bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A67: Syntheses and antitumor activities on NCI-60 human tumor cell line protocol of novel N-hydroxyethyl-4-aza-didehyropodophyllotoxin derivatives with halo substitutions on ring-E
Authors: Kumar Ajay , Kumar Vineet , Alegria Antonio E. , Sanjay Malhotra V.
Published: January 2014

Podophyllotoxin is a natural product obtained from endangered Berberidaceae family species. Derivatives namely etoposide, etopophos and teniposide have been developed from podophyllotoxin and are currently used in clinic for the treatment of a variety of malignancies since five decades. Synthesis of podophyllotoxin is not feasible so far and due to this reason structural modification of podophyllotoxin could not be explored very well. The structural complexity of podophyllotoxin, arising from the presence of four stereogenic carbons in ring C has restricted most of the structural activity relationship (SAR) studied by derivatization of the parent natural product rather than by de novo multi-step chemical synthesis. In past we have developed synthetic analogues of podophyllotoxin i.e. aza-podophyllotoxin derivatives an important scaffold to address this chemistry.

We have developed some heterocyclic analogues of podophyllotoxin i.e. N-hydroxyethyl-4-aza-podophyllotoxin derivatives. Owing to their promising activity against 60 cell lines at NCI, we further developed a novel library of N-hydroxyethyl-4-aza-didehyropodophyllotoxin derivatives substituted at ring-E by halogens. This was followed by a screen of in-vivo activity using a panel of tumor hollow-grafts implanted in mice consisting of breast (MDA-MB-231), non-small lung (NCI-H23 and NCI-H522), colon (SW-620 and COLO 205), melanoma (UACC-62, MDA-MB-435 and LOXIMVI), ovarian (OVCAR-5 and OVCAR-3) and CNS (U251 and SF-295) cell lines. These new compounds shows comparatively good activity against ovarian and melanoma cancer lines.

Citation Format: Ajay Kumar, Vineet Kumar, Antonio E. Alegria, Malhotra V. Sanjay. Syntheses and antitumor activities on NCI-60 human tumor cell line protocol of novel N-hydroxyethyl-4-aza-didehyropodophyllotoxin derivatives with halo substitutions on ring-E. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A67.
Abstract A68: Design, synthesis, and antiproliferative evaluations of 3-phenylquinolinylchalcone derivatives against non-small cell lung cancers and breast cancers
Authors: Tzeng Cherng-Chyi , Tseng Chih-Hua , Chen Yeh-Long
Published: January 2014

Chalcones are natural products which have displayed a wide variety of biological activities, including anti-malarial, anti-protozoal, anti-inflammatory, immunomodulatory, nitric oxide inhibition, tyronase inhibition, and anticancer activities. Due to their abundance in plants and ease of synthesis, the chalcone class of compounds has attracted extensive studies. On the other hand, quinoline skeleton is one of the key building elements for a large number of natural and synthetic heterocycles which possess a wide variety of biological effects such as antimalarials, bactericidal, antitumor, anti-inflammatory, antiproliferative, and antiviral activities. Therefore, a series of chalcone derivatives in which an aryl moiety was replaced with quinoline nucleus have been synthesized and evaluated for their antiproliferative activities. These newly synthesized chalcone derivatives were evaluated in vitro against a panel of six cancer cell lines including three non-small cell lung cancer cells (H1299, H460, and A549), three breast cancer cells (MCF-7, MDA-MB-231, and SKBR-3), and a normal mammary epithelial cell (M10), Among them, (E)-1-(5-bromothiophen-2-yl)-3-(3-(4-methoxyphenyl)quinolin-2-yl)prop-2-en-1-one (1) was active against the growth of H1299 and SKBR-3 with IC50 values of 0.71 and 0.52 μM respectively which was more active than the positive topotecan (IC50 values of > 10.0 μM in each case). Compound 1 was the most active against the growth of MDA-MB-231 with an IC50 value of < 0.1 μM and was not cytotoxic to the normal mammary epithelial cell (M10) with an IC50 value of 9.38 μM. Mechanism studies indicated that compound 1 induced cell cycle arrest at G2/M phase followed by DNA fragmentation via activation of caspase-3, cleavage of PARP, and consequently caused the cell death. Further structural optimization is currently ongoing.

