bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3689: Targeting cell survival pathways with the combination of honokiol and resveratrol for prevention of head and neck cancer
Authors: Amin A.R.M. Ruhul , Jung Kyung-Ho , Wang Dongsheng , Arbiser Jack L. , Chen Zhuo G. , Shin Dong M. 
Published: June 2012

Abstract
Natural dietary agents have drawn great attention for cancer prevention because of their wide safety margin and ready availability. However, single agent intervention has failed to bring the expected outcomes in clinical trials. In the current study, we investigated a combinatorial approach using two natural compounds, honokiol (isolated from the bark of the magnolia tree) and resveratrol (a major constituent of red wines and grapes), and found that their combination at low doses (at which single agents induce minimal cell growth inhibition) strongly inhibited cell growth as measured by SRB assay. Moreover, the combination of low dose honokiol (which alone induces 10-15% apoptosis) with low dose resveratrol (also induces ∼10% apoptosis) strongly increased apoptosis (to 60-80%) in multiple head and neck cancer cell lines as evidenced by annexin V-PE staining and PARP cleavage. Interestingly, normal human fibroblasts (BJ) or immortalized normal bronchial epithelial cells (BEAS-2B) were resistant to apoptosis induced by the combination of the two compounds (less than 10% apoptosis). To understand the mechanism of apoptosis, we fractionated cytosolic and mitochondrial fractions to study the release of cytochrome c from the mitochondria to the cytosol, and found that the combination of honokiol and resveratrol more efficiently caused release of cytochrome c compared with either single agent alone. Further mechanistic studies suggested that the combination of the two agents inhibited phospho-STAT3 and phospho-AKT and reduced NF-κB protein level more efficiently than either single agent. Moreover, although single agent treatment has only minimal effect on expression of NF-κB and the STAT3 targets Bcl-2, Mcl-1 and survivin, the combination of the two agents strongly inhibited expression of these proteins, further supporting the involvement of mitochondria-mediated apoptosis. However, expression of Bcl-xL, another proapoptotic Bcl-2 protein remained unchanged after treatment with the compounds. We also found transient inhibition of phospho S6 kinase, a downstream target of p-AKT. NF-κB, phospho-STAT3 and phospho-AKT pathways are frequently over-active in head and neck cancer, suggesting that the combination of honokiol and resveratrol might be an effective strategy for the prevention of head and neck cancer and providing an important rationale for future preclinical and clinical development. (Supported by U01CA101244, R01CA112643, and P50CA128613 to DMS)
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 3689. doi:10.1158/1538-7445.AM2011-3689
Abstract 3707: Sulindac sulfide inhibits growth and induces apoptosis of human colon tumor cells by a cGMP-dependent pathway leading to suppression of β-catenin transcription activity
Authors: Li Nan , Tinsley Heather , Whitt Jason , Gary Bernard , Lu Wenyan , Li Yonghe , Keeton Adam , Piazza Gary 
Published: June 2012

Abstract
Sulindac and other nonsteroidal anti-inflammatory drugs have shown promise for chemoprevention of colorectal cancer, but toxicities arising from cyclooxygenase (COX) inhibition limit their clinical use. Previous reports suggest that sulindac may exert its antitumor effects by a COX-independent target involving cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE) inhibition, although the specific isozymes involved and mechanism have not been well defined. In this study, we show that sulindac sulfide (SS) inhibits the growth of human colon tumor cells, HCT116, HT29 and SW480 with IC50 values of 60-80μmol/L. Within this concentration range, SS did not affect the growth of human-derived normal colonic epithelial cells, NCM460. Furthermore, SS induced apoptosis of colon tumor cells but not NCM460 cells. SS inhibited cGMP PDE activity in colon tumor cell lysates with minimal effect on cGMP PDE activity in NCM460 cell lysates. By determining the sensitivity of all eleven PDE isozymes to SS, the cGMP-specific PDE5 was found to be the most sensitive with an IC50 value for enzyme inhibition of 38µmol/L. In addition, PDE5 was found to be overexpressed in colon tumor cell lines compared with NCM460 cells. Knockdown of PDE5 expression in colon tumor cells with siRNA resulted in a significant reduction of tumor cell growth and increased apoptosis. Moreover, SS increased intracellular cGMP levels, activated protein kinase G (PKG) and suppressed the expression of β-catenin in colon tumor cells. SS also inhibited the transcriptional activity of β-catenin and reduced the expression of the β-catenin regulated proteins cyclin D1 and survivin, which are important mediators of tumor cell proliferation and apoptosis, respectively. Our results suggest that the chemopreventive properties of sulindac are closely associated with PDE5 inhibition and involve the activation of cGMP signaling to suppress β-catenin mediated transcriptional activity. Funding provided by NIH/NCI grants CA131378 and CA148817.
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 3707. doi:10.1158/1538-7445.AM2011-3707
Abstract 3709: Molecular targets of total methanolic and ethyl acetate fraction of triphala in colon cancer
Authors: Ravoori Srivani , Higashi Richard M. , Gupta Ramesh C. , Vadhanam Manicka V. 
Published: June 2012

