bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2468: Inhibition of autophagy as a potential mechanism by which pantoprazole, a proton pump inhibitor (PPI), enhances the therapeutic effect of docetaxel chemotherapy for solid tumors
Authors: Tan Qian 
Published: August 2012

Abstract
Purpose: Luciani and colleagues (JNCI 2004; 96:1702-13) have shown that PPIs can increase the effects of chemotherapy, most likely by modifying the acid-base balance across the cell membrane of intracellular organelles such as lysosomes. Lysosomes are required for autophagy, a process important for the survival of cells under certain forms of stress and a possible target for anticancer therapy. Here we evaluated the effect of pantoprazole (PTP) to (i) inhibit autophagy, and (ii) modify the cytotoxic effects of the anticancer drug docetaxel (DOC) in vivo and in vitro. Methods: Autophagy was evaluated by assessing both endogenous LC3B protein and with an optical LC3B fusion reporter (LC3B-GFP-RFP) that enables monitoring of autophagosome formation and fusion with the lysosome. Cytotoxicity of DOC +/−PTP was evaluated by a colony-forming assay for PC3 parental cells, and for cells transfected with shRNAs to inhibit autophagy. Growth delay of three human xenografts was evaluated following multiple doses of DOC+/−PTP. The distribution of drug effects in relation to blood vessels was quantified by γH2AX, and cleaved caspase 3. Results: PTP increased endosomal pH and inhibited autophagy in a dose and time dependent manner. PTP alone was not cytotoxic but increased the cytotoxicity of DOC for PC3 cells, with smaller effects against cells with reduced ability to undergo autophagy. Pre-treatment with PTP increased the growth delay caused by DOC in three different xengografts, with minimal increase in toxicity. Effects of DOC evaluated by γH2AX and by cleaved caspase 3 decreased with increasing distance from tumour blood vessels, but were enhanced by pre-treatment with PTP. Conclusions: PTP increases the therapeutic effectiveness of DOC in vitro and in vivo, and a potential mechanism is inhibition of autophagy. DOC is the preferred chemotherapy for men with metastatic castration-resistant prostate cancer, and we plan a phase II study of PTP + DOC in such patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2468. doi:1538-7445.AM2012-2468
Abstract 2473: Extracellular matrix density and acinus formation in breast cancer
Authors: Swamydas Muthulekha , Yang Chihchao , Stephens Amanda , Dean Delphine , Deitch Sandy , Burg Karen JL , Dreau Didier 
Published: August 2012

Abstract
The extracellular matrix (ECM) contributes to the generation and dynamic of normal breast tissue, in particular the generation of polarized acinar and ductal structures. In vitro 3D cultures conditions mimic the formation and function of breast structures. Variations in the composition of the ECM have been shown to directly influence the formation and organization of acinus-like and duct-like structures. Furthermore, the density of the extracellular matrix appears also to play a role in normal mammary tissue development and in tumor formation. Here we show that the density of the ECM directly influences the number and the organization of the acini. Briefly, MCF10A cells were incubated in increasing densities of a combination Matrigel®/Collagen I matrix. Following a week incubation, the moduli distant from and close to the acinus-like formations were measured by atomic force microscopy. Additionally, the number of acinus-like structures was determined. To investigate the acinus organization, expressions of E-cadherin and laminin were estimated by immunochemistry. Results indicate that the modulus of the ECM was increased near the acinus-like structures. Also, the number of acinus-like structures decreased with the increase in Matrigel®/ collagen I density (p&lt;0.05). Finally, based on the expression of the basement membrane protein laminin, the organization of the acinus-like structures presence was altered as the density of the ECM increased (p&lt;0.05). These observations highlight the role of ECM density in the dynamic remodeling of breast tissues. (This works is supported by grants from the Department of Defense Era of Hope research program (BC044778) and the National Science Foundation EFRI program (CBE0736007).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2473. doi:1538-7445.AM2012-2473
Abstract 249: The role of cholesterol in ultraviolet light B-induced apoptosis
Authors: George Kimberly S. , Elyassaki Walid , Wu Qiong , Wu Shiyong 
Published: August 2012

