bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3669: Bisphosphonate use following first primary ER+ breast cancer and risk of second primary breast cancer
Authors: Monsees Genevieve M. , Newcomb Polly , Malone Kathi , Li Christopher
Published: June 2012

Background: Recent studies suggest that bisphosphonates, drugs commonly prescribed for the prevention and treatment of osteoporosis, may reduce risk of developing a first breast cancer. This is the first population-based assessment of the effect of bisphosphonate use on risk of developing a second breast cancer among breast cancer survivors.

Methods: Within a population-based nested case-control study of women diagnosed with a first primary ER+ invasive breast cancer (BC) at ages 40-79, we assessed the association between bisphosphonate use after first breast cancer diagnosis and risk of asynchronous primary in the contralateral breast (CBC). Conditional logistic regression was used to compare 359 CBC cases to 649 incidence density matched controls (women not diagnosed with CBC). Analyses of duration were restricted to women followed for similar time periods.

Results: Use of nitrogenous bisphosphonates for ≥12 months following first primary ER+ BC diagnosis was associated with a 56% decrease in CBC risk relative to no bisphosphonate use in this period (95% CI: 0.24-0.80, p-value: 0.008). Increasing duration of bisphosphonate use was associated with greater reductions in CBC risk (OR≥6months: 0.52, 95% CI: 0.31-0.89, p-value: 0.02; OR≥16months: 0.42, 95% CI: 0.21-0.83, p-value: 0.01; OR≥36months: 0.25, 95% CI: 0.07-0.84, p-value: 0.03). Use within 6 months also appeared protective (OR: 0.50, CI: 0.29-0.88, p-value: 0.02).

Conclusions: This study suggests that use of nitrogenous bisphosphonates, following diagnosis with ER+ BC, may reduce second primary CBC. Given bisphosphonate tolerability and other potential benefits in this high-risk population, bisphosphonate therapy may be a feasible approach for CBC risk reduction, and merits further investigation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3669. doi:10.1158/1538-7445.AM2011-3669
Abstract 3684: Saffron protects against liver cancer in animal model: Molecular and imaging insights
Authors: Amin Amr , Mahmoud-Ghoneim Doaa , Corr Peter , Hamza Alaaeldin , Daoud Sayel
Published: June 2012

Saffron is a natural product that is a promising chemo-preventive agent against different cancer. The aim of the present work was to investigate the chemo-protective effect of saffron ethanol extract on chemically-induced liver cancer in rats. Hepatocarcinogenesis was induced by a single intraperitoneal injection of diethyl nitrosamine (DEN) (200 mg/kg body weight) and 2 weeks later, the carcinogenic effect was promoted by 2-acetylaminofluorene (2-AAF) (0.05%). 42 Wister rats were divided into seven groups: negative control, positive control (DEN+2-AAF), saffron-alone group (saffron for 22 weeks, no DEN or 2-AAF) and 3 preventive groups (where saffron was administered at 300, 150 and 75 mg/kg for 2 weeks before and 20 weeks after inducing cancer). The incidence and multiplicity of liver tumors as well as the expression of cancer marker, glutathione S-transferase placental form, were significantly reduced in preventive groups. This hepatopreventive effect was confirmed by the decreasing in cancer marker, α feto protein in plasma. Immunohistochemical analyses showed a decrease in cell proliferation marker (Ki67) and an increase of TUNEL-and caspase 3-positive apoptotic cells along with strong expressions of p53 in liver of preventive groups. These protective effect found to be mediated by anti-inflammatory and antioxidant effects. The anti-inflammatory activity was confirmed by saffron-based inhibition of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression. The effect of saffron on the expression of nuclear factor nuclear factor-Kappa B (NF-kappa B) was also assessed. The expression of NF-kappa B in the preventive groups was significantly low compared to positive control. The in vitro antioxidant capacity of saffron (FRAP Assay, DPPH Scavenging activity and ABST+ Assay) was significantly high in ethanol-based extract. In addition, NF-kappa B transcription factor seems to regulate the saffron chemo-protective effects. Finally, texture analysis was applied to analyze in vivo MRI images and results were consistent with that of histopathology.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3684. doi:10.1158/1538-7445.AM2011-3684
Abstract 3703: Chemopreventive efficacy of vandetanib, a multikinase inhibitor, in a primary respiratory tract epithelial cell transformation assay
Authors: Sharma Sheela , Zou Minxu , Lee Jin , Steele Vernon E.
Published: June 2012