Abstract
We previously demonstrated that the methanolic extract of triphala, a herbal preparation of a mixture of three fruits, namely, Terminalia chebula, Emblica officinalis and Terminalia bellerica was effective against colon cancer cells. In order to identify its mechanism of action, HCT-116 cells (1×106 cells) were seeded in 25mm2 petri dishes and treated with varying concentration of total extract. Cells stained using Alexa Fluor 488 Annexin V/Dead Cell Apoptosis assay revealed a dose dependent increase in early apoptosis which plateaued with 200 µg/ml, and a dose dependent increase in late apoptosis upto 400 µg/ml. This and previous finding of down-regulation of cyclin D1 suggested that the inhibitory action of triphala is facilitated both by antiproliferation and induction of apoptosis. In addition, significant downregulation of select upstream and downstream molecules of NFκB signaling was observed. In order to identify the bioactive components of the mixture, the total methanolic extract was subfractionated with various organic solvents and tested for antiproliferative activity using HCT-116 cells. The efficacy was determined to be in the following order: ethyl acetate fraction&gt;total methonolic fraction&gt;chloroform fraction&gt;butanol fraction&gt;hexane fraction&gt;residual aqueous fraction. When normal colon cells CRL-1459 (5×103 cells) were treated with either the total methanolic or ethyl acetate fraction, the IC50 was found to be 7 fold higher for both the fractions compared to colon cancer cells, suggesting that the antiproliferative activity is specific to malignant cells. FTICR-MS analysis of the effective fractions revealed enrichment of most of the phenolics such as gallic acid, ellagic acid, and several other tannins into the ethyl acetate fraction. In order to identify the molecular targets of the ethyl acetate fraction, HCT-116 (1×106 cells) were seeded in 6 well plates and treated with LPS, 100 or 200 µg/ml ethyl acetate extract of triphala or both for 6 hours. qRT-PCR analyses revealed that the ethyl acetate fraction is more effective in down-regulating both constitutive and induced expression of TNFα and COX2 compared to the total methanolic extract. In addition, down-regulation of LPS-induced NFκB expression was more pronounced with ethyl acetate extract compared to methanolic extract. Ethyl acetate extract was also effective in downregulating the cell cycle regulatory molecule cyclin D1. However, the total extract was more effective in modulating the expression of IL-6 and IFNγ, suggesting that the various fractions of triphala may have distinct targets of colon carcinogenesis.
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 3709. doi:10.1158/1538-7445.AM2011-3709
Abstract 371: Comparison of toxicity and study design issues of nanoparticle and small molecule anticancer agents in preclinical models and phase I clinical trials
Authors: Morgan Katherine P. , Caron Whitney P. , Walsh Mark D. , Zamboni Beth A. , Zamboni William C. 
Published: June 2012

Abstract
Background: Carrier-mediated agents (CMA) are classified as nanoparticles, nanosomes (nanoparticle sized liposomes) and conjugates. Anticancer CMA offer many unique advantages over their traditional small molecule (SM) counterparts, including improved solubility, longer duration of exposure, tumor-selective delivery, increased antitumor response and reduced toxicity. The interpatient variability in pharmacokinetics (PK) and pharmacodynamics (PD) associated with nanoparticles are greater than that observed with SM. The starting dose for phase I studies of SM and CMA anticancer agents is based on the toxicity profile of the most sensitive species (e.g. rat or canine). However, the optimal animal model for toxicologic and pharmacologic studies of CMA is unclear. Our preliminary data suggests that dogs are highly sensitive to nanoparticles and thus may not be an appropriate animal model in determining the starting dose of CMA for phase I clinical trials. We evaluated preclinical toxicology data and how this affected the design and progression of phase I studies of CMA compared to SM anticancer agents.
Methods: In preclinical studies, the maximum tolerated dose (MTD) in rats and dogs was evaluated for CMA and their respective SM. In phase I clinical trials of CMA and their respective SM in patients with advanced solid tumors, the basis for starting dose, the number of dose escalations, number of patients and the ratio of MTD to starting dose was determined.
Results: Starting dose in phase I studies of CMA was based on dogs.

