bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pancratistatin Selectively Targets Cancer Cell Mitochondria and Reduces Growth of Human Colon Tumor Xenografts
Authors: Griffin Carly , Karnik Aditya , McNulty James , Pandey Siyaram 
Published: January 2011

Abstract
The naturally occurring Amaryllidaceae alkaloid pancratistatin exhibits potent apoptotic activity against a large panel of cancer cells lines and has an insignificant effect on noncancerous cell lines, although with an elusive cellular target. Many current chemotherapeutics induce apoptosis via genotoxic mechanisms and thus have low selectivity. The observed selectivity of pancratistatin for cancer cells promoted us to consider the hypothesis that this alkaloid targets cancer cell mitochondria rather than DNA or its replicative machinery. In this study, we report that pancratistatin decreased mitochondrial membrane potential and induced apoptotic nuclear morphology in p53-mutant (HT-29) and wild-type p53 (HCT116) colorectal carcinoma cell lines, but not in noncancerous colon fibroblast (CCD-18Co) cells. Interestingly, pancratistatin was found to be ineffective against mtDNA-depleted (ρ0) cancer cells. Moreover, pancratistatin induced cell death in a manner independent of Bax and caspase activation, and did not alter β-tubulin polymerization rate nor cause double-stranded DNA breaks. For the first time we report the efficacy of pancratistatin in vivo against human colorectal adenocarcinoma xenografts. Intratumor administration of pancratistatin (3 mg/kg) caused significant reduction in the growth of subcutaneous HT-29 tumors in Nu/Nu mice (n = 6), with no apparent toxicity to the liver or kidneys as indicated by histopathologic analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Altogether, this work suggests that pancratistatin may be a novel mitochondria-targeting compound that selectively induces apoptosis in cancer cells and significantly reduces tumor growth. Mol Cancer Ther; 10(1); 57–68. ©2011 AACR.
Effects of Patupilone on the Pharmacokinetics and Pharmacodynamics of Warfarin in Patients with Advanced Malignancies: A Phase I Clinical Trial
Authors: Tsimberidou Apostolia-Maria , Takimoto Chris H.M. , Moulder Stacy , Uehara Cynthia , Mita Monica , Mita Alain , Urban Patrick , Tan Eugene , Wang Yanfeng , Vining David , Kurzrock Razelle 
Published: January 2011

Abstract
Patupilone is a novel microtubule-targeting cytotoxic agent, which exerts its antitumor effect through microtubule stabilization. Pharmacokinetics, pharmacodynamics, and safety of warfarin when administered concomitantly with patupilone were investigated, and antitumor activity was assessed. This was a phase I, two-center, drug–drug interaction study. In the core phase of the study, treatment consisted of warfarin 20 mg orally (days 1 and 29) and patupilone 10 mg/m2 i.v. (days 8 and 29). Patients benefiting from patupilone treatment continued treatment every 3 weeks (extension phase) until progression of disease, death, or unacceptable toxicity. Seventeen patients were treated (core phase, 17; extension, 9). The geometric mean ratios (comedication/monotherapy) for Cmax and area under the curve0–168 of warfarin were near unity and their 90% confidence intervals were within the equivalence limits of 0.80 and 1.25. The half-life, plasma clearance, and International Normalized Ratio (INR) of warfarin were not affected by patupilone coadministration. The most common adverse events were diarrhea, nausea, vomiting, abdominal pain, anorexia, dehydration, asthenia, and peripheral neuropathy. Five (29.4%) patients experienced grade 3 study drug-related adverse events (diarrhea, 17.6%; increased INR, 11.8%; dehydration, 5.9%; and neutropenia, 5.9%). One patient with triple-negative breast cancer (estrogen receptor, progesterone receptor, and HER2/neu negative) had a partial response (35% decrease in tumor measurements by Response Evaluation Criteria in Solid Tumors), and 11 had stable disease for 6 weeks or more (≥12 weeks, 6 patients). The pharmacokinetics and pharmacodynamics of warfarin were not affected by patupilone coadministration, suggesting that patupilone has no clinically relevant effect on CYP2C9 metabolism. Patupilone showed antitumor activity in triple-negative breast cancer. Mol Cancer Ther; 10(1); 207–17. ©2011 AACR.
Abstract A101: Dose-related suppression of rat oral carcinogenesis by the EGF receptor-tyrosine kinase inhibitor, gefitinib
Authors: Horn Thomas L. , Johnson William D. , Lubet Ronald A. , Steele Vernon E. , McCormick David L. 
Published: January 2011

