bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3540: Down-regulation of solute carrier family 17 member 1(SLC17A1) expression contributes to chemotherapy resistance in acute myeloid leukemia
Authors: Lee Chansu , Park Juwon , Oh Jeong In , Kim Byung-Su , Kwon Jung Hye , Kim Byoung Kook , Ahn Kwang-Sung , Yoon Sung-Soo 
Published: February 2011

Abstract
Cytosine arabinoside (Ara-C), an structural analogue of deoxycytidine, is generally considered to be the major drug in the treatment of AML. In acute myeloblastic leukemia (AML) treatment, resistance to cytotoxic nucleoside analogues is a major problem. To investigate novel genes associating with becoming Ara-C resistant cells, whole genome SNP chip analysis was performed. However, there was no significant in Ara-C metabolite genes. In that analysis, 12 region of loss of heterozygote (LOH) was found in non-CR group. SLC17 family gene and HIST1H family gene located in major of LOH in non-CR group. Since SLC29A1 expression levels directly affected the Ara-C mediated Apoptosis, we selected SLC17A1 among them and functional analysis of SLC17A1 was performed. Its expression levels were examined in four different AML cell lines using RT-PCR. Its expression level was a little different but that gene seemed to be constitutively expressed. To detect the pattern change of SLC17A1 in survival AML cells against Ara-C treatments, four AML cell-lines underwent 10−8 M of Ara-C addition/ depletion for 2 and 4 cycles. The results showed that expression of SLC17A1 was decreased more than SLC29A1 expression in the same treated condition. To examine whether the expression levels of SLC17A1 was associated with Ara-C resistance, Ara-C resistant HEL cell was established in vitro and in vivo (HEL-R1 and HEL-R1-vivo). Our results indicated that SLC17A1 mRNA expression of both resistant cells is decreased or less increased than HEL cells in Ara-C treatment. And the reduction of SLC17A1 mRNA by shRNA of SLC17A1 effectively suppressed Ara-C mediated apoptosis. Our results suggested that the function of SLC17A1 gene was similar to that of SLC29A1. Taken together, the expression levels of SLC17A1 also might involve the cytotoxic effects of Ara-C treatment. SLC17A1 could be a novel gene controlling Ara-C mediated apoptosis.
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 3540.
Abstract 3547: The differences in intestinal absorptions between CZ48 and its parental Camptothecin
Authors: Liu Xing , DeJesus Albert , Cao Zhisong , Giovanella Beppino 
Published: February 2011

Abstract
The determination of oral bioavailability is a critical step in early phase drug development. In part, the ability to predict whether a drug will be effectively transported across the gastrointestinal mucosa can be estimated from the physicochemical properties of the compound. Currently, the Caco-2 human colon carcinoma cell line is often used by the pharmaceutical industry to evaluate intestinal absorption of drugs. The purpose of the present study was to investigate the membrane transport mechanism of CZ48, a hydrated C20-propionate ester of Camptothecin (CPT), in the Caco-2 cell culture model, in order to understand the possible role of membrane transporters on its oral bioavailability and disposition. Caco-2 cells were grown onto Millicell™ to form monolayers. Directional transport of CZ48 and CPT was determined. The results indicated that apical (AP) to basolateral (BL) transport of CZ48 and CPT was distinctively different from BL to AP transport, with AP to BL transport surpassing the BL to AP transport. The ratio of BL-AP/AP-BL transport rate was 0.36 and 3.0 for CZ48 and CPT at the concentration of 5µM, respectively. The results also showed that AP to BL permeability of CZ48 was ten times lower than CPT, but the accumulation of CZ48 in intact cells was higher than CPT (0.67 and 0.49 nmol, respectively). In conclusion, the p-glycoprotein may be involved in the transepithelial transport of CPT. An additional carrier mechanism may be involved in the AP uptake of CZ48, since Apical transport of CZ48 in the Caco-2 cells is mediated, at least in part, by uptake of a nucleic bases into cells via an nucleobase transporter.
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 3547.
Abstract 3673: Identifying the target of an orphan compound: CB30865 is a Nampt inhibitor
Authors: Fleischer Tracey C. , Flick Jeff S. , Terry-Lorenzo Ryan T. , Gao Zhong-Hua , Murphy Brett R. , Willardson J Adam , Boniface J Jay 
Published: February 2011