Citation Format: Cherng-Chyi Tzeng, Chih-Hua Tseng, Yeh-Long Chen. Design, synthesis, and antiproliferative evaluations of 3-phenylquinolinylchalcone derivatives against non-small cell lung cancers and breast cancers. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A68.
Abstract A78: Broccoli-derived compounds down regulate C-C chemokine ligand 2 expression and monocyte attraction through androgen-dependent pathway in LNCaP prostate cancer cells
Authors: Wang Thomas , Kim Eun-Kyung , Milner John , Kim Young
Published: January 2014

Inflammation has an important role in prostate tumorigenesis. The recruitment of inflammatory monocytes to the tumor site is precipitated by increased levels of the chemo-attractant C-C chemokine ligand 2 (CCL2). In the present study, we test the hypothesis that broccoli-derived cancer protective compounds, indole-3-carbinol (I3C) and 3', 3'-diindolylmethane (DIM), exert anti-inflammatory effects by decreasing CCL2 levels and thereby down regulating CCL2 mediated pathways. Dihydrotestosterone (DHT) induced a time (0-72 hrs) and concentration-dependent (0-1 nM) increase in CCL2 mRNA levels in androgen-responsive LNCaP cells. Consistent with increase in CCL2 mRNA, we also observed increased secretion of CCL2 protein in the media of DHT-treated LNCaP cells. This effect of DHT was mediated through an androgen receptor (AR)-dependent pathway as small inhibitor RNA against AR negated the induction. Conditioned media from androgen-treated cells promoted human monocyte THP-1 cell migration and this effect was blocked by antibody against CCL-2. Both I3C and DIM inhibited promotional effects of DHT on CCL2 expression and monocyte migration in-vitro. These results indicate the effect of I3C and DIM on CCL2 and monocyte migration was androgen dependent. Hence, androgen appeared to stimulate CCL2 secretion and thereby promotes inflammatory micro-environments in prostate tumors. These results suggest that the androgen mediated inflammatory processes are modulated by broccoli-derived compounds.

Citation Format: Thomas Wang, Eun-Kyung Kim, John Milner, Young Kim. Broccoli-derived compounds down regulate C-C chemokine ligand 2 expression and monocyte attraction through androgen-dependent pathway in LNCaP prostate cancer cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A78.
Abstract A84: ω3 rich diet protects against Kras-induced metaplasia via repression of NF-κB
Authors: Principe Daniel R. , Mascarinas Windel Emman T. , Chheda Chintan , Adrian Kevin , Mangan Riley , Boven Lindsay C. , Grippo Paul J.
Published: January 2014

Expression of mutant Kras is observed and often implicated in both pancreatitis and pancreatic cancer. Yet, the means by which inflammation occurs is relatively unexplored, although a previous report supports that induction of inflammation in the presence of oncogenic Kras initiates an NF-κB–mediated positive feedback loop that incorporates Cox-2 and production of PGE2 which further amplify mutant Kras. The involvement of PGE2 is interesting, as recent data suggests diets rich in ω6 fatty acids promote Kras induced pancreatic inflammation and neoplastic lesions. However, the precise mechanism and role of epigenetic events derived from diets rich in fatty acids have yet to be completely resolved. In this work, we demonstrate that a key step in this process is the induction and accumulation of NF-κB in pancreatic epithelia, a factor sufficient to promote chronic inflammation and progression to pancreatic adenocarcinoma. In HPDE cells, inhibition of NF-κB shows promise, as treatment with the IKK inhibitor Bay11-7085 noticeably reduced levels of the pro-proliferative factor pAkt. In EL-Kras mice fed a diet rich in ω6 fatty acids, NF-kB is upregulated in the pancreas, predominantly in metaplastic lesions. Conversely, these transgenic mice fed an ω3 fatty acid diet show little, if any, NF-kB expression, which is similar to the response in mice fed an intermediate, isocaloric high fat diet. pAkt is known to act upstream of NF-κB, implicating that NF-κB may be involved in a positive feedback loop with a variety of Kras effectors culminating in pancreatitis and eventually pancreatic neoplasia/adenocarcinoma. It has also been demonstrated that the ω6 Cox2-metabolite PGE2 is mediating this response, though in cultured human pancreatic epithelia, Cox-2 inhibition showed no significant change on levels of NF-κB. Yet, Cox2 inhibition in the stroma may be synergistic with epithelial inhibition of NF-κB, offering protection against the progression from inflammation to cancer. This data provides support to multiple targets of chemoprevention and therapy, including Ras and IKK/NF-κB, for pancreatic neoplasia and cancer.

