deacetylase 6 enhances transformed cell sensitivity to anti-cancer agents
Authors: Namdar Mandana , Venta-Perez Gisela , Ngo Lang , Marks Paul A 
Published: February 2011

Abstract
Histone deacetylase (HDAC) inhibitors have emerged as promising targeted anti-cancer agents when used both in monotherapies and in combination with other anti-cancer agents. Histone deacetylase 6 (HDAC6) is a structurally and functionally unique member of the histone deacetylase family. HDAC6 has two catalytic sites, a ubiquitin binding site, cytoplasmic localization and deacetylates a number of non-histone proteins such as tubulin, HSP90 and peroxiredoxins. This study aims to unravel HDAC6-mediated anti-cancer effects and explore the therapeutic potential of HDAC6-specific inhibition in combination with other anti-cancer therapies.
We found that chemical inhibition with the HDAC6 specific inhibitor tubacin, reduces cell proliferation but does not effect cell viability in transformed cells. Tubacin significantly enhances cell death induced by anti-cancer agents such as the topoisomerase II inhibitors, etoposide and doxorubicin, as well as the pan-HDAC inhibitor SAHA in transformed cells (LNCaP, MCF-7), an effect not observed in normal cells (HFS). The inactive analog of tubacin, nil-tubacin, does not sensitize transformed cells to these anti-cancer agents. Furthermore, downregulation of HDAC6 expression by shRNA in LNCaP cells enhances cell death induced by SAHA, etoposide and doxorubicin. To explore the mechanisms of tubacin sensitization of transformed cells to anti-cancer agents, we have demonstrated that the combination treatments increases PARP cleavage and that the pan-caspase inhibitor Z-VAD-fmk, partially inhibits cell death induced by combination therapy.
Thus, HDAC6 inhibition can significantly increase transformed cell sensitivity to anti-cancer agents and highlights the importance of HDAC6 as a target for cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-33.
Abstract LB-335: Retinoic acid regulates TRAIL-R1 expression through a retinoic acid receptor-dependent mechanism and enhances death receptor-induced apoptosis
Authors: Dhandapani Latha , Yue Ping , Ramalingam Suresh S. , Khuri Fadlo R. , Sun Shi Yong 
Published: February 2011

Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 1 (TRAIL-R1) also known as death receptor 4 (DR4), is a death domain containing transmembrane receptor involved in TRAIL-mediated apoptosis. One biological function of retinoic acid (RA) among many others is to regulate apoptosis, in part through TRAIL induction. The current study reveals another novel mechanism by which RA modulates apoptosis. For the first time, we found that RA increased TRAIL-R1 expression in various types of human cancer cell lines; this effect could be abrogated by the transcriptional inhibitor actinomycin-D. Moreover, RA increased TRAIL-R1 mRNA level and transactivated its promoter. These data collectively indicate that RA induces TRAIL-R1 expression at the transcriptional level. We also found that RA-induced TRAIL-R1 expression could be abolished by some retinoic acid receptor (RAR) antagonists, whereas various RAR agonists upregulated TRAIL-R1 expression, suggesting that RA induces a RAR-dependent TRAIL-R1 expression. Importantly, we identified two putative RA responsive elements (RARE) named RARE-Pal17 (a palindrome separated by 17 bases) and RARE-DR11 (a direct repeat separated by 11 bases) in the 5′ flanking region of TRAIL-R1 gene. Deletion and mutation of RARE-DR11, but not RARE-Pal17, abrogated RA's effect on transactivation of TRAIL-R1 promoter. In agreement, ChIP assay detected only RARE-DR11 binding, but not RARE-Pal17 binding, in RA-treated cells. These data collectively indicate that the RARE-DR11 is an active one that is responsible for TRAIL-R1 gene transactivation by RA. Furthermore, RA, when combined with TRAIL or agonistic anti-TRAIL-R1 antibody, augmented apoptosis in cancer cells. Taken together, the current study provides compelling evidence that TRAIL-R1 is a RAR target gene and mediates modulation of death receptor-induced apoptosis by RA, thus highlighting a novel mechanism by which RA modulates apoptosis.(SSR, FRK and SYS are Georgia Cancer Coalition Distinguished Cancer Scholars. This study was supported by funds from the Georgia Cancer Coalition Distinguished Cancer Scholar, NIH Head and Neck SPORE P50 CA128613 and DOD VITAL awards)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-335.
Abstract LB-339: Claudin-7 increases chemosensitivity to cisplatin in human NCI-H522 lung cancer cells
Authors: Hoggard John E. , Lu Zhe , Lu Qun , Chen Yan-Hua 
Published: February 2011