Abstract
Activation of the epidermal growth factor receptor (EGFR) stimulates signal transduction pathways that regulate cell proliferation and may be causally involved in carcinogenesis. Recent data suggest that EGFR expression is a predictive biomarker for the risk of oral cancer in humans, and that alterations in EGFR expression or action may be directly involved in oral carcinogenesis. Gefitinib (N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)-quinazolin-4-amine; ZD1839; Iressa) is a specific inhibitor of EGFR tyrosine kinase (EGFR-TK). The present study was performed to evaluate the activity of gefitinib as an inhibitor of oral cancer induction in rats. Squamous cell carcinomas of the tongue were induced in male F344 rats by drinking water administration of 4-nitroquinoline-1-oxide (NQO; 20 ppm for 10 weeks). After NQO administration was completed, rats were randomized into groups of 25 and received [a] unsupplemented basal diet only (dietary control); [b] basal diet + gefinitib (50 mg/kg diet); or [c] basal diet + gefinitib (100 mg/kg diet). All diets were fed continuously from week 10 until the end of the study at week 26. Dietary administration of gefinitib induced a dose-related inhibition of oral cancer induction (cancer incidences of 57% and 36% in low and high dose groups, respectively, versus 80% incidence in the dietary control group; p &lt; 0.01), and prevented the body weight loss that is commonly seen in this model in animals with advanced oral cancer. While reducing the incidence of invasive oral cancers, gefinitib increased the incidence of squamous epithelial hyperplasia (35% and 40% in low and high dose groups, respectively, versus 16% in dietary controls); the increased incidence of oral epithelial hyperplasia suggests that gefinitib prevented the progression of hyperplastic lesions into invasive oral cancers. Gefinitib induced no evidence of systemic toxicity in any treated animal. PCR analysis demonstrated comparable levels of EGFR transcripts in oral cancers and site-matched phenotypically normal oral tissues harvested from age-matched animals treated with NQO. Thus, the utility of EGFR-TK as a target for oral cancer chemoprevention in this model is not clearly associated with differential expression of EGFR in neoplastic oral tissues. These data demonstrate that EGFR inhibitors may be useful for the prevention of oral cancer, and that overexpression of EGFR in these cancers is not essential for chemopreventive efficacy. (Supported by N01-CN-85163 and N01-CN-25113 from the NCI.)
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A101.
Abstract A105: Androgen regulation of 5α-reductase isoenzymes in prostate cancer: Implications for prostate cancer prevention
Authors: Li Jin , Ding Zhiyong , Wang Zhengxin , Logothetis Christopher J. , Mills Gordon B. , Kim Jeri 
Published: January 2011

Abstract
Finasteride, a specific inhibitor of SRD5A2, one of three isoenzymes of 5α-reductase, reduced prostate cancer incidence by 25% in the Prostate Cancer Prevention Trial, but the molecular mechanisms of its effect remain undelineated. Androgen receptor (AR) signaling is important during prostate cancer pathogenesis and progression, and 5α-reductase converts testosterone to dihydrotestosterone (DHT). We investigated how androgen regulates expression of isoenzymes of 5α-reductase encoded by different genes—SRD5A1, SRD5A2, and SRD5A3—and in turn how finasteride may affect this regulation. By using different prostate cell lines, we found that androgen regulates the mRNA level of 5α-reductase isoenzymes in a cell type-specific manner. This regulation, we demonstrated, requires AR and occurs at the transcriptional level. Moreover, we found that finasteride affects androgen regulation of 5α-reductase expression in a cell type- and AR status-dependent manner. Finasteride counteracts testosterone-driven but not dihydrotestosterone-driven regulation of 5α-reductase expression in LAPC-4 cells, which express wild type AR. However, finasteride does not affect testosterone or dihydrotestosterone regulation of 5α-reductase expression in LNCaP cells, which express a mutant AR (T877A). Our findings suggest that dihydrotestosterone is the major regulator of 5α-reductase expression and that finasteride may produce additional antitumor effects through other mechanisms besides inhibiting 5α-reductase activity. The differential expression levels of 5α-reductase isoenzymes may be one of the factors conferring response or resistance to finasteride treatment and thus may prove significant in prostate cancer prevention.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A105.
Abstract A14: DNA alterations to the Cullin-3/Ring box protein-1 E3 ubiquitin ligase complex represent a novel mechanism of NF-κB activation in lung cancer
Authors: Pikor Larissa , Thu Kelsie L. , Lockwood William W. , Chari Raj , Wilson Ian M. , MacAulay Calum E. , English John C. , Tsao Ming- Sound , Gazdar Adi F. , Lam Stephen , Lam Wan L. 
Published: January 2011

