bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A35: Chemoprevention of colon carcinogenesis in F344 rats by Se,Se′-1,4-phenylenebis(1,2-ethanediyl)bis-isoselenourea (PBISe) a novel analog of PBIT, an iNOS inhibitor
Authors: Janakiram Naveena B. , Mohammed Altaf , Ravillah Durgadevi , Choi Chang In , Zhang Yuting , Desai Dhimant , Amin Shantu , Rao Chinthalapally V. 
Published: May 2012

Abstract
Inducible nitric oxide synthase (iNOS) is potential target for inflammation and cancer. Previously, we have shown that S,S′-1,4-Phenylenebis(1,2-ethanediyl)bisisothiourea (PBIT) inhibit colon carcinogenesis induced by azoxymethane (AOM). Although, colon cancer inhibitory efficacy of PBIT has been significant, selective iNOS inhibitors do not completely abrogate NO production due to the exogenous bioavailability and NO generation by eNOS in tumor tissues. To create an iNOS selective and multi-targeted molecule, we have developed a novel isosteric analogue of PBIT, namely PBISe in which sulfur was replaced with selenium. We examined the chemopreventive efficacy of PBISe on AOM-induced rat colon carcinogenesis model using aberrant crypt foci (ACF) as end point. At seven weeks of age, rats (12/group) were fed the control diet (AIN 76A) and colonic ACF were induced by AOM. Three days after second AOM treatment, rats were fed the diets containing 0, 10 and 20 ppm of PBI-Se and continued on the respective diets for 8 weeks before ACF were evaluated histopathologically. Furthermore, PBISe (0–12 µM) and PBIT (0 – 100 µM) were studied for the markers of growth inhibition and induction of apoptosis in the human colon cancer CaCo2 cell line. In addition, inhibitory effect of PBISe and PBIT on proinflammatory signaling molecules iNOS, IL-8 and IL-6 were studied by RT-PCR. Results suggest that dietary administration of 10 and 20ppm of PBISe significantly suppressed AOM-induced total colonic ACF formation (32 – 41%, p&lt; 0.001), and multi crypt (4 or more) aberrant foci (29 – 47%, p&lt; 0.001) respectively. Dietary PBISe suppressed AOM-induced colonic ACF in a dose-dependent manner and it required less than half the dose of PBIT to inhibit total ACFs in rats. Both PBIT and PBISe in CaCo2 cells induced dose-dependent apoptosis. PBIT and PBISe treatment on CaCo2 cells showed significant decrease in cell cycle protein cyclin D1 (∼70%, p&lt;0.0001) and iNOS (∼99%, p&lt;0.0001). Also, treatment with PBIT (30 and 60 M) significantly decreased cytokine induced IL-6 at both the doses whereas PBISe had no such effect. PBIT significantly attenuated the LPS-induced IL-6 and IL-8 production in a dose dependent manner. Whereas, PBISe significantly increased IL-8 and attenuated IL-6 production in CaCo2 cells suggesting differential modulatory effects on immune cells/inflammatory pathways. Incorporation of selenium into the structure of PBIT has provided the agent with additional novel cytotoxic and immunologic properties. Results from in vitro and in vivo bioassay clearly suggest that PBI-Se could be further developed for prevention and treatment of colon cancer.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A35.
Abstract A39: In vitro mechanisms of cadmium-induced apoptosis in human liver carcinoma (HEPG2) cells
Authors: Skipper Anthony C. , Tchounwou Paul B. , Yedjou Clement 
Published: May 2012

Abstract
Cadmium is a heavy metal that has been shown to manifest its toxicity in humans and animals. Many documented in vitro studies have shown that cadmium produces various genotoxic effects such as DNA damage and chromosomal aberrations. Diseases like autoimmune thyroidism are thought to be caused, in large part, by overexposure to cadmium. Although there have been numerous studies examining the effects of cadmium in animal models and a few case studies involving communities where cadmium contamination has occurred, the mechanisms of the carcinogenic activity of cadmium is not clearly defined. Therefore, the purpose of this study was to elucidate some of the molecular mechanisms that are involved in cadmium-induced toxicity in human liver carcinoma (HepG2) cells. To achieve this goal, we performed the MTT assay to measure cell viability. Annexin V assay and DNA fragmentation analysis were performed for early and late apoptosis, respectively. The result of MTT assay indicated that cadmium induces toxicity to HepG2 cells in a dose-dependent manner, showing a 24 h-LD50 of 3.6 µg/mL cadmium chloride. Similarly, a strong dose-response relationship (p &lt; 0.05) was obtained in connection with cadmium chloride-induced apoptosis. Cadmium chloride-induced apoptosis was characterized by a significant increase in the percentages of annexin-V positive cells, as well by the occurrence of nucleosomal DNA fragmentation. In summary, this study indicated cadmium chloride is highly cytotoxic to HepG2 cells. This cytotoxic effect may be mediated at least in part through phosphatidylserine externalization and occurrence of nucleosomal DNA fragmentation.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A39.