Targeted therapies by means of compounds that inhibit multiple target molecules represent a new perspective in the treatment and prevention of cancer. Vandetanib (Zactima™) is an orally active, selective inhibitor of VEGFR-2 (vascular endothelial growth factor receptor-2) receptor tyrosine kinase that also demonstrates activity against EGFR (epidermal growth factor receptor) and RET (rearranged during transfection) tyrosine kinases. As there are indications of Vandetanib being effective in advanced NSLC patients for disease free survival, we have tested Vandetanib for efficacy in a primary rat tracheal epithelial (RTE) cell transformation model, which was originally developed for identifying potential chemopreventive agents belonging to different chemical classes/biological activity. RTE cells were treated with B[a]P alone or with five nontoxic concentrations of Vandetanib and the resulting foci at the end of 30 days were scored for inhibition of transformation. In addition, the effect on mechanistic biomarkers at different stages of RTE cell transformation was tested. The results indicated that Vandetanib at half-log concentrations ranging from 0.003 – 0.3 μM, elicited an excellent dose-related inhibition of transformation (75-93%) compared to B[a]P group. There was also a 2-fold induction of apoptosis at 0.3 μM, and it inhibited survivin, a late stage biomarker, at all concentrations by 18-28%. Remarkably, a significant dose-dependent inhibition (39- 93%) of phosphorylated tyrosine kinase activity was also observed in Vandetanib-treated groups compared to B[a]P group. In conclusion, the data shows that there is a very good correlation between the inhibition of B[a]P-induced transformation and corresponding inhibition of activated tyrosine kinase and other biomarkers. Based on this data, animal studies are planned to develop this drug for lung cancer prevention by administering it directly to the lungs (Supported by NCI #N01-CN-43301).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3703. doi:10.1158/1538-7445.AM2011-3703
Abstract 3747: Leukocyte LINE1 and Alu DNA methylation and gastric cancer risk in the Shanghai Women's Health Study cohort
Authors: Gao Ying , Chow Wong-Ho
Published: June 2012

Aberrant DNA methylation is a well-recognized feature of malignant epithelial component in human carcinomas. Recent data also suggested a link between blood leukocyte DNA methylation and cancer risk. However, data on DNA methylation from a prospective study, which may provide evidence for causality, are unavailable. We explored the association between methylation levels in two repetitive elements, i.e. Alu and LINE-1, in blood leukocyte DNA and gastric cancer risk in a case-control study nested in the Shanghai Women's Health Study cohort. A total of 213 incident gastric cancer cases and 426 age- and menopause status- matched controls were included in the study. Using prediagnostic DNA extracted from blood leukocytes, methylation of LINE1 and Alu were evaluated using bisulfate-pyrosequencing. Odds ratios (OR) and 95% confidence intervals (CI) were calculated from logistic regression adjusting for potential confounders. Decreased Alu methylation was associated with increased gastric cancer risk at the lowest quartile (OR=1.85, 95%CI=1.10-3.11) compared to the highest quartile. We did not observe appreciable changes in the association with increasing interval between blood draw and cancer diagnosis or reference date for controls. Excluding the cases diagnosed within 1 year after study enrollment and their matched controls did not alter the results substantially. When stratified by potential effect modifiers, a significant interaction was observed with isoflavone intake (p=0.04), with a positive association between Alu methylation and gastric cancer risk restricted to individuals with high isoflavone intake. Associations with Alu were also strengthened among subjects with tea use and high intake of folate and fruit. Conversely, lower methylaiton levels of LINE1 were associated with slightly decreased, but not statistically significant, risk of gastric cancer. This prospective study suggests that DNA methylation of Alu in blood leukocytes may be inversely associated with risk of gastric cancer. The divergent associations with Alu and LINE1 raise the possibility that the role of DNA methylation in these two regions is different in gastric cancer etiology, and warrant further research.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3747. doi:10.1158/1538-7445.AM2011-3747
Abstract 3751: Expression analysis of the IL28A, IL28B, IL29 and IL28L genes in primary human peripheral blood mononuclear cells and hepatocytes: Effects of activation mode, time-course and genotypes
Authors: Muchmore Brian , Park Heiyoung , Dickensheets Harold , O'Brien Thomas , Rehermann Barbara , Donnelly Raymond , Prokunina-Olsson Ludmila
Published: June 2012

Expression analysis of the IL28A, IL28B, IL29 and IL28L genes in primary human peripheral blood mononuclear cells and hepatocytes: Effects of activation mode, time-course and genotypes.

Chronic hepatitis C virus (HCV) infection is the leading cause of liver cancer and liver transplantation in the United States. Recently, several genome-wide association studies (GWAS) identified genetic variants within the IL28A/B locus on chromosome 19q13.2 as the strongest predictors of outcome of HCV infection and response to treatment (e.g. rs12980275, p=2.84×10-27, OR=17.7; 95% CI=10.0-31.3, Tanaka, Nat. Gen. 2009). This region harbors the highly homologous IL29, IL28A, IL28B genes and a pseudogene IL28-like (IL28L), also known as interferon-lambda-1, interferon-lambda-2, interferon-lambda-3 and interferon-lambda-4-pseudo, respectively. We hypothesized that the associated genetic variants might affect mRNA expression of one or more of these genes.