Abstract
Background: Drug discovery based on cellular phenotypes is impeded by the challenge of identifying the molecular target. To alleviate this problem, Myriad Pharmaceuticals has developed a chemical proteomics process to identify cellular proteins that bind to small molecules. CB30865 is a potent and selective cytotoxic compound of previously unknown mechanism of action (1). Using our technology, we have unequivocally demonstrated that CB30865 cytotoxicity is due to inhibition of nicotinamide phosphoribosyltransferase (Nampt). Nampt catalyzes the first step in the synthesis of NAD from nicotinamide. Cancer cells develop dependence on Nampt due to increased energy requirements and the elevated activity of NAD consuming enzymes such as sirtuins and mono and poly(ADP-ribose) polymerases.
Materials and Methods: Direct target affinity purification (DTAP) was performed using analogs of CB30865 (MPI-0479883, MPI-0482594) coupled to beads. Purified proteins were identified by nano-flow reversed-phase liquid chromatography and tandem mass spectrometry using an LTQ-Orbitrap. In vitro Nampt activity was measured in a coupled biochemical assay based on the production of fluorescent resorufin. Nampt cellular activity was assayed by measuring levels of NAD and NAD-dependent polyADP-ribosylation.
Results: As reported (1), 3-pyridyl, but not 2-pyridyl, analogs of CB30865 were potently cytotoxic. A 55 kD protein was purified efficiently using DTAP with MPI-0479883 (a 3-pyridyl CB30856 analog) but not MPI-0482594 (a 2-pyridyl analog). Preincubation of cellular lysates with uncoupled 3-pyridyl but not 2-pyridyl analogs potently blocked binding of the 55 kD protein. Based on LC-MS/MS analyses, the 55 kD protein was identified as Nampt. Immunoblotting of DTAPs using a Nampt specific antibody confirmed the MS identification. Furthermore, biochemical and cellular assays of Nampt activity demonstrated pyridyl-isomer specific enzyme inhibition. Finally, cellular Nampt inhibition and cytotoxicity were completely rescued by treating cells with 10 µM nicotinic acid as an alternate NAD source.
Conclusions: The chemical proteomics DTAP approach is a powerful tool to identify molecular targets of orphan compounds. We demonstrate this here through identification of Nampt as the molecular target of CB30865 and further implicate NAD metabolism as a functional target for cancer.
(1) Skelton LA, Ormerod MG, Titley J, Kimbell R, Brunton LA, Jackman AL. A novel class of lipophilic quinazoline-based folic acid analogues: cytotoxic agents with a folate-independent locus. Br J Cancer. 1999 Apr;79(11-12):1692-701.
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 3673.
Abstract 3700: Effect of gender on pharmacokinetic disposition of pegylated liposomal CKD-602 (S-CKD602) and optisomal topotecan (TLI) in rats
Authors: Song Gina , Wu Huali , La-Beck Ninh M. , Zamboni Beth A. , Srychor Sandra , Santory Melissa M. , Deither Steven R. , Zamboni William C. 
Published: February 2011