Abstract A58: Cul3-mediated Nrf2 ubiquitination and ARE activation are dependent on the partial molar volume at position 151 of Keap1
Authors: Eggler Aimee L. , Small Evan , Hannink Mark , Mesecar Andrew D. 
Published: May 2012

Abstract
Nrf2 is a transcription factor that activates transcription of a battery of cytoprotective genes by binding to the antioxidant response element (ARE). Nrf2 is repressed by the cysteine-rich Keap1 protein, which targets Nrf2 for ubiquitination and subsequent degradation by a Cul3-mediated ubiquitination complex. Several promising chemopreventive agents, including sulforaphane, activate Nrf2 in Keap1 C151-dependent manner. We find that modification of C151 of human Keap1 by mutation to a tryptophan relieves the repression by Keap1 and allows activation of the ARE by Nrf2. Keap1 C151W has a decreased affinity for Cul3, and can no longer serve to target Nrf2 for ubiquitination, though it retains its affinity for Nrf2. A series of 12 mutant Keap1 proteins, each containing a different residue at position 151, was constructed to explore the chemistry required for the effect. The series reveals that the extent to which Keap1 loses the ability to target Nrf2 for degradation, and hence the ability to repress ARE activation, correlates well with the partial molar volume of the residue. Other physico-chemical properties do not appear to contribute significantly to the effect. Based on this finding, a structural model of the Keap1-Cul3 binding interface was constructed to investigate the potential mechanism of action of a tryptophan or other group at position 151. Several residues surrounding position 151, K131, R135 and K150, were observed in the model to be close enough to be involved in a steric clash with the tryptophan. Keap1 proteins containing these residues mutated to alanine, along with C151W, were evaluated for their ability to repress Nrf2. We find that none of mutations were able to restore the ability of Keap1 C151W to repress Nrf2. Additional residues are being investigated in effort to determine which residue(s) might be responsible for translating the increase in partial molar volume at position 151 to a lack of Nrf2 repression. This work has significant implications for how chemopreventive electrophiles that modify C151 disrupt the repressive function of Keap1.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A58.
Abstract A65: Caspase 14 is a target of black-raspberry-mediated inhibition of human cervical cancer cell proliferation
Authors: Zhang Zhaoxia , Knobloch Thomas J. , Seamon Leigh G. , Backes Floor J. , Stoner Gary D. , Paskett Electra D. , Cohn David E. , Fowler Jeffrey M. , Weghorst Christopher M. 