We performed mRNA expression analysis of IL28A, IL28B, IL29 and IL28L in human peripheral blood mononuclear cells (PBMCs) and primary hepatocytes using highly specific custom-designed assays to overcome the up to 97% sequence homology between these genes. In PBMCs and hepatocytes, mRNA transcripts were not expressed under baseline conditions, but activation of these cells with IFN-alpha or IFN-lambda did moderately induce expression of some transcripts after 24 hours of activation. However, when IL28A, IL28B, IL29 and IL28L were activated with the immunostimulant poly I:C, a Toll-like receptor-3 agonist that mimics infection by RNA viruses, expression of all transcripts was strongly increased. Gene expression was measured at 0, 1, 2, 4, 8 and 24 hours and was compared to the 2-hour point, at which expression was first stably seen. We observed a suggestive association between time-specific activation of all transcripts and genetic variants correlated with HCV infection and treatment outcome. In hepatocytes, mRNA levels of all transcripts were increased in carriers of risk alleles associated with poor treatment outcome at 24 hours compared to 2 hours (60-fold for IL28A, 85-fold for IL28B, 222-fold for IL29 and 5-fold for IL28L) suggesting that under certain circumstances increased baseline interferon production in carriers of risk variants could be deleterious. The clinical relevance of our in vitro findings should be validated by similar studies in primary liver and blood samples derived from HCV-infected individuals.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3751. doi:10.1158/1538-7445.AM2011-3751
Abstract 3758: The relationship of calcium and magnesium intakes, VDR polymorphisms and the risk of colorectal adenoma: results from the Tennessee Colorectal Polyp Study
Authors: Xiangzhu Zhu , Shrubsole Martha J. , Ness Reid M. , Cai Qiuyin , Edwards Todd L. , Long Jirong , Chen Zhi , Deng Xinqing , Sun Pin , Luo Jianfeng , Smalley WalterSmalley E. , Zheng Wei , Dai Qi
Published: June 2012

Background: Epidemiological studies suggest that high calcium intake and adequate vitamin D levels may reduce risk of colorectal cancer or adenoma although findings have not been entirely consistent. Some previous studies found that the association between calcium intake and colorectal cancer or adenoma was modified by polymorphisms in vitamin D receptor (VDR) gene. In addition to regulating calcium level, vitamin D is also involved in magnesium homeostasis. However, no study has investigated possible interaction between magnesium intake and VDR polymorphisms. Objectives: To investigate whether intakes of calcium, particularly magnesium, interact with VDR genetic variants in relation to colorectal adenoma risk. Methods: Included in the study are 958 adenoma cases and 909 healthy controls from the Tennessee Colorectal Polyp Study (TCPS), an ongoing colonoscopy-based case control study conducted in Nashville, TN. Genotyping was performed using the Affymetrix Human Mapping 500K array set. Dietary nutrients intakes were obtained from food frequency questionnaire (FFQ) and dietary supplements and adjusted for total energy intake using the residual method. Multivariate unconditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI). Multiplicative interactions for gene-nutrients interactions were evaluated in logistic regression models by using likelihood ratio tests. Results: Eighteen tagging SNPs in the VDR gene were analyzed. Two SNPs (rs12717991, rs2189480) were significantly associated with a reduced risk of colorectal adenoma. Furthermore, intakes of calcium (p for interaction, 0.01) and magnesium (p for interaction, 0.03) significantly interacted with rs2189480 in relation to adenoma risk. The inverse association with rs2189480 was of borderline significance among participants with a low calcium intake (P for trend=0.06) with ORs (95% CI) of 0.80 (0.58, 1.10) and 0.67 (0.41, 1.10), respectively, for GT and TT. Among participants with high intake of magnesium, the inverse association was significant (P for trend=0.007) with ORs (95%CI) of 0.52 (0.38, 0.72) and 0.72 (0.44, 1.18), respectively for GT and TT. Conclusions: These findings suggest that some genetic variations in the VDR gene may interact with dietary intakes of calcium and magnesium intake in the risk of colorectal adenoma.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3758. doi:10.1158/1538-7445.AM2011-3758
Abstract 3767: Familial colorectal cancer registry in Hispanics: A feasibility study
Authors: Diaz-Algorri Yaritza , Joy Leilani , Balbuena-Merle Raisa , Acosta Delma , Nunez Cristina , Torres-Cintron Mariela , Figueroa-Valles Nayda , Cardona Alberto , Lacourt-Ventura Mercedes , Bernabe-Dones Raul , Lopez-Enriquez Reynold , Haile Robert , Mosquera-Fernandez Rafael , Members APG , Cruz-Correa Marcia
Published: June 2012

BACKGROUND: In Puerto Rico (PR), colorectal cancer (CRC) represents the second most common cause of cancer in men and women. Incidence and mortality of CRC are increasing in Puerto Rican Hispanics, especially among young individuals. Screening rates for CRC are lower in Hispanic-American individuals compared to non-Hispanic patients. However, there is limited data on genetic epidemiological CRC disparities in Hispanic patients.

OBJECTIVES: (1) To prospectively identify and recruit 30 probands with a family history of CRC and 15 family-history negative (2) To prospectively identify and recruit selected relatives from the 45 probands.

METHODS: Eligible cases are Hispanic patients with incident diagnosis of CRC, ≥ 21 years old. We identified the probands and their selected family members using the Puerto Rico Central Cancer Registry from July 1, 2007 to the present.

PRELIMINARY DATA AND RECRUITMENT: Seven hundred and fifty-one communications were sent to the physicians, three hundred and seventy-four communications were responded (374/751=49.8%).Three hundred and forty-one communications were sent to the patients, one hundred and forty-seven letters were responded (147/341=43.1%) and 16 refused.