Abstract
Modification of major lipid raft components, such as cholesterol and ceramide, plays a role in regulation of programmed cell death under various stimuli. However, the relationship between cholesterol level modification and the activation of apoptotic signaling cascades upon ultraviolet B light has not been established. In this report, we demonstrate that upon UVB irradiation cholesterol levels in membrane rafts of skin cells increase, which leads to Fas aggregation in the rafts. Utilizing a continuous velocity floatation technique, we show that Fas accumulated in the lipid rafts of human melanoma M624 cells after UVB-irradiation. The subsequent events of DISC formation were also detected in the lipid raft fractions. Depletion of cholesterol by methyl-β-cyclodextrin reduces Fas aggregation, while overloading increases. Disruption of lipid rafts also prevents Daxx from dissociating from Fas in the lipid rafts, which is accompanied with a reduced apoptotic, but increased non-apoptotic death of UVB-irradiated human keratinocytes, HaCaT cells. Results indicate that cholesterol located in the plasma membrane of skin cells is required for lipid raft domain formation and activation of UVB-induced apoptosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 249. doi:1538-7445.AM2012-249
Abstract 2491: High-dose acetaminophen with N-acetylcysteine rescue enhances the efficacy of cisplatin chemotherapy
Authors: Nguyen Tam , Neuwelt Alexander J. , Wu Jeffrey , Foreman Nicholas K. , Neuwelt Edward A. , Rapkin Louis B. 
Published: August 2012

Abstract
Acetaminophen (AAP) has been shown to enhance cisplatin (CDDP) cytotoxicity in hepatoblastoma cell lines. Further, one published case report demonstrated clinical efficacy of administering acetaminophen in conjunction with cisplatin and followed 6 hours later with n-acetylcysteine (NAC) rescue. In this study, atypical rhabdoid tumor (ATRT) and germinoma cells were treated with CDDP and AAP with or without NAC rescue. We then evaluated the cells with western blots for cleaved PARP and caspase 3 to demonstrate effects on apoptosis. Further, MTS assays were performed to evaluate cell viability of treated cells. To evaluate the effects of the various treatments on oxidative stress, dihydroethidium (DHE) and 2′,7′-dichlorofluorescin (DCFH) assays were performed to test for superoxide and hydrogen peroxide levels, respectively. It was demonstrated that AAP enhances CDDP cell kill and apoptosis in germinoma and ATRT cell lines. Further, both AAP and CDDP, independently and together, cause increased oxidative stress as measured by DHE and DCFE, but this oxidative stress is only reversed by NAC in the DCFE assay. This makes sense because NAC, a glutathione precursor, detoxifies peroxide but not superoxide. Further, our group has learned of five previously unpublished patients with recurrent liver tumors (hepatocellular carcinoma and hepatoblastoma) treated with AAP and CDDP with delayed NAC rescue. All patients tolerated the treatment well. Two of the five patients responded to the treatment, suggesting the potential of this approach.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2491. doi:1538-7445.AM2012-2491
Abstract 2496: Characterization of genes critical for chondro-osseous differentiation, metastasis and osteotropism in Ewing Tumors
Authors: Hauer Kristina , Burdach Stefan , Richter Günther H. 
Published: August 2012