Citation Format: Daniel R. Principe, Windel Emman T. Mascarinas, Chintan Chheda, Kevin Adrian, Riley Mangan, Lindsay C. Boven, Paul J. Grippo. ω3 rich diet protects against Kras-induced metaplasia via repression of NF-κB. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A84.
Abstract B100: Association between ambient ultraviolet radiation and risk of esophageal cancer
Authors: Tran Bich , Lucas Robyn , Kimlin Michael , Whiteman David , Rachel Neale
Published: January 2014

Background and Aims: Ecological studies have suggested an inverse relationship between latitude and risks of some cancers. However, associations between solar ultraviolet radiation (UVR) exposure and esophageal cancer risk have not been fully explored. We therefore investigated the association between nevi, freckles and measures of ambient UVR over the life-course with risks of esophageal cancers.

Methods: We compared estimated lifetime residential ambient UVR among Australian patients with esophageal cancer (330 esophageal adenocarcinoma (EAC), 386 esophago-gastric junction adenocarcinoma (EGJAC), and 279 esophageal squamous cell carcinoma (ESCC)), and 1471 population controls. We asked people where they had lived at different periods of their life, and assigned ambient UVR to each location based on measurements from NASA's Total Ozone Mapping Spectrometer database. Freckling and nevus burden were self-reported. We used multivariable logistic regression models to estimate the magnitude of associations between phenotype, ambient UVR and esophageal cancer risk.

Results: Compared with population controls, patients with EAC and EGJAC were less likely to have high levels of estimated cumulative lifetime ambient UVR (EAC OR 0.59, 95% CI 0.35 – 0.99, EGJAC OR 0.55, 0.34 – 0.90). We found no association between UVR and risk of ESCC (OR 0.91, 0.51 – 1.64). The associations were independent of age, sex, BMI, education, state of recruitment, frequency of reflux, smoking status, alcohol consumption, and H.pylori serostatus. Cases with EAC were also significantly less likely to report high levels of nevi than controls.

Conclusion: These data show an inverse association between ambient solar UVR at residential locations and risk of EAC and EGJAC, but not ESCC.

Citation Format: Bich Tran, Robyn Lucas, Michael Kimlin, David Whiteman, Neale Rachel. Association between ambient ultraviolet radiation and risk of esophageal cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B100.
Abstract B107: The preclinical effects of purified mollusk extracts in a short term mouse model for early-stage colon cancer
Authors: Esmaeelian Babak , Benkendorff Kirsten , Leu Richard Le , Abbott Catherine
Published: January 2014

The Australian whelk, Dicathais orbita, is a novel source of bioactive compounds with anticancer properties. Crude extracts from this mollusk have been found to have anticancer activity against a range of cell lines in vitro and were also effective at inducing apoptosis in vivo in a short-term rodent model for colorectal cancer. However, one important limitation of the preclinical model was toxicity in the liver due to lack of purification in the extract. Consequently, the aim of this research was to purify the bioactive compounds tyrindoleninone, tyrindolenine and the oxidation product 6-bromoisatin from the crude extract of D.orbita using flash column chromatography. The retention times and mass spectrum of the isolated compounds were obtained by liquid chromatography-mass spectrometry. These compounds were then tested for anti-cancer activity using a short-term (2 weeks) in-vivo mouse model using azoxymethane injection. Distal colon epithelial proliferation and apoptosis were evaluated using immunohistochemical staining and hematoxylin staining. Liver toxicity was assessed using serum alanine aminotransferase (AST), aspartate aminotransferase (ALT) and alkaline phosphatase (ALP) levels. Histopathology evaluation of liver was also performed by staining with hematoxylin and eosin. The results showed that the purified compounds had a greater anticancer effect than the crude extract, as evidenced by a significantly higher apoptotic index in the distal colon without any toxicity on liver. In conclusion this study has provided further scientific evidence for establishing the usefulness for this mollusk extract as a new medicine for the treatment or prevention of colon cancer.