Abstract
Background: Nuclear factor kappa B (NF-κB) signaling is essential for lung cancer development, and therefore, may serve as a target for intervention. However, the genetic mechanisms responsible for its activation are not fully understood. Kelch-like ECH-associated protein 1 (KEAP1) binds protein substrates to the Cullin-3 (CUL3)/Ring box protein-1 (RBX1) E3 ubiquitin ligase complex where ubiquitination signals substrates for proteosomal degradation. Recently, inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ), an activator of NF-κB, was shown to be a substrate of KEAP1, implicating KEAP1's involvement in regulating NF-κB signaling. Loss of function of KEAP1 leads to IKKβ accumulation and NF-κB activation. We hypothesized that DNA deletions of the other E3 complex components (CUL3 and RBX1) are frequent alterations that disrupt complex function and contribute to NF-κB activation in lung cancer.
Methods: We screened DNA copy number profiles of 261 non-small cell lung cancer (NSCLC) tumors for DNA alterations at the KEAP1, CUL3, RBX1, and IKK loci. Profiles were generated by array comparative genomic hybridization on the SMRT array (sub-megabase resolution tiling) platform. We also analyzed mRNA expression of these genes and 9 well annotated NF-κB target genes, using gene expression profiles generated with Agilent gene expression microarrays for a subset (n=48) of the tumors.
Results: Our investigation of genetic disruption to the E3 ubiquitin ligase complex components revealed 54% of tumors harbored DNA copy number loss of at least one complex component (KEAP1, CUL3, or RBX1) or gain of IKKβ. Moreover, at the expression level, 81% of tumors analyzed had aberrant expression of one of these genes (underexpression of complex components or overexpression of IKKβ). Interestingly, the copy number alterations identified appeared to segregate with adenocarcinoma (AC) or squamous cell carcinoma (SCC) histology; KEAP1 loss was more prevalent in AC while CUL3 loss and IKKβ gain were more frequent in SCC. When NF-κB target gene expression was analyzed, we observed higher expression of 5/9 genes in tumors with underexpression of an E3 ubiquitin ligase complex component relative to matched non-malignant tissue from the same individual.
Conclusions: The presence and strikingly high frequency of genetic disruption and aberrant expression of the E3 ubiquitin ligase complex components (KEAP1, CUL3, and RBX1) revealed in this study provides evidence of its importance in lung cancer. These data suggest that DNA level alterations to this complex may represent a novel mechanism of NF-κB activation in lung cancer.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A14.
Abstract A18: Silver nanoparticles induce apoptosis by regulation of cyclic AMP response element-binding protein in lung cancer cells
Authors: Park Hee Sun , Jang Sunhyae , Cha Hye Rim , Park Ji Won , Shin Ji Young , Kim Sun Young , Koo Ja Seok , Kim Ju Ock 
Published: January 2011

Abstract
Recently, much effort has been devoted to the development of biomedical applications for nanoparticles (NPs). Silver NPs have been shown various therapeutic effects such as antimicrobial, antioxidant, and anti-inflammatory effects. Recently silver NPs have been shown to induce the apoptotic pathway in vitro. But exact mechanism is not yet established. We conducted this study to determine the mechanisms of silver NPs on cellular apoptosis in non-small cell lung cancer (NSCLC) cell lines using cyclic AMP response element-binding protein (CREB) activity which has been implicated to contribute an important pathobiologic role in lung carcinogenesis and is considered a potential therapeutic target for NSCLC. We hypothesized that constitutively increased CREB and its related signaling pathways can be blocked by silver NPs. To determine cytotoxic effect of silver NPs, several NSCLC cell lines were treated with various concentrations for different times. Among these lung cancer cell lines, H520, human lung squamous carcinoma cell lines, was the most sensitive. FACS analysis also showed that silver NPs induced cell death of H520 cells. Treating H520 cells with silver NPs (100, 200, or 500 M) inhibited CREB activation by blocking the activity of extracellular signal kinase/ribosomal s6 kinase and also by blocking the activity of phosphatidylinositol 3-kinase/Akt. We subsequently confirmed the expression of Bax and Bcl-2 in H520 cells was substantially regulated by silver NPs. We also demonstrated that silver NPs induced the cleavage of apoptosis-related proteins, poly (ADP-ribose) polymerase and caspase-3. In this study, we suggest that silver NPs induce apoptosis in H520 cells by regulation of CREB signaling pathways and may be useful as a therapeutic strategy for cancer.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A18.
Abstract A20: Evidences that GPR43, a G-protein-coupled receptor for short chain fatty acids, suppresses colon cancer
Authors: Tang Yong , Chen Yakun , Jiang Hongmei , Robbins Gregory , Nie Daotai 
Published: January 2011

