bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1511: mda-7/IL-24 potently induces apoptosis in human leukemia cells through a process involving induction of ER stress
Authors: Rahmani Mohamed , Mayo Mandy , Dash Rupesh , Dent Paul , Fisher Paul B. , Grant Steven 
Published: February 2011

Abstract
mda-7/IL-24, a member of the IL-10 cytokine gene family, has been shown to induce cell death in various epithelial cancer cell types while exhibiting relatively little toxicity toward normal cells. Currently, the effects of mda7/IL-24 on myeloid leukemia cells (AML) have not been extensively characterized. In the present study, we report that treatment with recombinant GST-mda7/IL24 strikingly induces apoptosis in diverse myeloid leukemia cell lines including U937, MV4-11, EOL-1 (both FLT3 mutant), and MLL/ENL cells, which display certain leukemia stem cell-like properties. In addition, mda7/IL24 potently induces apoptosis in and suppresses the colony formation capacity (L-CFU) of primary blasts isolated from multiple patients with AML. In contrast, mda-7/IL-24 exerted only minimal effects on normal CD34+ progenitor cells. These effects were associated with profound mitochondrial injury manifested by cytochrome c and AIF release into the cytosol, caspase-3 activation, and PARP cleavage. The apoptotic effects of mda7/IL24 were associated with a potent induction of ER stress in leukemia cell lines as well as in primary AML blasts, manifested by accumulation of GADD153/CHOP, GADD34, GRP78, and IRE1α. Notably molecular studies with shRNA directed against IRE1α revealed that knockdown of IRE1α significantly enhanced mda7/IL24-mediated apoptosis in U937 cells, suggesting that induction of IRE1α plays a protective role against mda7/IL24 lethality. In addition treatment with mda7/IL24 resulted in down-regulation of the anti-apoptotic protein Mcl-1, and marked accumulation of the pro-apoptotic proteins Bim and Noxa. Notably, ectopic expression of Mcl-1 or knock-down of Bim or Noxa with shRNA markedly decreased mda7/IL24-mediated cell death in leukemia cells. Collectively, these findings indicate that mda7/IL24 strikingly induces apoptosis in human myeloid leukemia through a process that involves ER stress induction, Mcl-1 downregulation, and Bim and Noxa upregulation. They also suggest that mda7/IL24 warrants attention as a potential addition to the therapeutic armamentarium in leukemia and possibly other hematologic malignancies.
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 1511.
Abstract 1512: The linamarase/linamarin/glucose oxidase cocktail cures human gliomas in rats
Authors: Izquierdo Marta L. , Gil Jon , Girald Willie 
Published: February 2011

Abstract
Glioblastoma multiforme (GBM) is one of the dedliest forms of cancer, with an average survival time of approximately one year despite aggressive surgery, radiotherapy and chemotherapy. We will report a therapeutic procedure with potential clinical utility, by which the two main energy pathways of the tumor cells, oxidative phosphorylation and aerobic glycolysis, are simultaneously disrupted. First, the neoplastic cells must receive the plant linamarase gene (LI), which mediates the transformation of linamarin (LIN) into cyanide, glucose and acetone. Shortly after, we administer a systemic treatment with both linamarin and glucose oxidase (GOD) for 7 days. This creates a synergistic effect by which the neoplasm collapses in a few days. Autophagy is the cellular death mechanism involved in the eradication of the tumor. One hundred percent of the tumors disappear and neither relapse nor side effects are manifested. This therapeutic procedure also destroys the highly metastatic stem cell population from the human glioblastoma implants, thus preventing recurrence of the disease. This simple treatment is the first that can cure in a few days human brain tumors xenotransplanted into the brain of nude rats.
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 1512.
Abstract 1519: Tyrosine kinase inhibitors are potent reversal agents for MRP7 (ABCC10)-mediated multidrug resistance
Authors: Sodani Kamlesh , Kuang Ye-Hong , Shen Tong , Vispute Saurabh , Tiwari Amit K. , Lei Yu , Lee Jeferson , Chen Xiang , Ashby Charles R. , Chen Zhe-Sheng 
Published: February 2011