Citation Format: Babak Esmaeelian, Kirsten Benkendorff, Richard Le Leu, Catherine Abbott. The preclinical effects of purified mollusk extracts in a short-term mouse model for early-stage colon cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B107.

Note: This abstract was not presented at the conference.
Abstract B20: Secreted Protein Acidic and Rich in Cysteines-Like 1 Suppresses Aggressiveness and Predicts Better Survival in Colorectal Cancers
Authors: Hanguang Hu , Hang Zhang , Weiting Ge , Xiyong Liu , Jiaping Peng , Shujing Yu , Yun Yen , Shu Zheng
Published: January 2014

Background: Secreted protein acidic and rich in cysteines-like 1 (SPARCL1) is an extracellular matrix glycoprotein with malignancy suppressing potential. The hypothesis that SPARCL1 reduces cancer invasiveness and predicts better survival in colorectal cancers (CRC) was investigated.

Material and Methods: Stable SPARCL1 transfectants, RKO-SPRCL1, and corresponding vector control were constructed and implanted into nude mice to generate a mouse xenograft model of liver metastasis. Also, a retrospective outcome study was conducted on the COH set (222 CRCs) and ZJU set (412 CRCs). The protein expression level of SPARCL1 was determined by immunohistochemistry. The Kaplan-Meier and COX analyses were employed for survival analysis. The association of SPARCL1 with MET was sought by RT-PCR and Western blot analysis.

Results: The ectopic expression of SPARCL1 significantly reduced the potential for anchorage-independent growth, migration and invasion, and it induced cell differentiation in RKO and SW620 cells. In mouse xenograft model, the expression of SPARCL1 significantly reduced the liver metastasis (P = 0.001). The patient-based studies revealed that the expression of SPARCL1 was related to better differentiation (P < 0.01), less lymph node involvement (Odds Ratio, OR=0.67, 95% CI 0.45-1.00) and less distant metastasis (OR=0.38, 95% CI 0.18-0.79). The Kaplan-Meier and COX analysis demonstrated that the expression of SPARCL1 was associated with better overall survival (Log–rank P < 0.01; hazard ratio, HR=0.57, 95% CI 0.39-0.84). Transfection of SPARCL1 induced MET of colon cancer cells.

Conclusion: SPARCL1 functions as a tumor suppressor promoting differentiation possibly via MET, which inhibits the aggressiveness of CRC.

Citation Format: Hu Hanguang, Zhang Hang, Ge Weiting, Liu Xiyong, Peng Jiaping, Yu Shujing, Yen Yun, Zheng Shu. Secreted protein acidic and rich in cysteines-like 1 suppresses aggressiveness and predicts better survival in colorectal cancers. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B20.
Abstract B21: Comparative Analysis of Peptide Nucleic Acid (PNA)-Mediated Real-Time PCR Clamping and DNA Direct Sequencing for KRAS Mutation Detection in Malignant Effusion
Authors: Park Chan Kwon , Yeo Chang Dong , Lee Sang Haak , Yoon Hyoung Kyu , Kim Seung Joon
Published: January 2014

Detection of mutations in clinical cancer specimen is important, and malignant pleural effusion could be important clinical specimen for KRAS mutation study in non-small cell lung cancer (NSCLC) patients. Direct sequencing is known to be the standard for detecting KRAS mutations. However, peptide nucleic acids (PNA)-mediated PCR clamping method is a recently introduced method for analyzing KRAS mutations with increased sensitivity and stability. Therefore, we attempted to compare to both methods through serum, effusion, tissue, and cell block if it was available.

A total of 48 malignant effusion being mainly NSCLC was analyzed for KRAS mutations using the PNA-mediated PCR clamping technique and direct sequencing. Proportion of mutation between PNA and sequencing were 14.6% (6.07-27.76) and 10.4% (3.47-22.66) on each. Diagnostic accuracy of mutation detection was that sensitivity 100% (47.82-100.0), specificity 95.35% (84.19-99.43), positive predictive value 71.43%(29.04-96.33), and negative predictive value 100% (91.41-100.0).

In conclusion, we demonstrated the PNA is favorable source for KRAS mutation test in the malignant effusion.