One hundred and fifty-nine participants (probands and relatives) were enrolled. One hundred and two probands (mean age 56.9 ±13.3 yrs., 54.9% male); 30 with and 72 without family history of CRC. At present, we collected 153 (96.2%) risk factors questionnaires, 135 (84.9%) blood samples and 60 (52.6%) blocks of tissue.

CONCLUSIONS: Successful implementation of logistics for identification of incident CRC through the PR Central Cancer Registry during a three-year period. We established the first Familial CRC island-wide registry in Puerto Rico through the implementation of a network of community physicians, laboratories and professional societies. We are developing a tissue and blood bank with epidemiological, nutritional, and demographic data that will assist us to understand the genetic epidemiology of CRC in Puerto Ricans.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3767. doi:10.1158/1538-7445.AM2011-3767
Abstract 3829: Inducible silencing of PKD3 reveals a critical role for PKD3 in prostate cancer growth and metastasis
Authors: LaValle Courtney R. , Zhang Liyong , Eiseman Julie , Wang Q. Jane
Published: June 2012

Protein kinase D is a family of novel serine/threonine kinases that act as major mediators of several signaling pathways related to cancer development. Increasing evidence has demonstrated that specific PKD isoforms are deregulated in human cancers and that PKD plays an active role in cancer cell proliferation, migration, and invasion. Here, we present evidence on the development of a PC3 tetracycline-inducible PKD3 knockdown prostate cancer cell line and its application in both the study of PKD3 function in cells and the validation of PKD3 as a therapeutic target in vivo. We show that tetracycline treatment results in >50% knockdown of endogenous PKD3 expression in two distinct clones expressing PKD3 shRNA (shPKD3-C7 and shPKD3-C26), but has no effect on cells expressing scrambled shRNA (shSCR). Furthermore, endogenous PKD1 or PKD2 expression levels are not altered in PKD3 knockdown cells treated with tetracycline, supporting the specific targeting of the shRNA to the PKD3 isoform. Phenotypic analysis revealed that, similar to studies utilizing PKD siRNAs or novel PKD inhibitors, tetracycline-induced silencing of PKD3 causes potent arrest in cell growth and motility. Additionally, we found that conditioned media collected from tetracycline-treated shPKD3-C7 cells causes a reduction in PC3 cell migration, and we observed increased secretion of the tissue inhibitor of metalloproteinases-2 (TIMP-2) protein, which has important anti-angiogenic functions, from tetracycline-treated shPKD3-C7 cells. Western blotting revealed that both siRNA-mediated transient knockdown of PKD2 or PKD3 or treatment with novel PKD inhibitors led to decreased levels of the matrix metalloproteinases MMP-9, MMP-11, and MMP-14 in PC3 cells. Finally, we found that reduction of PKD3 expression by tetracycline-inducible shRNA significantly retarded both tumor growth in a subcutaneous xenograft model as well as tumor growth and metastasis in an orthotopic prostate cancer xenograft model. Taken together, these data suggest that PKD is a critical signaling protein that modulates prostate cancer cell growth and motility through a pathway involving multiple secreted factors, and that PKD3 is a potential therapeutic target in the treatment of prostate cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3829. doi:10.1158/1538-7445.AM2011-3829
Abstract 3862: Functional characterization of sFRP1 expression loss in human papillary bladder cancer
Authors: Rogler Anja , Hartmann Arndt , Goebell Peter , Wullich Bernd , Stoehr Robert
Published: June 2012

Introduction: Secreted frizzled-related protein 1 (sFRP1) is an inhibitor of the Wnt-signaling pathway and expression loss is associated with e.g. colon and breast cancer. Our previous studies revealed an involvement of sFRP1 loss in progression of papillary bladder cancer.

We therefore performed functional studies to characterise the role of sFRP1 in papillary bladder cancer cell lines.

Material and methods: Human papillary bladder cancer cell lines RT112 and BFTC 905 were used for the analyses. mRNA-expression status of sfrp1 and Wnt-target genes c-myc and cyclin D1 was determined using qRT-PCR. Methylation status of sfrp1 promoter was analysed with MS-PCR. sFRP1 knockdown was performed using sFRP1-specific siRNAs. 5’ Aza-2’deoxycytidine (5’Aza) treatment was used for promoter demethylation and restoration of sFRP1 expression. To determine Wnt pathway activity a luminescence-based TOP flash/FOP flash assay was used. Proliferation level was investigated with ELISA-based BrdU Cell Proliferation assay.

Results: RT112 is strongly expressing sfrp1 on mRNA level, whereas BFTC905 showed no sfrp1 expression. MS-PCR revealed sfrp1-promoter methylation in BFTC905. This methylation could be reversed after 5’-Aza-treatment and led to re-expression of sfrp1 on mRNA level. sfrp1 siRNA transfection in RT112 led to ∼80% gene silencing. sfrp1 knockdown resulted in an upregulation of c-myc (515%) and cyclin D1 (51,5%) on mRNA level, however TCF/LEF-presence could not be detected, neither in untreated nor in siRNA transfected RT112 cells. Untreated BFTC905 cells showed a very weak Wnt signalling activitiy, compared to positive control cell line SW480, but 7-fold higher than in untreated and siRNA treated RT112. sfrp1 knowdown in RT112 had no influence on cell proliferation.