Abstract
ATP binding cassette (ABC) transporters play a crucial role in the development of multidrug resistance (MDR) leading to failure of the cancer chemotherapy. Previously, we and others have reported that lapatinib, erlotinib (EGFR tyrosine kinase inhibitors/TKIs) and nilotinb, imatinib (BCR-Abl TKIs) reverse ABCB1- and ABCG2-mediated MDR. MRP7/ABCC10, a member of MRP family, shares a structural homology with other ABC transporters such as P-gp/ABCB1. MRP7 is involved in effluxing several anticancer drugs resulting in poor chemotherapeutic outcome. In an effort to reverse MRP7-mediated MDR, we discovered that EGFR TKIs lapatinib, erlotinib, and BCR-Abl TKIs imatinib, nilotinib enhances the sensitivity of MRP7-transfected HEK293 (HEK-MRP7-2) cells to the established MRP7 substrates, such as paclitaxel, docetaxel, vincristine and vinorelbine in concentration-dependent manner. However, there was no significant effect of these TKIs on the sensitivity of control HEK293-pcDNA3.1 cells. In addition, these TKIs increased the intracellular accumulation of [3H]paclitaxel, inhibiting MRP7-mediated [3H]paclitaxel efflux from HEK-MRP7-2 cells. Moreover, Western blot analysis showed no significant change in the MRP7 expression level in the MRP7 overexpressing cell line on treatment with aforementioned TKIs. We conclude that both EGFR TKIs (lapatinib, erlotinib) and BCR-Abl TKIs (imatinib, nilotinib) reverse MRP7-mediated MDR through inhibition of the drug efflux function of MRP7, suggesting that TKI based combinational chemotherapy may be useful in cancer clinical practice.
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 1519.
Abstract 152: Methylated-DNA enrichment and PCR array technology: A qPCR-based method to rapidly screen for changes in promoter DNA methylation patterns
Authors: Shaffer Jonathan M. , Gu Xiujing , Boon Kathy 
Published: February 2011

Abstract
As the only known enzymatic modification of DNA in mammals, methylation of cytosines at CpG dinucleotides is recognized as a “third pathway” in Knudson's two-hit hypothesis for cancer which suggests that at least two DNA insults (hits) are required for cancer progression. This epigenetic event alters gene expression patterns associated with normal development and disease progression without changing the actual DNA sequence. In cancer, hypermethylation of tumor suppressor gene promoters abolishes their transcription, while hypomethylation of proto-oncogene promoters increases their transcription, effectively driving tumorigenesis in either case. Given the importance of this event for tumorgenesis, various techniques have been developed to identify DNA methylation based diagnostic biomarkers. Unfortunately, these methods often fall short in terms of throughput capacity, cost, or equipment requirements.
This work presents a novel combination of technologies to efficiently screen for changes in DNA methylation patterns within a panel of genes simultaneously. Using lung cancer as an experimental model, this study establishes that methylated DNA enrichment combined with real-time PCR (qPCR) technology offers great potential to identify putative biomarkers. This one-day assay is quite simple, and with very little hands-on time it can be easily adapted for high-throughput screening. A genomic DNA sample of interest is sheared, denatured, and incubated with a highly specific anti-5-methylcytosine antibody immobilized to a resin. The methylated DNA is then released, purified over a column, and applied to a pathway-focused qPCR array. The sensitivity of the method is very high; even one methylated CpG dinucleotide is enough to selectively enrich for a methylated target of interest, and the assay detection limit is well below 2.5% of a target in a mixed genomic DNA background. Importantly, data derived from this method has been validated with data derived from the Illumina® Infinium® Methylation Assay platform, further attesting to the potential for discovering methylation biomarkers with this system.
In conclusion, the combination of methylated-DNA enrichment and qPCR array technology has been extensively optimized to discriminate methylated-CpG dinucleotides with low background. With this method, researchers will be able to quickly determine whether changes in gene expression (upregulation or downregulation) are associated with promoter methylation changes. This combination of methylated-DNA enrichment with qPCR array technology offers great potential as a methylated CpG dinucleotide screening tool, without the high cost.
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 152.
Abstract 1525: RLIP76 transports sunitinib and sorafenib and mediates drug resistance in kidney cancer
Authors: Singhal Sharad S. , Sehrawat Archana , Sahu Mukesh , Singhal Preeti , Vatsyayan Rit , Lelsani Poorna C R , Yadav Sushma , Awasthi Sanjay 
Published: February 2011