Citation Format: Chan Kwon Park, Chang Dong Yeo, Sang Haak Lee, Hyoung Kyu Yoon, Seung Joon Kim. Comparative analysis of peptide nucleic acid (PNA)-mediated real-time PCR clamping and DNA direct sequencing for KRAS mutation detection in malignant effusion. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B21.
Abstract B32: Role of megalin in uptake of 1α,25(OH)2D in colon cancer cells
Authors: Hibler Elizabeth A. , Jacobs Elizabeth T. , Jurutka Peter W.
Published: January 2014

Vitamin D has been proposed as a chemopreventive agent for colorectal cancer; however, the mechanisms governing the availability of the active form of vitamin D, 1α,25(OH)2D, remain unclear. There is growing evidence that uptake of vitamin D metabolites at the cellular level may involve receptor-mediated endocytosis in certain tissues. Megalin, or low-density lipoprotein 2, has demonstrated effects on uptake of Gc-globulin (GC)-bound vitamin D metabolites in kidney, bone, gallbladder, and mammary gland cells. However, this mode of metabolite uptake has not been tested in the colon. We measured activation of the VDR-RXR heterodimer in the context of a mammalian-2-hybrid (M2H) biological assay system as a marker for uptake of vitamin D metabolites in human HCT-116 colorectal carcinoma cells. Cells were transfected with control versus megalin siRNA or, alternatively, no siRNA but treatment with receptor associated protein (RAP), a ligand for megalin that blocks GC binding. Cells were then treated with ethanol (EtOH) vehicle versus 1x10-8 M, 2.5x10-9 M, or 5x10-10 M 1α,25(OH)2D. The results demonstrate that treatment with either megalin siRNA or RAP induced an overall statistically significant increase in activation of the VDR-RXR heterodimer (ANOVA p< 0.001) compared to control siRNA, after controlling for differences by replicate and 1α,25(OH)2D concentration. Furthermore, stratification by concentration and use of the Tukey HSD test for pairwise comparisons revealed that activation following treatment with megalin siRNA was greater than with RAP, but not statistically significantly different. Activation with megalin siRNA was significantly different from control siRNA at all three 1α,25(OH)2D concentrations compared to EtOH (p< 0.05); however, treatment with RAP only led to the significant increase at 1x10-8 M 1α,25(OH)2D. Further work is ongoing to test uptake of 25(OH)D and an additional assay based upon vitamin D response element binding. These results provide preliminary evidence that colon cells use megalin to regulate uptake of 1α,25(OH)2D and that its presence acts to limit uptake, especially when extracellular concentrations of 1α,25(OH)2D are high. These results identify megalin as a novel target and modulator of vitamin D metabolite delivery at the cellular level that may influence population-level cancer risk. Additional testing of these results under varied cell conditions and in multiple cell lines is necessary to further elucidate the role of megalin in uptake of vitamin D metabolites into cancer cells.

Citation Format: Elizabeth A. Hibler, Elizabeth T. Jacobs, Peter W. Jurutka. Role of megalin in uptake of 1α,25(OH)2D in colon cancer cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B32.
Abstract B37: Antiproliferative effects of pomegranate are associated with downregulation of homologous recombination pathway: Potential use in cancer prevention
Authors: Kovvuru Prasad , Shirode Amit , Reliene Ramune
Published: January 2014

High antioxidant capacity of pomegranate fruit is thought to be responsible for various health benefits, although the link between antioxidant capacity and antiproliferative effects has not been established yet. To better understand this relation we examined growth inhibition by pomegranate extract (PE) in association with antioxidant capacity and analyzed global gene expression changes in breast cancer MCF-7 cells. PE inhibited cell growth by induction of cell cycle arrest in G2/M and the induction of apoptosis. In contrast, antioxidants N-acetylcysteine and Trolox did not affect cell growth at doses containing equivalent antioxidant capacity as PE, suggesting that growth inhibition by PE cannot solely be attributed to its high antioxidant potential. DNA microarray analysis revealed that PE downregulated genes associated with mitosis, chromosome organization, RNA processing, DNA replication and DNA repair, and upregulated genes involved in regulation of apoptosis and regulation of cell proliferation. Of particular interest, both microarray and quantitative RT-PCR indicated that PE downregulated important genes involved in DNA repair by homologous recombination (HR), such as MRE11, RAD50, NBS1, RAD51, BRCA1, BRCA2 and BRCC3. Downregulation of HR genes correlated with increased levels of their predicted microRNAs, miR-183 (predicted target RAD50) and miR-24 (predicted target BRCA1), suggesting that PE may regulate microRNAs involved in DNA repair processes. Further, PE induced DNA double strand breaks (DSBs) that persisted and cells remained growth-inhibited for at least four days after the removal of PE. These data suggest that PE targets HR sensitizing cells to DSBs, cell cycle arrest and apoptosis. Downregulation of HR by PE is expected to specifically affect transformed and other rapidly growing cells because HR pathway is found to be dispensable for quiescent and post-mitotic tissues. HR not only repairs DSBs and replication-associated lesions but also may result in genome rearrangements and loss of heterozygocity, which drives oncogenic transformation. Hyperactive HR, genetic instability and elevated carcinogenesis has been exemplified in both humans and mice deficient in cell cycle control and DNA damage response genes including TP53 and ATM. Thus, these data suggest that downregulation of HR by PE may retard cell growth and prevent genetic instability and carcinogenesis.