Conclusion: sfrp1 knockdown in RT112 cells is associated with an up-regulation of proliferation-associated genes c-myc and cyclin D1, whereas this increased expression showed no effects on proliferation behaviour of the cells. Knockdown of sFRP1 did not result in significant Wnt-signaling activity in RT112 cells. Reduced sFRP1 expression might increase the proliferative potential of the cells; however additional genetic events might have to occur to induce increased proliferation of the cells. Ongoing analyses of BFTC905 with transient restoration of sFRP1 expression will give further insights into the role of sFRP1 in papillary bladder cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3862. doi:10.1158/1538-7445.AM2011-3862
Abstract 4346: Differential response of a novel protein kinase C-iota inhibitor (ICA-1) on neuroblastoma cells
Authors: Pillai Prajit P. , Acevedo-Duncan Mildred
Published: June 2012

Neuroblastoma is the most common extra cranial tumor diagnosed in children and in infants. The focus of this research was to establish the efficacy of ICA-1 as a novel chemotherapeutic agent for neuroblastoma. ICA-1 was designed to target Protein kinase C-iota (PKC-ι) which has been shown to promote resistance to drug-induced apoptosis in cancer cells, a major obstacle to good prognosis in neuroblastoma. Our preliminary results from in-vitro kinase activity assay demonstrated that ICA-1 selectively downregulated the activity of PKC-ι but had no effect on the activity of PKC-zeta, the closely related family member of the atypical PKC family. Phenotypically, neuroblastoma cells can be divided into 3 distinct groups- sympathoadrenal neuroblasts or N-type that form slow growing tumors, non-neuronal precursor cells or S-type which are non-malignant and I-type which are morphologically and biochemically intermediate to that of N and S cells. ICA-1 inhibited the cell proliferation of LA1-55n (N-type) and BE(2)-C (I-type) neuroblastoma cells. The IC50 was 0.1 µM for both cell lines. Interestingly, ICA-1 had no significant effect on the proliferation of LA1-5s (S-type) non-malignant cells. Furthermore, ICA-1 treatment also induced apoptosis in neuroblastoma cells as shown by TUNNEL assay, Caspase activation and PARP cleavage. Thus, our results provide evidence suggesting that ICA-1 is a promising chemotherapeutic for neuroblastoma with negligible toxicity to normal cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4346. doi:10.1158/1538-7445.AM2011-4346
Abstract 4397: Bioavailability of substituted quinoline, a gap junction enhancer
Authors: Ding Ying , Prasain Keshar , Hua Duy H. , Nguyen Thu Annelise
Published: June 2012

Breast cancer is one of the most malignant diseases that threaten the health of women all over the world, especially in western countries. It ranks the second leading cause of cancer deaths among women in the United States. Several drugs have been discovered to target different pathways of breast cancer cells; however, drug resistance and side effects have increasingly become a major concern. One of the effective methods is combinational treatment of different drugs. Loss of gap junctional intercellular communication (GJIC) is thought as one of the important hallmarks of cancer. It is believed that restoration of GJIC in cancer cells is related to reduction of tumorigenesis and increase of drug sensitivity. Gap junctions are intercellular channels connecting adjacent cells, allowing cells to transport small molecules (< 1.2kDa) from one cell to the next. This ordination of communication keeps cells at homeostasis. Previous report showed that combinational treatment of substituted quinoline (PQ1, a gap junction enhancer) and tamoxifen (a common used chemotherapeutic agent for breast cancers) can lower the concentration of tamoxifen in T47D breast cancer cells. It was also reported that PQ1 could increase 70% GJIC in T47D cells, whereas had no effect on GJIC in normal human mammary epithelial cells (HMECs) in vitro. However, the toxicity of PQ1 in vivo is still unknown. In this study, bioavailability of PQ1 was studied in mice. Twenty-five micrograms/kg body weight of PQ1 was administered orally to 5 week old mice. After 1, 12, or 24 hours of treatment, mice were sacrificed, and amounts of PQ1 in different organs were tested by HPLC and mass spectrometry. Expressions of connexin 43 and different protein markers (survivin, caspase-8, cleaved caspase-3, and aryl hydrocarbon receptor (AhR)) in organs were tested by western blot analysis. Hematoxylin and eosin staining was performed. Our results showed that compared to control, the expression of Cx43 in normal organs of the mice treated with PQ1 decreased, which is contrary to the effect of PQ1 on cancer cells. We also found that PQ1 can increase the expression of survivin and decrease the expression of caspase-8 and cleaved caspase-3 in nearly all the tested organs. Expression of AhR in liver was directly related with PQ1 amount, which means PQ1 is mediated through AhR and can be metabolized by liver. Histological results of the liver implied that PQ1 is not toxic to the tissue structure. Our studies demonstrate that PQ1 is a promising anti-cancer drug as well as in combinational treatment with other antineoplastic drugs with high specificity to cancer cells and low toxicity to normal organs.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4397. doi:10.1158/1538-7445.AM2011-4397
Abstract 4509: BAY 87-2243 targets hypoxia-induced activation and stabilization of HIF-1α: A novel approach to overcome resistance mechanisms in cancer therapy
Authors: Berhoerster Kerstin , Haerter Michael , Ellinghaus Peter , Heisler Iring , Beck Hartmut , Greschat Susanne , Thierauch Karl-Heinz , Wilhelm Scott , von Ahsen Oliver , Hess-Stumpp Holger , Ziegelbauer Karl
Published: June 2012