Published: May 2012

Abstract
Cervical cancer is the second most common female cancer worldwide and the seventh leading cause of cancer death in women. While significant advances have been made in early detection, it remains a challenge to manage pre-invasive and invasive cervical lesions. However, the long latency of cervical cancer development allows for the investigation and utilization of preventive and therapeutic interventions, including chemopreventive approaches. Phytochemical-based cancer chemoprevention and the role of bioactive food components have attracted significant interest due to their dramatic anti-proliferative and anti-tumorigenesis effects observed in preclinical studies. We have previously demonstrated that an extract of lyophilized black raspberries (LBR, Rubus occidentalis) inhibited the proliferation of human cervical cancer cell lines: HeLa (HPV16−/HPV18+, adenocarcinoma), SiHa (HPV16+/HPV18−, squamous cell carcinoma) and C-33A (HPV16−/HPV18−, squamous cell carcinoma) in a dose- and time-dependent manner. Here we investigate the modulation of apoptotic pathways as a potential mechanism. Expression profiling of 93 apoptosis-related genes was performed with the Applied Biosystems' TaqMan Gene Signature Human Apoptosis Array in HeLa, SiHa and C-33A human cervical cancer cells treated with vehicle control (0.02% DMSO) or LBR (200µg/mL) for 1 and 3 days. The following genes were differentially expressed (≥2-fold change) in a manner favorable to cancer prevention following LBR treatment: CARD9 (+4.4) and BCL2L10 (−4.0) in HeLa cells; BIRC1 (−2.3) and CASP14 (+4.2) in SiHa cells; CARD15 (+3.4), TNFRSF1B (+2.8), TNFRSF1A (+2.3), FADD (+2.3), BBC3 (+2.1), BOK (+2.1), RELB (+2.1), IKBKG (+2.0), HTRA2 (+2.0), DEDD2 (+2.0), BAD (+2.0) and BAX (+2.0) in C-33A cells. Two candidate genes from each cell line were chosen for subsequent validation: CARD9 and BCL2L10 in HeLa cells, BIRC1 and CASP14 in SiHa cells, FADD and BAX in C-33A cells. From these selected candidate genes, only CASP14 was validated as a &gt;2-fold expression change (+5.1) following LBR exposure in SiHa cells. CASP14 mRNA expression was undetectable (&gt;40 Ct values) in both HeLa and C-33A cells. Caspase 14, a cysteine-aspartic proteases, is directly involved in epithelial cell differentiation, and only indirectly with canonical apoptotic pathways. Caspase 14 plays a role in epithelial cell malignant transformation, and is progressive loss during cervical cancer progression. Consequently, up-regulation of CASP14 expression by LBR in cervical cancer cells may provide a potential mechanism for attenuating cervical carcinogenesis and progression. Further studies will define the contribution of CASP14 mRNA and protein up-regulation following LBR exposure in cervical cancer cells.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A65.
Abstract A72: Punicic acid, a fatty acid from pomegranate seed oil, inhibits breast cancer cell proliferation
Authors: Grossmann Michael E. , Mizuno Nancy K. , Schuster Todd , Cleary Margot P. 
Published: May 2012

Abstract
Introduction: Pomegranate (Punica granatum) is a well-known fruit used for alternative medicine. Various pomegranate extracts are utilized as supplements with a wide variety of purported health benefits including anticancer actions. These supplements contain a number of different components that may either activate or inhibit estrogen's action. Additionally factors associated with pomegranate fruit or extracts may lower oxidation of LDL cholesterol, reduced arterial plaques, lower oxidative stress, enhanced wound healing, inhibition of angiogenesis and tumor proliferation and increased tumor apoptosis. However, these studies have been conducted with fruit, seeds, pericarp or partially purified pomegranate extracts making it hard to determine what the active component(s) may be. Punicic acid is an omega-5 long chain polyunsaturated fatty acid found in pomegranate seed oil. A number of long chain fatty acids have been reported to have cancer preventive actions. Here we investigated the potential ability of punicic acid to affect growth of both an estrogen insensitive breast cancer cell line (MDA-MB-231) and an estrogen sensitive cell line developed from the MDAMB-231 cells (MDA-ER 7).
Methods: The two breast cancer cell lines were cultured in vitro in the presence of various amounts of punicic acid, conjugated linoleic acid, α-linolenic acid and other substances to evaluate cell proliferation, apoptosis, mitochondrial membrane permeability and cell cycle.
Results: We found that 40 µM punicic acid inhibited proliferation of MDA-MB-231 and MDA-ER 7 cells 92% and 96% respectively compared to untreated cells. Furthermore, punicic acid induced apoptosis in the MDA-MB-231 and MDA-ER 7 cells by 86% and 91% respectively compared to untreated control cells. Punicic acid also disrupted mitochondrial membrane potential of both cell lines. We next investigated whether lipid oxidation was required for the function of punicic acid by adding 20 µM of the antioxidant tocotrienol to the assays. This resulted in reversal of the effects of punicic acid on proliferation inhibition, apoptosis and disruption of the mitochondrial membrane potential in both the MDA-MB-231 and MDA-ER 7 cells. Finally, we evaluated the role of PKC signaling in the anticancer effects of punicic acid by performing proliferation assays in the presence of the PKC inhibitor bisindolymaleimide I. Proliferation inhibition by punicic acid was partially blocked in both the MDA-MB-231 and MDA-ER 7 cells.