Citation Format: Prasad Kovvuru, Amit Shirode, Ramune Reliene. Antiproliferative effects of pomegranate are associated with downregulation of homologous recombination pathway: Potential use in cancer prevention. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B37.
Abstract B48: Anticancer effect of guava leaves (Psidium guajava L.) in prostate cancer cells
Authors: Yang Woong Mo , Kim Mi Hye , Park Sang-Yoon , Ahn Kwang Seok , Lee Seok-Geun
Published: January 2014

This study was carried out to evaluate the anticancer effects of guava leaf extracts and its fractions. The chemical compositions of the active extracts were also determined. In the present study, we set out to determine whether the anticancer effects of guava leaves are linked with their ability to suppress constitutive AKT/mammalian target of rapamycin (mTOR)/ribosomal p70 S6 kinase (S6K1) and mitogen-activated protein kinase (MAPK) activation pathways in human prostate cancer cells. We found that guava leaf hexane fraction (GHF) was the most potent inducer of cytotoxic and apoptotic effects in PC-3 cells. The molecular mechanism or mechanisms of GHF apoptotic potential were correlated with the suppression of AKT/mTOR/S6K1 and MAPK signaling pathways. This effect of GHF correlated with down-regulation of various proteins that mediate cell proliferation, cell survival, metastasis, and angiogenesis. Analysis of GHF by gas chromatography and gas chromatography-mass spectrometry tentatively identified 60 compounds, including β-eudesmol (11.98%), α-copaene (7.97%), phytol (7.95%), α-patchoulene (3.76%), β-caryophyllene oxide (CPO) (3.63%), caryophylla-3(15),7(14)-dien-6-ol (2.68%), (E)-methyl isoeugenol (1.90%), α-terpineol (1.76%), and octadecane (1.23%). Besides GHF, CPO, but not phytol, also inhibited the AKT/mTOR/S6K1 signaling pathway and induced apoptosis in prostate cancer cells. Overall, these findings suggest that guava leaves can interfere with multiple signaling cascades linked with tumorigenesis and provide a source of potential therapeutic compounds for both the prevention and treatment of cancer.

Citation Format: Woong Mo Yang, Mi Hye Kim, Sang-Yoon Park, Kwang Seok Ahn, Seok-Geun Lee. Anticancer effect of guava leaves (Psidium guajava L.) in prostate cancer cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B48.
Abstract B63: Developing Novel STAT3 Inhibitors for the Treatment and Prevention of Cancer
Authors: Yang Zhengduo , Chen Haijun , Chu Lili , Zhang Yusong , Ding Chunyong , Terry Kristin , Zhou Jia , Shen Qiang
Published: January 2014