Conclusions: The degree of dose escalation from starting dose to MTD was significantly greater for CMA compared to SM drugs. This was also associated with a significantly greater number of dose levels, patients, and time required to complete phase I studies of CMA compared to SM. These findings necessitate the need to identify the most appropriate preclinical animal model to use to evaluate CMA toxicity in phase I studies.
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 371. doi:10.1158/1538-7445.AM2011-371
Abstract 3718: Well-done meat intake and meat-derived mutagen exposures in relation to breast cancer risk: The Nashville Breast Health Study
Authors: Fu Zhenming , Deming Sandra L. , Fair Alecia M. , Shrubsole Martha J. , Wujcik Debra M. , Shu Xiao-ou , Kelley Mark C. , Wei Zheng 
Published: June 2012

Abstract
Previous studies of the association of meat intake and meat-derived mutagen exposure with breast cancer risk have produced inconsistent results. We evaluated this association in a population-based case-control study of incident breast cancer conducted in Nashville,TN, United States, including 2,386 breast cancer cases and 1,703 healthy women controls. Telephone interviews were conducted to obtain information related to meat intake including amount, cooking methods, and doneness levels, as well as other known or hypothesized risk factors for breast cancer. Unconditional logistic regression was used to derive odds ratios (ORs) after adjusting for potential confounders. High intake of red meat was associated with a significantly elevated risk of breast cancer (P-trend &lt;0.001). The association was particularly strong for high intake of well-done red meat (P-trend &lt;0.001), with an adjusted OR of 1.5 (95% CI = 1.3-1.9) for the highest versus the lowest quartile. Associations between red meat and breast cancer risk were stronger for postmenopausal women than for premenopausal women. Meat-derived mutagens such as 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), were significantly associated with increased breast cancer risk among postmenopausal women only (P-trend = 0.002 and 0.003, respectively). The results from this study provide strong support for the hypotheses that high red meat intake and meat-derived mutagen exposure may be associated with an increase in breast cancer risk.
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 3718. doi:10.1158/1538-7445.AM2011-3718
Abstract 3724: Use of aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen and risk of postmenopausal breast cancer
Authors: Zhang Xuehong , Smith-Warner Stephanie , Giovannucci Edward , Rosner Bernard , Willett Walter , Hankinson Susan 
Published: June 2012

Abstract
Background Aspirin is widely used for cardiovascular disease prevention and has been consistently shown to be associated with a 20-30% lower risk of colon cancer. However, the associations between uses of aspirin, other NSAIDs, and acetaminophen and breast cancer incidence are uncertain. In addition, limited epidemiological studies have assessed these associations with breast cancer subtypes defined by hormone receptor status. Further, no known prospective cohort studies have been conducted on other clinical relevant subtypes including Triple-negative, Luminal A, Luminal B, HER2 positive, COX-2 negative and COX-2 positive.
Design We followed 84,602 postmenopausal women, free of cancer in 1980, until June 2008. During this time, we prospectively collected data on analgesic use, reproductive history, and other lifestyle factors every two years. A Cox proportional hazard model was used to estimate multivariable relative risks (RRs) and 95% confidence intervals (CIs) by adjusting for age, reproductive factors and other important risk factors for breast cancer.
Results A total of 4,754 pathologically confirmed incident invasive breast cancer cases were identified during 18 years of follow-up. Comparing with never use of aspirin, multivariable relative risks of regular aspirin use (at least 2 tablets/wk) for more than 20 years were 0.91 for overall breast cancer (95%CI: 0.81-1.01, P trend = 0.16), 0.90 for ER+PR+ breast cancer (95%CI: 0.77-1.06, P trend = 0.17), 1.03 for ER+PR- breast cancer (95%CI: 0.76-1.38, P trend = 0.94), and 0.92 for ER-PR- breast cancer (95%CI: 0.68-1.23, P trend = 0.98). Results did not vary substantially by past or current use, or frequency (days per week) of use. Use of other NSAIDs and acetaminophen also was not significantly associated with risk of breast cancer. Results were not changed after mutual adjustment for each of the drug. In addition, results were not modified by body mass index, alcohol consumption, family history of breast cancer, or postmenopausal hormone use. Further, no substantial associations were noted for other subtypes of breast cancer (ER-PR+, Triple-negative, Luminal A, Luminal B, HER2 positive, COX-2 negative and COX-2 positive).
Conclusions Although a small reduction in breast cancer risk cannot be excluded, our study suggest that use of aspirin, other NSAIDs, and acetaminophen was not importantly associated with incidence of postmenopausal breast cancer overall or other specific breast cancer subtypes.
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 3724. doi:10.1158/1538-7445.AM2011-3724
Abstract 3729: Global and longitudinal analyses of demographic and clinico-pathological characteristics of triple-negative breast tumor tissues
Authors: Brown Tony , Moskalik Aaron , Pande Nupur , Peters Elizabeth H. , Sullivan Stephanie , Cohen Dalia 
Published: June 2012