Abstract
Lung cancer is a leading cause of cancer death for both men and women worldwide. The 5-year survival rate for lung cancer is only 15%, and it accounts for approximately 1.4 million deaths every year. Recently, it has been reported that changes in expression level of claudin proteins, a family of tight junction integral membrane proteins, has been associated with several types of cancer tissues. Claudin proteins are vital components of the tight junction complex, playing a crucial role in maintaining cell polarity, adhesion, and paracellular permeability. Studies have illustrated that claudin-7 expression is lost in head, neck, invasive breast cancer, and certain types of lung cancer. The aim of this study is to investigate the role of claudin-7 in human lung adenocarcinoma cancer cells. We transfected claudin-7 cDNA tagged with myc into NCI-H522 cells, which have no detectable expression of claudin-7. H522 cells transfected with vector alone were used as a control. Claudin-7 expression in transfected cells was confirmed by western blot analysis and immunofluorescence microscopy probing for claudin-7 and myc tag. Flow cytometry analysis demonstrated that cells transfected with claudin-7 had a significantly higher percentage of cell apoptosis when compared to that of the vector transfected cells. Cell viability analyzed by MTT assays was significantly decreased, and cell apoptosis by Annexin V assays was significantly increased in claudin-7 transfected cells compared to that of vector transfected cells after cisplatin treatment. Cisplatin is an anti-cancer drug clinically used to treat tumors in several tissues including lung tumors. Furthermore, we found that claudin-7 transfected cells exhibited upregulation of caspase-3, -8, and -9. We propose that claudin-7 expression in H522 lung cancer cells increases chemosensitivity to cisplatin through increased activation of the caspase pathway. This work is supported by NIEHS.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-339.
Abstract LB-340: Inhibition of autophagy enhances the anticancer activity of the retinoic acid derivative VN/12-1 in endocrine resistant human breast cancer cell lines
Authors: Godbole Abhijit M. , Purushottamachar Puranik , Gediya Lalji K. , Njar Vincent C. O. 
Published: February 2011

Abstract
Breast cancer is the most common cancer and the second leading cause of cancer related deaths among women in the United States. Although endocrine therapies such as anti-estrogens and aromatase inhibitors have improved the overall survival, resistance to this therapy remains a major concern. Autophagy is a unique, regulated mechanism of cell survival by catabolism of proteins under nutrient deprivation or chemotherapeutic stress. It is an important cause of resistance to chemotherapeutic agents. VN/12-1, a novel 4-imidazolyl methyl ester of retinoic acid synthesized in our laboratory, showed excellent anti-proliferative activity (as shown by MTT assay) in endocrine resistant human breast cancer cell lines SK-BR-3 and MDA-MB-231. Its IC50 in SK-BR-3 cells was 5.2 μM compared to 15.2 μM (all-trans retinoic acid-ATRA) and 45.6 μM (letrozole). For MDA-MB-231 cells, IC50 of VN/12-1 was 7.3 μM compared to 53.7 μM (ATRA) and 74.3 μM (letrozole). At low micromolar concentrations of VN/12-1 treatment on these cells, western blot analysis and imaging studies confirmed the presence of autophagosomes. This was associated with up-regulation of proteins involved in endoplasmic reticulum (ER) stress, markers for DNA damage and downregulation of cyclin D1 and phosphorylated Akt. Co-treatment with chloroquine (an autophagy inhibitor) resulted in increased sensitivity of cells to VN/12-1 as indicated by decrease in cell viability from 71.22% for VN/12-1 (3 μM) alone, 90.18% chloroquine (3 μM) alone to 34.31% for the combination of VN/12-1 (3 μM) and chloroquine (3 μM) in SK-BR-3 cells. It also resulted in induction of apoptosis which was caspase mediated.
In summary, ER stress and DNA damage induced by VN/12-1 resulted in cell cycle arrest and induction of autophagy. Inhibition of autophagy by chloroquine overwhelmed this cellular stress and resulted in apoptotic cell death in endocrine resistant breast cancer cell lines.
Significance: VN/12-1 and its combination with autophagy inhibitor chloroquine is a novel therapeutic alternative to treat endocrine resistant breast cancer and hence warrants further pre-clinical and clinical development. This is the first in vitro study which showed an enhancement of anti-cancer activity of a retinoic acid derivative by an autophagy inhibitor in endocrine resistant human breast cancer cell lines.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-340.
Abstract LB-341: CD95/FAS promotes tumorigenesis
Authors: Chen Lina , Park Sun-Mi , Tumanov Alexei V. , Hau Annika , Sawada Kenjiro , Feig Christine , Turner Jerrold R. , Fu Yang-Xin , Romero Iris , Lengyel Ernst , Peter Marcus E. 
Published: February 2011