Abstract
GPR43 is a G protein-coupled receptor for short chain fatty acids (SCFAs). Expression of GPR43 is detected in hematopoietic tissues and the large intestine. SCFAs are derived from bacterial fermentation and metabolism of undigested dietary fibers and have been recognized for their cancer prevention activities in the colon. The role of SCFAs, particularly butyrate, in colon cancer therapy has been extensively studied, and its tumor suppressive functions are believed to be due to their intracellular actions, notably inhibition of histone deacetylase. In this study, we show that SCFAs also exert their anti-tumor effects via receptor GPR43 and that GPR43 is frequently lost in colon cancer cells. Immunohistostaining revealed that GPR43 immunoreactivity was high in normal colon tissues (N=31) but was markedly reduced or completely lost in most colorectal adenocarcinoma tissues (N=70) and their corresponding lymph node metastatic adenocarcinomas (N =38). RT-PCR analysis detected the presence of full length GPR43 mRNA in only one (HT-29) out of nine established human colon cancer cell lines. Restoration of GPR43 expression in HCT8 human colonic adenocarcinoma cells induced G0/G1 cell cycle arrest and activated caspases, leading to increased apoptotic cell death after propionate/butyrate treatment. Restored GPR43 expression, coupled with propionate treatment, induced an upregulation of p21 and a decrease in the levels of cyclin D3 and cyclin-dependent kinases (CDKs) 1 and 2, while the CDK4 and CDK6 levels remained unchanged. Our results suggest that GPR43 functions as a tumor suppressor by mediating SCFA-induced cell proliferation inhibition and apoptotic cell death in colon cancer.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A20.
Abstract A26: Impact of PARP1 on AR signaling and therapeutic response in prostate cancer
Authors: Schiewer Matthew J. , Goodwin Jonathan , Knudsen Karen A. 
Published: January 2011

Abstract
Poly (ADP-ribose) polymerase 1 (PARP1) modifies various nuclear proteins by poly (ADP-ribose)-ylation, and has a known role in a multitude of chromatin-associated functions, including: transcriptional coregulation, modification of chromatin structure, regulation of insulators, and well-established activities in DNA repair. With regard to nuclear receptors, PARP1 promotes recruitment of topoisomerase IIβ (TopoIIβ) to estrogen-regulated promoters, leading to promoter DNA cleavage, factor exchange, and transcriptional activation. However, PARP1 function is known to be context dependent. Here, the impact of PARP1 on AR signaling was assessed under conditions of prostate cancer relevance. As will be discussed, key preliminary data strongly suggest that PARP1 function is critical for the pro-tumorigenic functions of AR. First, pharmacological inhibition of PARP1 enzymatic activity potently suppressed ligand-dependent AR transcriptional activity on target genes of clinical relevance. As it is well established that AR is involved in all stages of disease, PARP inhibition could potentially serve to prevent progression. Second, the mechanism of PARP1-mediated AR regulation appears to be manifest at the level of chromatin, as inhibition of PARP1 failed to alter AR protein levels. This was assessed by chromatin immunoprecipitation assays to delineate the impact on AR signaling. Third, it was shown that suppression of PARP1 specifically inhibited AR-dependent prostate cancer cell proliferation in both early stage and late stage (castrate-resistant) models of disease. This observation could potentially lead to studies to determine if PARP inhibition can prevent the transition to castrate resistance, as there is some evidence that PARP inhibition can decrease relapse in models of mammary tumors. Lastly, it was observed that PARP1 inhibition cooperates with currently used genotoxic therapeutic modalities (IR and Docetaxel) in reducing cell survival, dependent on treatment scheduling. In sum, our data identify PARP1 as a critical effector of AR activity at the level of chromatin, and suggest that abrogation of PARP1 function may cooperate with existing therapeutics to improve the response to therapeutic intervention and may serve as a means to prevent disease progression.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A26.
Abstract A3: Urinary cadmium and mammographic density in premenopausal women
Authors: Adams Scott V. , Newcomb Polly A. , Shafer Martin M. , Atkinson Charlotte , Bowles Erin J. Aiello , Newton Katherine M. , Lampe Johanna W. 
Published: January 2011