The development of resistance against radio- or chemotherapy is one of the main causes for relapse after treatment and ultimately cancer progression. Local hypoxia within tumors is associated with radio- and chemoresistance as well as aggressive tumor growth and invasion (Vaupel et al., 2004). The transcription factor HIF-1α (hypoxia-inducible factor) is stabilized under low oxygen tension and heterodimerizes with HIF-1ß to regulate the expression of a plethora of genes involved in cellular energy metabolism, neoangiogenesis, anti-apoptotic and pro-proliferative mechanisms promoting tumor progression and metastasis (Calzada et al. 2007). Because hypoxia-induced upregulation of HIF-1α appears to be of pivotal importance in tumor resistance mechanisms during cancer treatment, we screened for inhibitors of hypoxia-induced HIF-1 activation.

A HCT116 cell line containing 4X-hypoxia response element-luciferase reporter was used in high-throughput screening of small molecule inhibitors under hypoxic condition (1% O2). Lead optimization resulted in the identification of BAY 87-2243, a highly selective and potent inhibitor of hypoxia-induced HIF-1α stabilization and activation. In vitro characterization showed that BAY 87-2243 specifically suppressed HIF-1 regulated target genes as assayed by qPCR. Analyses addressing the mode of action revealed that BAY 87-2243 acts upstream of VHL and PHD because the compound did not suppress HIF-1α protein stabilization and HIF target gene expression either in the presence of a PHD inhibitor in H460 cells or in VHL-null RCC4 cells. In preclinical animal models, BAY 87-2243 dosed orally was well tolerated at therapeutic doses up to 15 mg/kg and showed moderate to high anti-tumor growth inhibitory activity as monotherapy in various subcutaneous and orthotopic xenograft models. Analysis of tumor samples demonstrated a decrease of nuclear HIF-1α protein level by immunohistochemistry as well as a specific suppression of HIF-1 target genes. These data indicate that specific inhibition of hypoxia-induced HIF-1 activation is achievable with small molecule inhibitors and is a novel approach to cancer therapy.

Vaupel P, Mayer A, Hockel M (2004) Tumor hypoxia and malignant progression. Methods Enzymol 381:335-354

M. J. Calzada, L. del Peso, Hypoxia inducible factors and cancer. Clin. Transl. Oncol. 2007, 9(5), 278-289:

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4509. doi:10.1158/1538-7445.AM2011-4509
Abstract 4541: Binding and transcriptional activity of the androgen receptor isoforms in 22Rv1 prostate cancer cells
Authors: Mudryj Maria , Libertini Stephen J. , Chen Honglin , Al-Bataina Bushra , Kung Hsing-Jien , Ghosh Paramita M.
Published: June 2012

Prostate carcinoma (CaP) is a heterogeneous multifocal disease where gene expression and regulation is altered as the disease progresses but the androgen receptor (AR) continues to be a pivotal regulatory molecule. The 22Rv1 castrate resistant cell line, derived from the androgen dependent CWR22 xenograft model, continues to express the AR and remains androgen responsive. However, in additional to the full length AR, these cells also express several low molecular weight isoforms. These isoforms are the predominant (95%) forms present in the nucleus in castrate androgen levels. siRNA knockdown of all AR isoforms in castrate levels of androgen decreases cell growth indicating that AR is required for proliferation. Analysis of ChIP-promoter array data identified 128 binding sites (FDR<=0.05) in Rv1 cells proliferating in androgen-depleted media. A closer examination of these 128 binding sites revealed that 20% of the sites showed exactly the same start and end position in the absence or presence of DHT. The remainder (80%) were within ∼35-1000bp upstream of the start position or downstream of the end position. Only 6% of the binding sites contained the palendromic consensus AR-response element and 48% contained the AR half-site motif. The 128 binding sites were associated with 118 genes. To define the role of AR binding in regulating transcription, the expression of 20 of the 118 genes was analyzed following knockdown of AR in castrate levels of androgen. One third of these genes are transactivated, while 1/3 are repressed, arguing that AR activating and repressing complexes co-exist in these cells. Notably the expression of CDKN1B (p27) RNA and protein is highly activated following AR knockdown, suggesting that AR-dependent repression of this cell cycle inhibitor may be important for proliferation of 22Rv1 cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4541. doi:10.1158/1538-7445.AM2011-4541
Abstract 4555: ERβ alters cell growth and the DNA damage response in lung cancer cells
Authors: Nikolos Fotis , Rajapaksa Gayani K. , Thomas Christoforos G. , Gustafsson Jan-Ake
Published: June 2012