Abstract
Introduction: S-CKD602 is a pegylated liposomal formulation of CKD-602, a camptothecin analogue. Optisomal Topotecan (TLI) is a sphingomyelin stabilized liposomal formulation of topotecan. The cytotoxicity of CKD-602, topotecan and other camptothecin analogues is related to the duration of exposure. Pegylated and sphingomyelin liposomal formulations have been designed to prolong drug circulation time, increase tumor delivery, and improve the therapeutic index. The pharmacokinetics (PK) of liposomal agents is highly variable in patients. Moreover, the factors associated with this variability are unknown. Thus, we evaluated the plasma PK disposition of TLI and S-CKD602 in male and female rats.
Methods: TLI was administered at 0.93mg/kg IV x1 and S-CKD602 at 0.6 mg/kg IV x1 to male and female Sprague-Dawley rats via a bilateral jugular vein cannula. Plasma samples for TLI were obtained in 6 cohorts (n= 3 rats per cohort, total = 18 rats per gender): 1) pre, 1, and 3 min; 2) 5, 10, and 20 min; 3) 0.5, 1, and 2 h; 4) 4, 8, and 12 h; 5) 24, 36, and 48 h; 6) 60 and 72 h post dose. Plasma samples (n= 3 rats per time point per gender) for S-CKD602 were obtained prior to the end of the infusion, and at 4, 8, 24, 48, and 72 h after administration. Total (lactone and hydroxyl acid) form of sum total (encapsulated and released) CKD-602 and topotecan were measured via LC/MS. The clearance (CL) was estimated using noncompartmental PK analysis.
Results: For TLI, the CL in male and female rats were 0.026 ± 0.0038 and 0.021 ± 0.0015 L/h/kg, respectively. For S-CKD602, the CL in male and female rats were 0.0037 ± 0.0004 and 0.0027 ± 0.0001 L/h/kg, respectively. For TLI and S-CKD602, CL was 1.2-fold (p=0.14) and 1.4-fold (p=0.009) lower in female rats compared with male rats, respectively.
Conclusions: The CL of TLI and S-CKD602 was lower in female rats as compared with male rats. These studies suggest that gender may affect the disposition of liposomal formulations of drugs and may play a role in the high PK variability reported in patients treated with liposomal formulations of anticancer agents.
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 3700.
Abstract 3774: Congenital abnormalities and hepatoblastoma: A report from the Children's Oncology Group (COG)
Authors: Spector Logan G. , Puumala Susan E. , Tomlinson Gail E. , Georgieff Michael K. , Krailo Mark , Ross Julie A. 
Published: February 2011

Abstract
Hepatoblastoma (HB) is a rare pediatric tumor which comprises the majority of liver cancer in children. Previous research has established that Beckwith-Wiedemann Syndrome (BWS) and Familial Adenomatous Polyposis (FAP) predispose to HB, but information on its association with isolated congenital abnormalities is sparse. We examined data from a case-control study of HB conducted through the Children's Oncology Group (COG). Cases were diagnosed by COG institutions during 2000-2008 and controls were recruited from state birth registries, frequency matched for sex, region, year of birth, and low birth weight (a strong risk factor for HB). Data on congenital abnormalities among subjects and covariates were obtained by maternal telephone interview. There were 359 cases and 372 controls included in this analysis, which comprises approximately 90% of the final sample. Odds ratios (OR) and 95% confidence intervals (CI) describing the association between congenital abnormalities with HB, adjusted for birth weight and sex, were calculated using unconditional logistic regression. Twelve cases were reported to have BWS and 4 to have FAP, while no controls had either condition; further analyses excluded abnormalities among children with these syndromes to better examine isolated defects. There was a significant association of HB with kidney, bladder, or sex organ abnormalities (OR = 4.22; 95% CI: 1.57-11.29) which appeared to be specific to kidney/bladder defects (OR = 5.24; 95% CI: 1.40-19.59) but not those of sex organs (OR = 1.58; 95% CI: 0.45-5.55). Elevated but non-significant ORs were found for spina bifida or other spinal defects (OR = 2.39; 95% CI: 0.40-14.07), large or multiple birthmarks (OR = 1.63; 95% CI: 0.97-2.76). No significant associations of cleft lip or palate, Down syndrome or other numerical chromosomal anomalies, microcephaly, or rib abnormalities, although &lt;4 subjects were reported to have each of these defects, precluding precise estimation of ORs. These results confirm the previously noted associations of HB with BWS and FAP, and further suggest a novel association with kidney/bladder abnormalities. Supported by NIH CA111355, and the Children's Cancer Research Fund, Minneapolis, MN.
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 3774.
Abstract 3788: Critical role of adapter protein p66shc in phenethyl isothiocyanate-induced apoptosis in human prostate cancer cells
Authors: Xiao Dong , Singh Shivendra V. 
Published: February 2011