Abstract
Patients exhibiting triple-negative (ER-negative, PR-negative, HER2-) breast cancer pose a challenge to healthcare providers due to its relatively poor prognosis, aggressive tumor reoccurrence, and lack of targeted therapies. One critical resource that accelerates the molecular and pathophysiology of the triple-negative breast cancer subtype is the analyses of retrospectively collected, verified biospecimens. Unfortunately, limited availability of adequately annotated biospecimens as well as inconsistencies in clinical data that contradict pathology diagnosis can cause ambiguity in understanding demographic and clinico-pathological characteristics in patients. In this study, we systematically examined high quality-controlled and independently molecular and pathology verified breast tumor tissues collected from patients cases in Eastern Europe, Asia, and North America diagnosed with breast cancer between 2001 and 2010 to determine age-based distributions among pre-menopausal, menopausal, and post-menopausal women with triple-negative breast cancer. We defined the immunohistochemical (IHC) surrogates for the triple-negative subtype and assessed a total of 7,636 patients including 1,700 pre-menopausal patients (22%), 4,233 post-menopausal patients (55%), and 771 menopausal patients (10%). The average RNA RIN score was 8.3 across all samples. The median age at diagnosis was 56 (range 20-91 years). Results indicated that there was a decrease in ER expression with donor age, little to no change in PR or HER2 expression, and a progressively decreasing frequency of triple-negative with donor age. Our study demonstrates that independently verified and quality controlled biospecimens enable global and longitudinal analysis of demographic and clinico-pathological characteristics of patients.
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 3729. doi:10.1158/1538-7445.AM2011-3729
Abstract 3760: Associations of risk variants for 20 different malignancies with colorectal cancer in a multiethnic population
Authors: Cheng Iona C. , Caberto Christian , Wilkens Lynne R. , Schumacher Fredrick R. , Kolonel Laurence N. , Henderson Brian E. , Stram Daniel O. , Haiman Christopher A. , Marchand Loic Le ,   PAGE Consortium
Published: June 2012

Abstract
Familial clustering has been reported across different cancer sites, suggesting that cancer may be considered a broad phenotype with genetic risk factors that are shared across different malignancies. We, as part of the Population Architecture using Genomics and Epidemiology (PAGE) Study, explored the hypothesis that risk variants established for cancers at any site influence the risk of colorectal cancer. We selected 160 SNPs associated with 20 different cancer sites, including colorectal cancer, from genome-wide association studies published through May, 2009. These SNPs were genotyped in a nested case-control study of 2,077 colorectal cancer cases and 2,685 controls from five racial-ethnic groups (African American, European American, Latino, Japanese American, and Native Hawaiian) within the Multiethnic Cohort. Odds ratios and 95% Confidence Intervals were estimated by unconditional logistic regression to evaluate the association between SNPs and colorectal cancer risk, adjusting for age, sex, and race/ethnicity. We found that 22 risk variants were associated with colorectal cancer risk with P&lt;0.05: one acute lymphocytic leukemia SNP (ALL); one basal cell carcinoma SNP; two breast cancer SNPs; one chronic lymphocytic leukemia (CLL) SNP; four colorectal cancer SNPs (rs6983267, rs4939827, rs16892766, and rs10505477); five lung cancer SNPs; one nasopharyngeal cancer SNP; one neuroblastoma SNP; two pancreatic cancer SNPs; and four prostate cancer SNPs. With more associations than would be expected by chance (8 =160 tests × 0.05), these results suggest robust significant associations. The strongest association (P&lt;0.0001) was for a colorectal cancer risk variant at chromosome 8q24 (rs10505477). Other notable associations (P&lt;0.01) and their originally associated cancer site, excluding known colorectal cancer risk variants (rs6983267, rs4939827, and rs4242382), include rs17483466 (ACOXL) for CLL (P=0.003), rs4242382 (8q24) for prostate cancer (P=0.004), rs10994982 for ALL (P=0.0078), and rs4975616 (TERT-CLPTM1L) for lung cancer (P=0.0079). Future analysis will include approximately 3,600 additional colorectal cancer cases and controls from the Women's Health Initiative (WHI), Arthrosclerosis Risk In Communities Study (ARIC), and the Cardiovascular Health Study (CHS) as part of the PAGE initiative. In conclusion, these results may provide important insights into the biological pathways that are shared across different cancer sites.
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 3760. doi:10.1158/1538-7445.AM2011-3760