Lung cancer is the leading cause of cancer deaths worldwide, in both men and women. Estrogen receptors that mediate the biological effects of estrogen and ant-estrogens are very important for the regulation of cell proliferation and differentiation in various human tissues. Recent data suggest that estrogen receptors may affect the initiation and progression of lung cancer. Here we show that estrogen receptor beta (ERβ) is expressed endogenously and it is localized in both cytoplasm and nucleus in the lung cancer cell line A549. Treatment of these cells with 17beta-estradiol does not alter the subcellular distribution of ERβ. Induction in the expression of ERβ in the same cells inhibits cell growth and modulates their resistance to cytotoxic chemotherapy in a ligand-independent manner. These results suggest ERβ as an important player in biology of lung cancer and a potentially useful component in the clinical management of the disease.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4555. doi:10.1158/1538-7445.AM2011-4555
Abstract 4576: IMGN853, an anti-Folate Receptor I antibody-maytansinoid conjugate for targeted cancer therapy
Authors: Ab Olga , Bartle Laura M. , Rui Lingyun , Coccia Jennifer , Johnson Holly A. , Whiteman Kathleen R. , Kellogg Brenda , Clancy Lauren , Sun Xiuxia , Goldmacher Victor S.
Published: June 2012

Previously we reported (O. Ab; EORTC, 2010) that an antibody-maytansinoid conjugate (AMC) composed of an anti-FOLR1 antibody conjugated to the cytotoxic maytansinoid, DM4, via the disulfide-containing linker, SPDB, was potent in killing FOLR1-expressing cancer cells in vitro and in vivo. In light of the favorable results noted, we assessed the optimal antibody, linker, and maytansinoid agent for an AMC targeting FOLR1, as reported here.

Antibody selection. Anti-FOLR1 antibodies were generated by immunizing mice with human FOLR1-expressing cells, and a panel of FOLR1-specific antibodies was identified by flow cytometry binding assay. Several FOLR1-antibodies with high binding affinity to both human and monkey FOLR1 were chosen for further evaluation and were humanized using ImmunoGen's resurfacing technology.

Antibodies were conjugated to DM1 via the non-cleavable SMCC linker and the conjugates tested for activity against FOLR1-positive KB cells in vitro and in vivo. All conjugates had comparable cytotoxic potencies in vitro. However, the in vivo anti-tumor activity of one conjugate, M9346A-SMCC-DM1, was significantly better than that of SMCC-DM1 conjugates of other FOLR1 antibodies. Based on this finding, the M9346A antibody was chosen for further development.

Linker/maytansinoid selection. The M9346A antibody was linked to DM1 or DM4 via the disulfide-containing cleavable linkers SPP, SPDB or sulfo-SPDB, or via the non-cleavable SMCC linker. We compared the in vitro cytotoxic activities of these conjugates on KB, Igrov-1 and Jeg-3 cell lines. The conjugates with cleavable linkers displayed markedly greater in vitro activities than the SMCC conjugate. We then examined the in vivo activities of the conjugates in FOLR1-positive KB- and Ovcar 3-tumor models. Again, we found that the conjugates with cleavable linkers were more active in vivo than the noncleavable conjugate. Among the conjugates with cleavable linkers, the sulfo-SPDB-DM4 conjugate was the most active conjugate against the Ovcar-3 model, it had activity comparable to that of the SPDB-DM4 conjugate against KB tumors, and both were more active than the SPP-DM1 conjugate in the two xenograft models.

Taking into consideration that sulfo-SPDB-DM4 was the most efficacious design in vivo and the potential of the hydrophilic sulfo-SPDB-linker to enable better activity against PgP-expressing cells (previously reported data), M9346A-sulfo-SPDB-DM4 was selected to be the candidate for development and designated IMGN853. IMGN853 is a promising candidate for the treatment of FOLR1-expressing tumors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4576. doi:10.1158/1538-7445.AM2011-4576
Abstract 4597: Chemopreventive and chemotherapeutic potential of blueberry and black raspberry against lung cancer using mouse models
Authors: Gupta Ramesh C. , Jeyabalan Jeyaprakash , Kausar Hina , Aqil Farrukh , Vadhanam Manicka V. , Ravoori Srivani
Published: June 2012