Abstract
Phenethyl isothiocyanate (PEITC), a cancer chemopreventive constituent of edible cruciferous vegetables such as watercress, suppresses growth of human prostate cancer cells by causing apoptosis but the mechanism of cell death induction is not fully understood. Here, we provide experimental evidence to implicate adapter protein p66shc in regulation of PEITC-induced apoptotic cell death. Mouse embryonic fibroblasts lacking p66shc isoform were resistant to PEITC-mediated growth inhibition, cytoplasmic histone-associated apoptotic DNA fragmentation, and caspase-3 activation compared with wild-type fibroblasts. The PEITC treatment resulted in induction as well as increased Ser36 phosphorylation of p66shc in PC-3 (an androgen-independent cell line lacking functional p53) and LNCaP (an androgen-responsive cell line with intact p53) human prostate cancer cells. Moreover, siRNA knockdown of p66shc protein in PC-3 and LNCaP cells conferred significant protection against PEITC-induced cytoplasmic histone-associated DNA fragmentation, caspase-3 activation, and production of reactive oxygen species. Immunoprecipitation-immunoblotting experiments revealed increased binding of p66shc with prolyl isomerase 1 (Pin1), which is implicated in translocation of p66shc to mitochondria, upon treatment of PC-3 and LNCaP cells with PEITC compared with vehicle-treated control cells. Consistent with these results, treatment of PC-3 cells with PEITC resulted in translocation of p66shc to the mitochondria as judged by immunoblotting using cytosolic and mitochondrial fractions and immunofluorescence microscopy. Growth of PC-3 cells subcutaneously implanted in male athymic mice was significantly retarded by gavage with 9 μmol PEITC five times per week. The PEITC-mediated inhibition of PC-3 xenograft growth correlated with reduced cell proliferation, increased apoptosis, hyperphosphorylation of p66shc, and down-regulation of Pin1 protein level. Collectively, these results provide novel insight into the mechanism of PEITC-induced apoptosis to indicate critical role of p66shc in regulation of cell death. This investigation was supported by the National Cancer Institute grant 2 RO1 CA101753-06.
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 3788.
Abstract 3792: Phenethyl isothiocyanate inhibits oxidative phosphorylation to initiate reactive oxygen species-mediated death of human prostate cancer cells
Authors: Powolny Anna A. , Xiao Dong , de Moura Michelle Barbi , Bommareddy Ajay , Hahm Eun-Ryeong , Houten Bennett Van , Singh Shivendra V. 
Published: February 2011

Abstract
Phenethyl isothiocyanate (PEITC), a constituent of cruciferous vegetables (e.g., watercress), not only affords significant protection against chemically-induced cancer in experimental animals but also inhibits growth of human cancer cells in association with induction of apoptosis and autophagy. However, the mechanism by which PEITC causes cell death is not fully understood. Using LNCaP and PC-3 human prostate cancer cells as a model, we now demonstrate that the PEITC-induced cell death is initiated by reactive oxygen species (ROS) production due to inhibition of oxidative phosphorylation. Exposure of prostate cancer cells to pharmacologic concentrations of PEITC resulted in ROS production, which was accompanied by inhibition of complex-III activity, suppression of oxidative phosphorylation, and ATP depletion. These effects were not observed in a normal human prostate epithelial cell line (PrEC). The Rho-0 variants of LNCaP and PC-3 cells lacking normal oxidative phosphorylation were significantly more resistant to PEITC-mediated ROS generation, apoptotic DNA fragmentation, caspase-3 activation, and collapse of mitochondrial membrane potential compared with respective wild-type cells. The PEITC treatment resulted in activation of Bax in wild-type LNCaP and PC-3 cells, but not in their respective Rho-0 variants. Furthermore, Bax and Bak knockdown conferred significant protection against PEITC-induced apoptosis. The Rho-0 variants of LNCaP and PC-3 cells also resisted autophagy induction by PEITC treatment. In conclusion, the present study provides concrete experimental evidence to implicate ROS in initiation of PEITC-induced apoptosis and autophagy in human prostate cancer cells. This investigation was supported by the National Cancer Institute grant 2 RO1 CA101753-06.
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 3792.
Abstract 3836: Regulation of class III PI3K by class I PI3K/Akt inhibits autophagy through phosphorylation of UVRAG
Authors: Shu Shaokun , Sun Mei , Kim Donghwa , Cheng Jin Q. 
Published: February 2011