Abstract
Background: Mammographic density (MD), a strong marker of breast cancer risk, is influenced by genetic, environmental, and hormonal factors. Cadmium, a persistent and widespread environmental pollutant, has been associated with risk of breast cancer, and laboratory evidence suggests cadmium is a carcinogen in the breast. Urinary cadmium concentration is a measure of exposure to cadmium over a prior 20-30 years.
Methods: In a cross-sectional study of MD and urinary cadmium concentration, percentage MD (MD%) and Breast Imaging-Reporting and Data Systems (BI-RADS) density category were determined from screening mammograms of 190 premenopausal women ages 40-45 years recruited from a breast cancer screening program at a large integrated healthcare system. Women completed a health questionnaire, and the cadmium content of spot urine samples was measured with inductively-coupled plasma mass spectrometry and corrected for urine creatinine. Multivariable linear regression and logistic regression were used to estimate the strength of association between urinary cadmium and mammographic breast density, adjusted for age, parity, smoking history, race, and body mass index.
Results: Adjusted mean MD% among women in the upper tertile of creatinine-corrected urine cadmium was 4.6% higher (95% confidence interval (CI): −2.3 to 11.6%) than in women in the lowest cadmium tertile. Each twofold increase in urine cadmium was associated with higher odds of MD% in the upper tertile (odds ratio (OR): 1.29, 95% CI: 0.82-2.02) or a BIRADS category rating of “extremely dense” (OR: 1.75, 95% CI: 1.14-2.70).
Conclusions: Exposure to cadmium may be associated with increased breast density in premenopausal women. These results support earlier findings that cadmium may increase risk of breast cancer.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A3.
Abstract A32: Identification and characterization of colon cancer-associated antigens
Authors: Broussard Elizabeth K. , Coveler Andrew , Slota Meredith , Jackson Emily , Bates Nicole , Higgins Doreen , Childs Jennifer , Yang Yi , Disis Mary L. 
Published: January 2011

Abstract
Colon cancer (CRC) is an immunogenic tumor and adaptive immunity may play a role in inhibiting disease relapse. A vaccine to boost cellular immunity in CRC patients could prevent disease recurrence, but there have been few defined immunogenic proteins identified as vaccine candidates. TVG has shown that overexpressed tumor associated proteins, abundant in the cancer state but expressed at basal levels in normal cells, can be immunogenic. We hypothesized that ideal candidate antigens would be ones already validated as prognostic markers in multivariate analysis. We performed a directed literature review using search words e.g. colon cancer, prognosis, biomarker, multivariate analysis. We selected a panel of eight proteins based on (1) incidence of expression, (2) independent predictor of poor prognosis, (3) independent predictor of early disease recurrence, and (4) known biologic function in CRC pathogenesis. Using a web based algorithm program developed by TVG, we identified peptides that were predicted to be high affinity binders across multiple HLA DR alleles; characteristics we have shown to be associated with native epitopes of self tumor antigens. We selected and synthesized 19 peptides predicted to be the highest binders. We evaluated the potential immunogenicity of peptides with 1. IFN-g ELISPOT assays using PBMC from CRC patients and normal controls and 2. specific IgG antibody response with ELISA using sera from CRC patients and normal controls. We quantitated antigen gene expression using qPCR in cell lines representing microsatellite unstable (MSI), chromosome unstable (CIN) and CpG island methylator phenotype (CIMP) colorectal cancer. The eight proteins are: CDC25B, COX-2, EBAG9, EGFR, Fascin-1, IGF-1R, PRL-3 and VCP. Two of the eight proteins had already been shown to be human tumor antigens. For all candidate antigens there was a greater IFN-g response in CRC patients than in controls; for three proteins, this difference reached statistical significance. Six proteins were positive by ELISA. Seven antigen genes were overexpressed relative to normal colon. We conclude that: 1. biologically relevant CRC associated proteins can be identified that are associated with prognosis, 2. epitopes predicted to bind multiple DR alleles, derived from candidate antigens, elicit T cell responses greater in CRC patients than in normal controls, 3. there was an overexpression of candidate genes across three different CRC phenotypes, and 4. these antigens may represent novel immunologic targets for CRC.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A32.