Abstract
RLIP76 is a stress-responsive membrane protein implicated in the regulation of multiple cellular signaling pathways. It functions as the predominant glutathione-electrophile conjugate (GS-E) transporter in cells. We have shown that RLIP76 plays a crucial role in defending cancer cells from radiation and chemotherapeutic toxin-mediated apoptosis, and its inhibition by antibodies or depletion by siRNA or antisense causes apoptosis in a number of cancer cell types. Recently, we have demonstrated for the first time the striking anti-neoplastic effects with no evident toxicity in terms of either weight loss or metabolic effects for the antibody, antisense and siRNA in a renal cell xenografts model of Caki-2 cells (Singhal et al., Cancer Res., 2009, 69: 4244). Present studies were performed to determine if RLIP76 targeting is more broadly applicable in other kidney cancer cell lines, to compare the signaling effects of RLIP76 antisense with kinase inhibitors used in treatment of renal cell carcinoma, and to determine whether kinase inhibitors were substrates for transport by RLIP76. Results of these studies show that sorafenib as well as sunitinib are substrates for transport by RLIP76 thus are competitive inhibitors of GS-E transport. Furthermore, kinase inhibition in the ERK as well as PI3K pathways by RLIP76 depletion is more profound and consistent and is more widely apparent in a number of renal carcinoma cell lines. These studies support the validity of RLIP76 as a target in kidney cancer therapy, and the functional model in which RLIP76 provides protection from chemical and radiant stress through its transport activity. Results of these studies revealed for the first time that sorafenib as well as sunitinib, receptor tyrosine kinase inhibitors (RTKIs), are substrates for transport by RLIP76. These studies offer strong support for our overall hypothesis that RLIP76 is an overarching anti-apoptosis mechanism that, if inhibited, can be more broadly effective in the treatment of renal cell carcinoma. (Supported in part by NIH Grants CA 77495 and CA 104661 (to SA), Cancer Research Foundation of North Texas (to SSS & SY), Institute for Cancer Research and the Joe & Jessie Crump Fund for Medical Education (to SSS))
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 1525.
Abstract 1526: Epithelial mesenchymal transition (EMT) is associated with non-transporter resistance to taxanes in human ovarian cancer cell
Authors: Wang Cindy Y. , Duran George E. , Francisco E. Brian , Juric Dejan , Witten Daniela , Tibshrani Rob , Sikic Branimir I. 
Published: February 2011

Abstract
Taxanes are important drugs in the treatment of ovarian cancers, but their efficacy is limited by intrinsic and acquired drug resistance. Over-expression of the MDR1 gene and its product, P-glycoprotein, is a well-characterized resistance mechanism to taxanes, but non-MDR1 taxane resistance mechanisms are not well elucidated. To study the mechanisms of non-MDR1 multidrug resistance related to taxanes, we established multiple MDR1-negative and MDR1-positive taxane resistant variants from four ovarian cancer cell lines (A2780/1A9, ES-2, MES-OV and OVCAR-3) by continuous exposure of the cells to either paclitaxel or docetaxel with or without the P-glycoprotein inhibitor PSC-833 (Valspodar). We profiled gene expression and gene copy number alterations in these cell lines using cDNA microarrays, and identified a transcriptomic signature that predicts in vitro non-MDR1 resistance, a portion of which was imprinted by gene dosage changes. Functional network analyses for genes associated with the taxane resistance signature revealed two highly significant networks built around FN1 and CDKN1A which are associated with cell adhesion, cell-to-cell signaling and cell cycle regulation. We also identified epithelial-mesenchymal transition (EMT) marker genes which are significantly associated with non-MDR1 resistance. Migration potential in wound-scratch-assay was markedly enhanced in non-MDR1 resistant variants compared to parental cells. Our results suggest that ECM-interacting genes, EMT-like changes and cell cycle regulatory elements may play important roles in resistance to taxanes.
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 1526.
Abstract 153: DNA methylation alters DNA and chromatin structure leading to genetic instability in mammals
Authors: Wang Guliang , Vásquez Karen M. 
Published: February 2011

Abstract
Chromosomal breakpoints and translocation hotspots in human cancers are often found near sites of aberrant DNA methylation. DNA hypomethylation can lead to illegitimate recombination events and can stimulate V(D)J recombination in the immunoglobulin genes. However, this co-localization of chromosomal breakage cannot be explained by previously proposed mechanisms of CpG hypermethylation-induced genetic instability, e.g., deamination-induced point mutation, or epigenetic gene silencing, because these events should not lead directly to DNA double-strand breaks. In this study, we determined the effect of cytosine methylation on the stability of CpG-rich sequences in mammalian cells and on chromosomes in mice, without altering the global genome-wide DNA methylation status. We found that methylation of specific CpG repeats induced higher frequencies of deletions and rearrangements within and surrounding the methylated repeats than that found with unmethylated CpG repeats. In addition, we found that those mutations induced by the methylated CpG repeats had a broader size distribution than that found with unmethylated CpG repeats. In an effort to elucidate the mechanism of hypermethylation-induced genetic instability, we discovered that unusual structural features of the methylated CpG sequences precluded local nucleosome assembly, leading to an increase in mutations. Thus, we propose a novel process of DNA methylation-induced genetic instability in mammals in which methylation of CpG-rich sequences can alter both DNA and chromatin structures, leading to DNA double-strand breaks.
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 153.
Abstract 1534: Bioassay-guided identification of novel P-glycoprotein inhibitors from traditional Chinese medicines
Authors: Ravula Ranadheer , Wang Jeffrey , Huang Ying 
Published: February 2011