Abstract
It has been well documented that the class I PI3K (PI3KC1)/Akt pathway inhibits whereas class III PI3K (PI3KC3) induces autophagy. UVRAG forms a complex with Beclin1 and PI3KC3 leading to activation of autophagy process. In this study, we demonstrate that PI3KC1/Akt inhibits PI3KC3 kinase activity and autophagy induced by different stimuli, including mTOR inhibitor rapamycin, suggesting PI3KC1/Akt regulation of autophagy independent of mTOR. Further, Akt directly phosphorylates UVRAG on serine-509, which results in disruption of UVRAG-Beclin1-PI3KC3 complex, and inhibition of PI3KC3 and autophagy. Inhibition of PI3KC1 or depletion of Akt increases the ability of UVRAG to bind to Beclin 1. UVRAG-S509A, which is not phosphorylated by Akt, enhances whereas UVRAG-S509D, which mimics the phosphorylation by Akt, reduces the interaction between UVRAG and Beclin1. Notably, UVRAG-S509A abrogates the effect of Akt on PI3KC3 and autophagy. These findings establish the cross-talk between class I and class III PI3K and indicate that PI3KC1/Akt regulates autophagy through inhibition of PI3KC3 by phosphorylation of UVRAG.
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 3836.
Abstract 388: Epithelial to mesenchymal transition is associated with acquired resistance to sunitinib in patients with renal cell carcinoma: evidence from a xenograft study
Authors: Hammers Hans J. , Verheul Henk , Salumbides Brenda , Sharma Rajni , Jaspers Janneke , Rudek Michelle , Netto George , Pili Roberto 
Published: February 2011

Abstract
Purpose: Tyrosine kinase inhibitors (TKIs) targeting angiogenesis via inhibition of the vascular endothelial growth factor (VEGF) pathway have changed the medical management of metastatic renal cell carcinoma. While the treatment with TKIs has demonstrated clinical benefit these drugs will eventually fail patients. The potential mechanisms of resistance to TKIs are poorly understood. Experimental Design: To address this question we obtained an excisional biopsy of a skin metastasis from a patient with clear cell renal carcinoma who initially had a response on sunitinib and eventually progressed on therapy. Tumor pieces were grafted subcutaneously in athymic nude mice. Established xenografts were treated with sunitinib. Tumor size, microvascular density and pericyte coverage were determined. Plasma as well as tissue levels for sunitinib were assessed. A tumor derived cell line was established and assessed in vitro for a potential direct antitumor effects of sunitinib. Results: To our surprise, xenografts from the patient who progressed on sunitinib regained sensitivity to the drug. At a dose of 40 mg/kg sunitinib caused regression of the subcutaneous tumors. Histology showed a marked reduction in microvascular density and pericyte dysfunction. More interestingly, histological examination of the original skin metastasis revealed evidence of epithelial-to-mesenchymal-transition while the xenografts showed reversion to the clear cell phenotype. In vitro studies showed no inhibitory effect on tumor cell growth at pharmacologically relevant concentrations. Conclusions: The histological examination in this xenograft study suggests that reversible epithelial-to mesenchymal-transition may be associated with acquired tumor resistance to TKIs in patients with clear cell renal carcinoma.
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 388.