Abstract
Ewing Tumors (ET) are highly malignant, mainly localized in bone tissue and are molecularly defined by ews/ets translocations. Metastatic spread in ET is frequent and hematogenous. Microarray analysis revealed BRICHOS domain containing proteins important for chondrogenic differentiation and canonical Wnt antagonist Dickkopf, Xenopus, Homolog of, (DKK) 2 critical for terminal bone development, to be over-expressed in ET. However, none of them seemed directly induced via EWS-FLI1 transcription factor activity. RNA interference of DKK2 expression in ET suppressed in vitro proliferation and decreased the ability for colony formation as well as invasive growth of ET cells, while BRICHOS proteins seemed essential for the maintenance of a precursor state of chondrogenic differentiation. Similarly, local tumor growth and metastasis of ET after DKK2 knock down was significantly decreased in Rag2-/-αC-/- mice. In an orthotopic tumor growth model DKK2 knock down in ET cells resulted in a strongly decreased capacity for invasive growth into bone tissue while RNA interference of BRICHOS proteins surprisingly increased their invasiveness when compared to controls. Microarray analysis after DKK2 knock down and subsequent validation with real-time RT-PCR revealed DKK2-mediated induction of CD44, ICAM1, Matrix Metalloproteinase (MMP) 1, and endochondral bone development important Parathyroid Hormone-like Hormone (PTHRP) in ET. Furthermore, subsequent functional assays demonstrated that invasiveness of ET cells was Matrix Metalloproteinase (MMP) 1 mediated, while knock down of one BRICHOS protein resulted in an increased MMP9 expression, indicating the critical involvement of matrix metalloproteases for the invasive ET growth behavior. Thus, DKK2 and BRICHOS domain containing proteins orchestrate and promote bone invasiveness and metastatic spread of this tumor, and provide significant conceptual progress in understanding both the pathogenesis of invasive bone growth of ET in particular and osteotropism in general.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2496. doi:1538-7445.AM2012-2496
Abstract 2497: ET-743 interferes with EWS-FLI1 driven WRN expression in Ewing sarcoma cells and sensitizes to topoisomerase I inhibitors
Authors: Segars Laura E. , Mendoza Arnulfo , Helman Lee J. , Grohar Patrick J. 
Published: August 2012

Abstract
The hallmark of Ewing sarcoma is the EWS-FLI1 transcription factor believed to be responsible for oncogenesis and tumor progression. ET-743 (Trabectedin, Yondelis™) is a natural product recently identified as a particularly active agent for Ewing sarcoma cells in vitro. We have recently demonstrated that ET-743 interferes with the activity of the oncogenic transcription factor EWS-FLI1. In this report, we examine the link between EWS-FLI1 suppression and the DNA damage response. We hypothesize that blocking the EWS-FLI1 associated DNA damage response may confer additional sensitivity to specific cytotoxic agents. DNA repair pathways and EWS-FLI1 targets were evaluated by microarray expression, western blot analysis and siRNA interference. Microarray expression and western blot analysis revealed that ET-743 suppresses WRN and XRCC4 expression, critical proteins in the Non-Homologous End Joining Pathway (NHEJ) repair pathway. Further siRNA data showed that the EWS-FLI1 transcription factor drives the expression of WRN. These results suggest that WRN suppression by ET-743 is occurring through an EWS-FLI1 dependent mechanism. Since the NHEJ pathway is associated with resistance to specific chemotherapeutic agents, several combination therapies were investigated in vitro. ESFT cells show heightened sensitivity to the combination of ET-743 and the topoisomerase I inhibitor, SN-38. This result was unique to topoisomerase I inhibitors and further restricted to ESFT cell lines. Consistent with these results, previous reports have established that WRN deficient cells are hypersensitive to topoisomerase I but not topoisomerase II inhibitors. Additionally, we found that irinotecan augments the ET-743 mediated transcriptional inhibition of EWS-FLI1. Taken together these mechanisms account for the heightened sensitivity of the combination of ET-743 and irinotecan observed both in vitro and in vivo in two different ESFT xenograft models. In summary, by employing a mechanism based approach, we have identified a novel combination therapy of ET-743 and irinotecan. By linking the EWS-FLI1 transcriptional program to the DNA damage response in ESFT cells, we expose an inherent weakness to topoisomerase I inhibitors thus creating a cell type specific sensitivity to the drug. This report provides a novel method of oncogenic transcription factor targeting that involves direct suppression of downstream targets and exploitation of the resulting changes in gene expression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2497. doi:1538-7445.AM2012-2497
Abstract 2500: The pivotal role of p53 in doxorubicin-induced acute versus chronic cardiotoxicity
Authors: Zhu Wuqiang , Reuter Sean , Zhang Wenjun , Wagner Gregory R. , Payne Ronald M. , Caldwell Randall L. , Shou Weinian , Field Loren J. 
Published: August 2012