Abstract
Multi-drug resistance (MDR) is an obstacle for therapeutic success of anticancer agents. Overexpression of P-glycoprotein (P-gp), encoded by ABCB1 gene, plays a key role in conferring MDR via active efflux of anticancer drugs from cells. Previous efforts with several generations of P-gp inhibitors had not been successful in modulating clinical MDR. Recently, an increasing number of cancer patients are using complementary and alternative medicines, in particular, traditional Chinese medicines (TCMs), in combination with conventional anticancer agents. The purpose of this study is to examine the effects of TCM extracts on modulating P-gp function. We initiated our study from four single herbal products (Glycyrrhiza uralensis, Hibiscus syriacus, Tripterygium wilfordii, and Cephalotaxus sinensis) and one formula of herbal mixture (Si-Wu-Tang), using a bio-assay guided fractionation method. Crude extracts were firstly prepared with ethanol. The most active extracts identified were further extracted with hexane, chloroform, acetone and ethanol sequentially to obtain fractions of increasing polarity. The MDR modulating effects of the crude extracts and individual fractions were evaluated based on their capability to enhance daunorubicin (DNR) accumulation in P-gp over-expressing human leukemia cell line K562/DOX. The intracellular fluorescence intensity in the presence or absence of test drugs or known P-gp inhibitor cyclosporine A (10 µM) was measured by flow cytometer. The crude extracts were also tested for cytotoxicity against K562/DOX cells by the MTS cell proliferation assay. This study revealed that among the five TCMs, the crude extracts of Tripterygium wilfordii demonstrated a dose-dependent effect on increasing the DNR accumulation, indicating the presence of novel P-gp inhibitor(s). Upon further separation, the chloroform fractions of this herb showed the highest P-gp inhibitory activity. However, known compounds present in this herb, celastrol, triptolide and myristic acid did not show effects on DNR accumulation. Most of the plant extracts tested were able to inhibit the growth of K562/DOX cells with Cephalotaxus sinensis being the most effective, consistent with literature reports that this herb contains highly cytotoxic compound homoharringtonine and congeners. The potency of P-gp inhibition for the five TCMs was not correlated with their cytotoxicity. In conclusion, our results demonstrated that the chloroform fractions of Tripterygium wilfordii contain unknown components for P-gp inhibition. Our current efforts are focused on isolation and identification of active compounds from it.
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 1534.
Abstract 1537: Dual-specificity phosphatase-2 negatively controls chemoresistance in cancer cells
Authors: Shih-Chieh Lin , Shaw-Jenq Tsai 
Published: February 2011

Abstract
The limitation of clinical cancer therapy is due to a lot of mechanisms including influence of uptake, metabolism and export of drug from a single cell that contribute to drug resistance at the cellular level. In addition, tumor microenvironment also plays an important role in promoting drug resistance. For example, hypoxia has been reported to induce drug resistance by modulating expression of numerous genes. It has been shown that targeting individual hypoxia-regulated gene decreases drug resistance. However, it is an inefficient and infeasible way to target individual drug resistance-related genes one by one. Here we show that extracellular signal-regulated kinase 1/2 (ERK1/2), a survival pathway, is activated by hypoxia and blocking ERK1/2 pathway attenuates hypoxia-induced drug resistance. Furthermore, we also find that dual-specificity phosphatase-2 (DUSP2), a nuclear phosphatase that controls activity of ERK1/2, is inhibited by hypoxia through transcriptional repression. Inhibition of DUSP2 results in prolonged activation of ERK and increasing cell survival. Overexpression of DUSP2 causes cell apoptosis under normoxia and decreases hypoxia-induced drug resistance while stable knockdown DUSP2 increases drug resistance under normoxia. Moreover, re-expression of DUSP2 under hypoxia blocks tumor growth and enhances drug sensitivity in xenografted mice. Taken together, we identified an important role of DUSP2 involving hypoxia-mediated drug resistance and targeting DUSP2 might provide more specific and efficient way 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 1537.