Signal transducers and activators of transcription (STATs) are a family of transcription factors involved in the regulation of early embryonic development, immune response, cell proliferation, differentiation, and apoptosis. Particularly, STAT3 regulates lobuloalveolar apoptosis during involution in mammary gland development, and its activation is required for the growth of CD44+CD24- stem cell-like breast cancer cells and the development of multiple cancers including breast cancer. Increased STAT3 transcriptional activity was found to correlate with ER-negative phenotype in breast cancer cell lines and in primary human invasive ductal breast carcinomas. Thus, STAT3 represents a promising target for therapeutic and preventive intervention of breast cancer. Yet current strategies of inhibiting STAT3 activity did not sufficiently block STAT3 activation in cancer cells due to their limited potency, poor solubility or bioavailability. Despite several STAT3 inhibitors have been advanced into early clinical trials, there is an urgent need to develop a more successful strategy targeting STAT3 for cancer therapies, and preventive use in particular. We attempted to identify potent and orally active STAT3 inhibitors for such purposes and have designed, synthesized and screened a series of novel STAT3 inhibitors utilizing fragment-based drug design strategy. A number of small molecules with new scaffolds have been discovered with low-micromolar to nanomolar potency in inhibiting the proliferation of various human breast cancer and pancreatic cancer cells. The identified compound HJC0152 significantly suppresses basal and IL-6-stimulated STAT3 promoter activity and STAT3 phosphorylation, reduces total STAT3 protein expression, induces G2/M cell cycle arrest, and induces early apoptosis. HJC0152 has demonstrated a better potency in suppressing the growth of MDA-MB-231 breast xenograft tumors via intraperitoneal and oral administrative routes, with remarkably improved aqueous solubility (3,300 fold improvement) and less toxicity than the lead compounds. In conclusion, we have developed a new class of orally active STAT3 inhibitors with superior drug-like properties for further preclinical therapeutic and preventive evaluation.

Citation Format: Zhengduo Yang, Haijun Chen, Lili Chu, Yusong Zhang, Chunyong Ding, Kristin Terry, Jia Zhou, Qiang Shen. Developing novel STAT3 inhibitors for the treatment and prevention of cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B63.
Abstract CN05-02: Arsenic carcinogenesis
Authors: Argos Maria
Published: January 2014

Elevated concentrations of arsenic in groundwater pose a public health threat to millions of people worldwide, including severely affected populations in Bangladesh. While arsenic is an established human carcinogen and has been associated with a multitude of health outcomes in epidemiologic studies, a mode of action has yet to be determined for some aspects of arsenic toxicity. In this presentation, we will emphasize the role of recent genetic and molecular epidemiologic investigations of arsenic toxicity. Additionally, we will discuss considerations for the public health impacts of arsenic exposure through drinking water with respect to primary and secondary prevention efforts, including discussion of an on-going chemoprevention trial of selenium and vitamin E supplementation among individuals with manifest arsenic toxicity in Bangladesh.

Citation Format: Maria Argos. Arsenic carcinogenesis. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN05-02.
Abstract CN06-02: Epigenetic Deregulation of MicroRNAs During Tobacco Carcinogen-Induced Transformation of Bronchial Epithelial Cells
Authors: Belinsky Steven A. , Spira Avrum , Tellez Carmen
Published: January 2014

Epigenetic silencing of genes and microRNAs (miRs) via chromatin remodeling and cytosine methylation has emerged as a major mechanism in lung cancer etiology. The reversal of gene and miR silencing using pharmacological agents by affecting cytosine-DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), or histone deacetylases (HDACs) offers new strategies for prevention and intervention for lung cancer. We have developed an in vitro model using hTERT/cdk4 immortalized human bronchial epithelial cell lines (HBECs) that identifies molecular changes driving transformation of preneoplastic lung epithelial cells during exposure to carcinogens found in mainstream and environmental tobacco smoke. Our studies provided a mechanistic link between increased DNMT1 protein, de novo methylation of genes, and reduced DNA repair capacity that together seemed causal for transformation. Our recent studies show that the exposure of HBECs to carcinogens for 4 wk induces a persistent and irreversible, multifaceted dedifferentiation program characterized by the epithelial-to-mesenchymal transition (EMT). EMT induction was epigenetically driven, initially by chromatin remodeling involving H3K27me3 enrichment, with ensuing DNA methylation sustaining the silencing of miR-200b, -200c, and -205 implicated in this developmental program and persisting in malignant tumors. Over expression of these miRs reversed transformation. Next generation sequencing of transformed HBEC lines has identified 25 miRs whose silencing may be regulated through chromatin remodeling and promoter methylation. The impact of specific miRs identified by sequencing on transformation, regulation by chromatin, and their prevalence in lung cancer will be described. (Supported by R01 ES008801 and P50 CA58184).