Abstract
FAS/CD95 has been known as a typical death receptor that enhances cell apoptosis mainly in the immune system. Recent studies indicate that CD95 expression is rarely absent or down-regulated in solid tumors and CD95L, the cognate ligand that binds cell membrane CD95, is constantly shown to be elevated in patient serum as well as tumor microenviroment, raising the question whether CD95 acturally enhances tumorigenesis and through what mechanisms. By stably knocking down endogeneous CD95 expression level using lentivirus based shRNA in six different tumor cell lines that represent liver (HepG2), colon (HCT116), renal (CAKI-1), breast (MCF7), ovary (SKOV3ip1 and HeyA8), in all cases the CD95 knockdown tumor cell lines show a clear reduction in proliferation rate comparing with the corresponding vector control cells. Injection CD95 knockdown SKOV3ip1 cells i.p. into nude mice according to method of well established xenograft ovary cancer animal model again shows a reduced tumor load and this is also confirmed by using a early passage human ovary cancer cell line MONTY-1. Human neutralizing anti-CD95L mAb (NOK-1) rather than mouse anti-CD95 mAb (MFL3) injection into these xenografted nude mice significantly reduced the tumor load, indicating that it's the CD95L secreted by tumor cells rather than the mice microenviroment that stimulates the tumor proliferation. Knocking down FasL expression from the six tumor cell lines mentioned above reduced cell proliferation even more dramatically than knocking down Fas and some cell lines, like HepG2, CAKI-1, MCF7 and HeyA8, even stop growing with reduced FasL expression. The reduced tumor formation by losing FAS/CD95 was also confirmed in vivo in two animal models: DEN induced liver cancer model by using FAS/CD95 liver specific knockout mice and Ade-Cre induced ovary cancer mouse model by generating Fas knockout mice from a mice stain with background of mutated k-ras and deleted Pten expression (LSK-K-ras(G12D/+)Pten(loxP/loxP)). The tumorigenic activity of CD95 is further identified as mediated through the CD95L-CD95-JNK-c-Jun-Fos and EGR1 pathway. These results demonstrate that CD95 plays a major growth promoting role during tumorigenesis and suggest that efforts to inhibit its activity rather than to enhance its activation should be considered during cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-341.
Abstract LB-358: Carcinogen-induced epigenetic silencing of miR-205 and miR-200 family promotes EMT and transformation of lung epithelial cells
Authors: Tellez Carmen S. , Juri Daniel , Do Kieu , Bernauer Amanda , Thomas Cindy , Leng Shuguang , Tessema Mathewos , Damiani Leah A. , Belinsky Steven A. 
Published: February 2011

Abstract
An in vitro carcinogen-induced transformation model was developed using immortalized bronchial epithelial cells (HBECs) to identify key molecular changes in preneoplastic lung epithelial cells that occur during the development of lung cancer in smokers. HBECs were treated for twelve weeks (one exposure per week) with low-doses of tobacco carcinogens (MNU and BPDE) that resulted in transformation from genotoxic stress (DNA damage). The HBECs displayed a morphological change consistent with an epithelial-to-mesenchymal transition (EMT) after 4 weeks of carcinogen treatment that persisted in colonies that were recovered and expanded from soft agar (transformed cell line). Expression of mesenchymal markers vimentin, fibronectin, and N-cadherin increased significantly, while the epithelial marker E-cadherin was significantly decreased. The most notable changes associated with EMT included 4 - 55 fold reduced expression of miR-200b, -200c, and -205 that correlated with 2-1500 fold increased expression of E-box binding transcription factors (SNAI1, ZEB1, ZEB2) and basic helix-loop-helix transcription factor (TWIST1). Restoring the expression of miR-200b, -200c or -205 in carcinogen transformed cells prevented growth in soft agar; meanwhile the cells maintained a fibroblast-like mesenchymal appearance. Levels of DNA methyltransferase 1 (DNMT1) protein also increased significantly during carcinogen treatment and stable knockdown of DNMT1, but not DNMT3A and DNMT3B prior to carcinogen prevented EMT and transformation. ChIP for H3K4me2 (indicative of active/open chromatin) revealed a progressive decrease of this mark at the promoters of miR-200b, -200c, and -205 over 12 weeks of carcinogen treatment and during transformation. A modest enrichment for H3K9me2 (inactive/closed chromatin mark) was observed at all time points. In contrast, H3K27me3 (indicative of inactive/closed chromatin) was enriched at the miR promoters after 4 weeks of carcinogen treatment and enrichment declined over time. Bisulfite sequencing revealed CpG DNA methylation increased from 3% to 42% in the miR-200 family and miR-205 promoters during transformation. To examine the clinical relevance of miR-200b, -200c, and -205 their expression was analyzed in lung tumors relative to distant normal lung tissue from 24 patients. Reduced expression of at least one miR was observed in 50% of lung adenocarcinomas. These findings implicate a major role for epigenetic regulation of EMT that extends beyond that of cancer metastasis to causality for development of premalignant lung cancer. Supported by ES008801.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-358.