Berries, particularly blueberry (BB), black raspberry (BRB), are gaining increased attention for their chemopreventive and chemotherapeutic activities and have been tested in limited clinical studies with mixed results. Previous studies with strawberry and BRB failed to elicit protection against NNK/PAH-induced lung carcinogenicity in the A/J mice (the Stoner studies). However, a low dose of a mixture of different berries (BB, BRB, blackberry, and strawberry) elicited modest inhibition of cigarette smoke-mediated lung carcinogenicity in our study. In this study we investigated chemopreventive and chemotherapeutic activities of BB and BRB using two different animal models: To determine the DNA adduct-inhibiting potential female A/J mice were provided AIN-93M diet or diets supplemented with lyophilized powder of BB or BRB (5% each, w/w) and then challenged with continuous low doses of dibenzo-[a,l]pyrene (DBP) by subcutaneous polymeric implants (two, 20 mm long, 1.4 mm dia; DBP load 5%). Three weeks later animals were euthanized and the target tissue (lung) DNA was analyzed by 32P-postlabeling assay. The DNA adduct burden (as adducts/109 nucleotides) in animals receiving the BB (67 ± 16), BRB (68 ± 9) diets was found to be unaffected compared with control diet (54 ± 17), indicating that the berry bioactives were ineffective against the DNA adduct-forming ability of DBP under the conditions used. To determine the chemotherapeutic potential, female nude mice received AIN-93M (control) diet or diet supplemented with a mixture of BB and BRB (2:1) and 4 days later inoculated with human lung cancer A549 cells (3×106 cells). Four weeks into the ongoing study, the berry diet has shown significant (nearly 60%) inhibition of the lung tumor xenograft (186 ± 117 versus 79 ± 47). The anti-tumor activity elicited by the berry diet in xenograft model is consistent with the anti-tumor activity of anthocyanidins reported by us in cell culture and nude mice (Kausar et al. AACR 51: 1884, 2010). In conclusion, our data suggest that the anti-lung cancer potential of the berries may be associated with mechanisms other than inhibition of carcinogen-induced DNA adducts. (Supported from CA-118114, KLCRP and Agnes Brown Duggan Endowment).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4597. doi:10.1158/1538-7445.AM2011-4597
Abstract 4623: Capsaicin represses transcriptional activity of β-catenin in human colorectal cancer cells
Authors: Lee Seong-Ho , Richardson Raphael L. , Baek Seung J.
Published: June 2012

Capsaicin is a pungent ingredient in chili red peppers and has been linked to suppression of growth in various cancer cells. However, the underlying mechanism(s) by which capsaicin induces growth arrest and apoptosis of cancer cells is not completely understood. In the present study, we investigated whether capsaicin alters β-catenin signaling in human colorectal cancer cells in vitro. Exposure of human colorectal cancer cells to capsaicin suppressed cell proliferation. Transient transfection with β-catenin responsive reporter gene indicated that capsaicin suppressed transcriptional activity of β-catenin. Capsaicin treatment resulted in a decrease of intracellular β-catenin levels and a reduction of β-catenin transcripts. These results were confirmed by a reduced luciferase reporter activity driven by β-catenin promoter. In addition, capsaicin destabilized β-catenin through enhancement of proteosomal-dependent degradation. Western blot and immunoprecipitation studies indicated that capsaicin treatment disrupted interaction of TCF-4 and β-catenin and suppressed TCF-4 expression. This study identifies an important capsaicin-mediated pathway that contributes to anti-cancer activity of human colorectal cancer cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4623. doi:10.1158/1538-7445.AM2011-4623
Abstract 4625: Curcumin suppresses the expression of HER-2 gene and interferes with redox regulated pathways in SK-BR-3 breast cancer cells
Authors: Thomas T.J. , Venkiteswaran Sripriya , Thomas Thresia , Yang PingAr , Hsu Hui-Chen
Published: June 2012

Curcumin (diferuloylmethane), a polyphenolic phytochemical, is the major pigment in turmeric, a popular spice in Oriental cuisine. Curcumin is known for its anti-inflammatory, antioxidant, and anti-carcinogenic properties. We studied the effect of curcumin on cell growth, gene regulation, cell cycle and cell signaling parameters in a HER-2 over-expressing human breast cancer cell line, SK-BR-3. Curcumin inhibited the growth of SK-BR-3 cells with an IC50 value of 5 ± 1 µM, as determined by trypan blue exclusion assay at 48 and 72 h. In contrast, measurement of apoptosis, using the APO-BRDU assay, showed < 5% apoptosis after exposing SK-BR-3 cells to 5 µM curcumin for 24, 48, or 72 hours. Apoptosis increased to ∼ 80% at 25 µM concentration. To understand the basis of these phenomena, we examined the effects of curcumin on several molecular parameters. At 25 µM concentration, curcumin suppressed the expression of HER-2 gene by a significant 70% (P<0.005) at 16 and 24 hours after treatment, as measured by real time qPCR assay. Curcumin further caused a 2- to 4-fold increase in p21 and p27 mRNA levels. Twenty five µM concentration of curcumin also suppressed the expression of cyclin B1, cyclin D1 and cyclin E mRNA levels. In addition, curcumin arrested cells in the G2/M phase of cell cycle, and decreased cyclin A, cyclin B1 and cyclin E protein levels. At 10 to 50 µM concentrations, curcumin also caused a decrease in phospho-HER-2 and total-HER-2 protein levels. Pre-treatment with the anti-oxidant glutathione partially reversed apoptosis induced by curcumin and restored HER-2 and cyclin D1 protein levels. These results indicate that the apoptotic effects of curcumin on HER-2 over-expressing breast cancer cells result from interference with redox-mediated cell growth regulatory pathways. Increased levels of glutathione attenuated the effects of curcumin, an important consideration for translational research and clinical trials on curcumin. Since some of its growth inhibitory effects can be restored by exogenous glutathione, cellular redox status is an important factor in curcumin sensitivity of breast cancer cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4625. doi:10.1158/1538-7445.AM2011-4625