Conclusions: Our in vitro assays indicated that punicic acid inhibited both estrogen sensitive and estrogen insensitive cell lines equally. Additionally the results indicate that the antiproliferative effect of punicic acid on human breast cancer cells appears to be at least partially dependent on lipid peroxidation and the PKC pathway.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A72.
Abstract A73: Bladder cancer inhibition by allyl isothiocyante
Authors: Bhattacharya Arup , Tang Li , Geng Feng , Paonessa Joseph D. , Chen Shang C. , Wong Michael K.K. , Zhang Yuesheng 
Published: May 2012

Abstract
Nearly all cancers of the urinary bladder originate from its inner surface (epithelium). While most bladder cancers are diagnosed at an early stage, recurrence rate is extremely high. There is an urgent need for agents capable of inhibiting bladder cancer development and recurrence. Allyl isothiocyanate (AITC), an ingredient of many common cruciferous vegetables, was previously shown to kill bladder cancer cells in vitro. Our objective was to evaluate the chemopreventive potential of AITC against bladder cancer. The anticancer activities of AITC were assessed using multiple bladder cancer cell lines in vitro and two rat bladder cancer models in vivo (an orthotopic model and a subcutaneous model). Its toxicity toward normal human bladder epithelial (NHBE) cells was also examined. Pharmacokinetic study of AITC and histological examination of normal and malignant bladder tissues of AITC-treated rats were undertaken as well.
Proliferation of bladder cancer cells was potently inhibited by AITC (IC50 of approximately 3 µM), which was associated with G2/M arrest and apoptosis. AITC was markedly less toxic to NHBE cells (IC50 of 69 µM). Low oral dose of AITC (1 mg/kg), starting one day after cancer cell inoculation significantly inhibited the development of orthotopic bladder cancer, but was ineffective against subcutaneous xenografts of the same cancer cells. This differential effect was explained by our finding that urinary concentrations of AITC equivalent were 2–3 orders of magnitude higher than that in the plasma, and that its levels in the orthotopic bladder cancer tissues were also 3 orders of magnitude higher than that in the subcutaneous cancer tissues. Thus, AITC is selectively delivered to bladder cancer tissue through urinary excretion and potently inhibits bladder cancer development in vivo. Besides its potential use for prevention of primary bladder cancer, AITC appears to represent a novel and very attractive approach in the management of recurrence of superficial bladder cancer, since all currently available intravesicle therapies against bladder cancer recurrence mandate urethral catherization. In addition, this new knowledge opens the possibility for adjuvant or multimodality combination approaches for the prevention and treatment of bladder cancer. Supported by NCI grant CA124627.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A73.
Abstract A74: Inhibition of azoxymethane-induced preneoplastic lesions in the rat colon by a novel resistant starch cooked by different methods
Authors: Zhao Yinsheng , Hasjim Jovin , Ai Yongfeng , Jane Jay-lin , Birt Diane F. 