Abstract
Introduction: Doxorubicin (DOX) is an effective anticancer chemotherapeutic which also induces acute and chronic cardiotoxicities. Inhibition of p53 activity is cardioprotective against acute cardiotoxicity in adult mice receiving high doses of DOX. However, functional p53 also reduces DOX-induced mitochondrial DNA oxidation. To explain these paradoxical results, we examined the role of p53 in DOX-induced acute and chronic cardiotoxicity with a clinically relevant juvenile mouse model. Methods: Two week old MHC-CB7 mice (which express dominant-interfering p53 in cardiomyocytes, CMs) and their non-transgenic (NON-TXG) littermates were given weekly DOX injections for 5 weeks (25 mg/kg total dose). Animals were studied 1 week (acute stage) or 13 weeks (late stage) after the last DOX injection. Cardiac function was measured with echocardiography. CM apoptosis was quantified using anti-active caspase-3 staining. The level of p53, Akt (an anti-apoptotic protein), and ataxia telangiectasia mutated (ATM, a marker for DNA-damage response) was measured by western blot using whole cell and mitochondrial fractions. Results: During acute stage, left ventricular (LV) systolic function was preserved (Fractional Shortening, FS, 58 ± 2.0% vs. 45 ± 1.3%, p&lt;0.008) and CM apoptosis was reduced (0.003 ± 0.002/mm2 vs. 0.011 ± 0.002/mm2, p&lt;0.008) in MHC-CB7 mice vs. NON-TXG mice. DOX increased mitochondrial p53 and decreased phosphorylated Akt in NON-TXG mice, and increased phosphorylated ATM in MHC-CB7 mice. During late stage, LV systolic function in MHC-CB7 mice markedly deteriorated, reaching values similar to those in NON-TXG mice (FS = 52 ± 2.5% vs. 50 ± 2.0%, p&gt;0.05). CM apoptosis was elevated in MHC-CB7 mice as compared to NON-TXG mice (0.076 ± 0.007 mm2 vs. 0.042 ± 0.008 mm2, p&lt;0.008). Phosphorylated Akt and ATM were normalized during late stage. Conclusions: Although inhibition of p53 activity protects against DOX-induced CM apoptosis and preserves cardiac function during acute stage, it exacerbates CM apoptosis and cardiac dysfunction during late stage. Ongoing experiments will determine the correlation between mitochondrial DNA damage during acute stage and CM apoptosis during late stage in DOX-treated MHC-CB7 mice. Acknowledgement: This work was supported by a grant (HL85098) from National Institutes of Health (to L.J.F.). Wuqiang Zhu was supported by a postdoctoral fellowship (121101) from American Cancer Society.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2500. doi:1538-7445.AM2012-2500
Abstract 2521: Targeting CD44 in head and neck squamous cell carcinoma (HNSCC) with a new humanized antibody RO5429083
Authors: Perez Aymee , Neskey David M. , Wen Judy , Goodwin Jarrard W. , Slingerland Joyce , Pereira Lutecia , Weigand Stefan , Franzmann Elizabeth J. 
Published: August 2012