Published: May 2012

Abstract
The purpose of this study was to test the inhibitory effects of a novel resistant starch cooked by two different methods on azoxymethane (AOM)-induced colon carcinogenesis in rats. The novel resistant starch (RS)(patent pending) was processed from commercial high amylose cornstarch. A normal cornstarch (CS) and the high amylose cornstarch (HA) were used as negative and positive control starch groups, respectively. Two cooking methods were applied to all the three starches: (1) making each starch into bread using a standard bakery procedure (cB). (2) using boiling water, high moisture cooking method (cW). Then the starches were mixed with other ingredients based on AIN-93 formulations into 6 rat diets: bread normal-cornstarch diet (cB-CS), bread high-amylose-cornstarch diet (cB-HA), bread novel-resistant-starch diet (cB-RS), boiling-water-high-moisture normal-cornstarch diet (cW-CS), boiling-water-high-moisture high-amylose-cornstarch diet (cW-HA), and boiling-water-high-moisture novel-resistant-starch diet (cW-RS). Six groups of 5-week-old male Fischer 344 rats including 15 animals each were injected with two doses of 20 mg/kg bw AOM one week apart and fed the above diets respectively. Another six groups of male Fischer 344 rats with 5 animals in each group were injected with saline and fed the same six kinds of diets as the AOM treated groups. The rats were fed for 8 weeks after the second injection and then killed. Caecum weight and pH, Aberrant Crypt Foci (ACF) and Mucin Depleted Foci (MDF) were investigated. ACF and MDF were only seen with AOM treatment. The ACF numbers for cB-CS, cB-HA, cB-RS, cW-CS, cW-HA, and cW-RS groups were 29, 29, 17, 225, 256, and 121, respectively. The MDF numbers for the above diet groups were 6.1, 4.9, 1.9, 10.7, 8.7 and 2.1, respectively. ACF and MDF numbers were significantly reduced in rats fed novel resistant starch diet in comparison with rats fed the other two diets (P&lt;0.0001). When comparing the two cooking methods, the cB diet groups also showed a significantly decrease in preneoplastic lesion numbers compared with the cW diet groups (P&lt;0.0003). Increased caecum weight and decreased caecum pH were also observed in the novel resistant starch diet group in comparison with the other two diet groups (P&lt;0.05). These results suggested that the novel resistant starch, which is less digestible than regular cornstarch or commercial high amylose cornstarch, may inhibit colonic carcinogenesis. The cooking method could also be important since the bread baking procedure showed significantly more effectiveness in the inhibition than the boiling water high moisture method. The inhibition might be related to increased caecal fermentation.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A74.
Abstract A79: Human breast tissue bioavailability of topically applied limonene
Authors: Miller Jessica A. , Thomson Patricia , Hakim Iman A. , Lopez Ana Maria , Vining Donna , Chew Wade M. , Chow H-H Sherry 
Published: May 2012

Abstract
Purpose: Limonene is a monocyclic monoterpene found at high concentration in citrus peel oil and has demonstrated anti-cancer effects in preclinical studies of mammary carcinogenesis. However, the effective oral dose determined in rodents extrapolates to a human dose that may not be feasible for long-term consumption. Limonene is highly lipophilic and has been long explored as an enhancer for percutaneous absorption of pharmaceutical drugs, including tamoxifen. Preliminary work from our group demonstrated that topically applied limonene is absorbed through the mouse skin and accumulates in the mammary glands.
Methods: We conducted a pilot clinical study to determine whether limonene would be bioavailable in the breast following topical application. In the first study phase, we recruited 19 healthy women to apply limonene containing massage oil to the breast daily or 3x/wk. Nipple aspirate fluid (NAF) and plasma samples were collected before and after 4 weeks of limonene massage application. Sample limonene concentrations were determined using gas chromatography-mass spectrometry. In the second study phase, we recruited 25 healthy women to undergo 4 weeks of daily limonene massage oil application to the breast. Potential agent effect biomarkers were determined in NAF and plasma collected before and after the limonene massage application.
Results: In samples collected from the first study phase, no significant increase in NAF and plasma limonene levels was observed following the limonene massage application, possibly because limonene deposits in the fatty breast tissue with minimal secretion to NAF or systemic circulation. Changes in agent effect biomarkers in NAF, including TGF-beta, EGF, and adiponectin, were evaluated in the second study phase for determination of the breast tissue limonene bioavailability. There were no consistent changes in the agent effect biomarkers overall or in pre-menopausal women following the limonene massage application. However, among the post-menopausal women (n =8), there were significant increases in NAF levels of TGF-beta (p = 0.005) and EGF (p = 0.032), and there was an increasing trend in adiponectin (p = 0.164, n=5 due to limited NAF volume).
Conclusions: We conclude that breast massage application of limonene containing massage oil did not result in consistent changes in limonene secretion to the NAF and the potential drug effect biomarkers in NAF. However, limonene massage application increased the NAF expression of TGF-beta and EGF in post-menopausal women, indicative of the intervention effects in the breast tissue. Further studies are needed to explore the potential effects of topical limonene massage intervention on carcinogenesis biomarkers in a larger cohort of post-menopausal women. Supported by Department of Defense, BCRP Idea Award, BC061529
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A79.