Abstract
Introduction: HNSCC is a debilitating and deadly disease for which current treatments are extremely toxic and ineffective. Increasing data suggest that persistent cancer stem cells (CSC), resistant to standard chemo and radiation therapy, give rise to disease recurrence. Thus, poor outcomes may reflect ineffective CSC killing. CD44 is a promising therapeutic target that has two defined roles in tumorigenesis: it is a putative cancer initiating cell or CSC marker and it promotes migration and proliferation through interaction with EGFR, Rho and Ras signaling. Therefore therapies that target CD44 may destroy the CSC population, which is resistant to therapy while precisely eradicating the proliferating population of cancer cells. Methods: RO5429083 is a novel functional monoclonal antibody, developed by Roche, that targets a glycosylated, conformation dependent epitope of CD44. To evaluate CD44 as a therapeutic target in vivo, we established CAL 27 (HNSCC cell line) xenografts in nude mice and treated them with RO5429083 (Roche) in comparison to cisplatin (DPP), a conventional drug used in HNSCC treatment. After treatment, the mice were sacrificed, and the tumors were embedded in paraffin for IHC analysis. We also analyzed the effect of RO5429083 in vitro on peripheral blood lymphocytes (PBMCs). Results: RO5429083 treatment displayed a remarkable tumor growth inhibition in CAL 27 xenografts compared to DPP or control (P&lt;0.005). Moreover, treatment with this new humanized antibody inhibited constitutive EGFR phosphorylation on CAL 27 xenografts. In addition, treatment of PBMCs from healthy donors with RO5429083 produced an expansion of cytolytic natural killer (NK) cells. Conclusion: Based on our studies the anti-CD44 antibody RO5429083 effectively inhibits tumor growth in the CAL 27 model of HNSCC. In addition to decreasing EGFR signaling, RO5429083 appears to have a protective effect on PBMCs and expands the NK cell population. In conclusion, we anticipate that anti-CD44 therapy will effectively target the stem cell population while boosting the number of NK cells, and thus may synergize with drugs that work via antibody-dependent cell-mediated cytotoxicity (ADCC) such as Cetuximab.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2521. doi:1538-7445.AM2012-2521
Abstract 253: The cancer testis antigen MAGED2 protects human melanoma cells from TRAIL-induced apoptosis by suppressing TRAIL-R2 expression
Authors: Tseng Hsin-Yi , Chen Li Hua , Ye Yan , Jiang Chen Chen , Hersey Peter , Zhang Xu Dong 
Published: August 2012

Abstract
Melanoma-associated antigen D2 (MAGED2), a member of the MAGE-II cancer testis antigen family, is expressed by almost all normal tissues and many different cancer tissues. Although it has been reported that MAGE proteins have a pro-survival role in cancer cells such as malignant mast cells, the potential biological significance of MAGE proteins in melanoma remains to be established. Here, we show that MAGED2 is involved in the protection of melanoma cells against apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL) through suppressing the expression of TRAIL-R2, the major TRAIL death receptor that mediates TRAIL-induced apoptosis in melanoma. siRNA knockdown of MAGED2 sensitised melanoma cells to apoptosis induced by TRAIL. This was associated with enhanced activation of the caspase cascade and formation of the TRAIL death-inducing signalling complex (DISC), suggesting that MAGED2 acts at or above the DISC to protect melanoma cells against TRAIL-induced apoptosis. Indeed, inhibition of MAGED2 by siRNA resulted in up-regulation of TRAIL-R2 on the melanoma cell surface, which appeared to be specific, because knockdown of MAGED2 did not impinge on the expression of other TNF receptor family members, nor did it up-regulate TRAIL-R2 in melanocytes. Up-regulation of TRAIL-R2 by inhibition of MAGED2 was mediated by a p53-responsive transcriptional increase, in that p53 was also up-regulated in melanoma cells with MAGED2 knocked down, and that knockdown of MAGED2 did not up-regulate TRAIL-R2 in melanoma cells deficient in p53. In summary, our results identify MAGED2 as an important mechanism that suppresses TRAIL-R2 expression, thus protecting melanoma cells from TRAIL-induced apoptosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 253. doi:1538-7445.AM2012-253