Citation Format: Steven A. Belinsky, Avrum Spira, Carmen Tellez. Epigenetic deregulation of microRNAs during tobacco carcinogen-induced transformation of bronchial epithelial cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN06-02.
Abstract ED02-03: Animal models for human pancreatic cancer prevention
Authors: Rao Chinthalapally V.
Published: January 2014

Pancreatic cancer has the worst prognosis and is the fourth leading cause of cancer-related deaths in the United States. The five-year survival for this disease is <6% and it is lethal to almost all of the patients diagnosed. As with many epithelial cancers, pre-invasive precursors in the pancreas progress slowly over many years to decades to development of invasive pancreatic cancers in humans. Lack of early detection and effective interventions are major factors contributing to the poor prognosis and dismal survival rates of pancreatic cancer patients for more than sixty years. Detection of pancreatic cancer at an early stage might permit life-saving interventions. Use of tumor xenografts and/or orthotopic models to predict valid targets and for design and development of drugs for pancreatic cancer patients has been disappointing. Animal models with etiological relevance that recapitulate the molecular pathology of human pancreatic intraepithelial neoplasia (PanINs) and their progression to pancreatic ductal adenocarcinoma (PDAC) are ideal models for establishing pancreatic cancer prevention and treatment strategies. Recent advent in genetically engineered mouse (GEM) models, such as development of transgenic KrasG12D-dependent mouse models of PDAC, that mimic human PDAC offer opportunities to identify putative targets of pancreatic lesion development and targeted drug strategies for PDAC prevention. We will present recent advances on i) selection of optimal Kras mouse models for prevention and early diagnosis, and ii) application of Whole Transcriptome (SOLiD) approaches to identify druggable targets for PanINs and PDAC. Then, iii) we will provide a few examples of development of molecularly targeted chemopreventive drugs using the krasG12D mouse model.

Citation Format: Chinthalapally V. Rao. Animal models for human pancreatic cancer prevention. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr ED02-03.
Abstract ED02-04: Using mouse models to develop new drugs and strategies for prevention
Authors: Liby Karen T.
Published: January 2014

Numerous high-profile publications have confirmed that an individual tumor contains hundreds of mutations, that a tumor will continue to acquire mutations as it progresses, and that significant tumor heterogeneity exists not only between tumors but also within a tumor. Because of these challenges, prevention of cancer should be more effective than treating end-stage disease. Mouse models are useful tools for developing new drugs and strategies for cancer prevention, and we have used mouse models of breast, pancreas, and lung cancer to ask different types of questions. Our data demonstrate the benefits of early intervention in the process of carcinogenesis. Moreover, multifunctional drugs that target key regulatory nodes are more effective than targeted therapies for prevention, and combining drugs that target different pathways or cell types can enhance the potency and reduce the toxicity of individual drugs.

Citation Format: Karen T. Liby. Using mouse models to develop new drugs and strategies for prevention. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr ED02-04.
Abstract ED05-03: Building transdisciplinary teams to address cancer health disparities: The Centers for Population Health and Health Disparities (CPHHD) experience
Authors: Paskett Electra D.
Published: January 2014

Cancer health disparities are evident in many underserved and minority populations. Strategies to understand and intervene on these disparities are often complex and occur at multiple levels, and need input from investigators from various disciplines to understand the factors that impact these disparities. In addition, community members, who have the best understanding and knowledge of what is wrong, and how to address disparities in their communities, also need to be involved from the beginning to make relevant and long-lasting differences. The CPHHD initiative, started in 2003, has used 3 main principles to address cancer health disparities in a variety of underserved/minority populations in different regions of the U.S. These principles include: establishing transdisciplinary teams, guided by a theoretical framework developed by the CPHHD initiative to investigate the multi-level factors related to disparate health outcomes, using Community-Based Participatory Research (CBPR). This presentation will describe the multi-level theoretical framework for addressing disparities and how transdisciplinary teams are formed and work together with communities to address disparities in breast, cervical, and prostate cancer among different underserved populations.

Citation Format: Electra D. Paskett. Building transdisciplinary teams to address cancer health disparities: The Centers for Population Health and Health Disparities (CPHHD) experience. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr ED05-03.
Abstract ED06-02: MicroRNAs and cancer progression
Authors: Croce Carlo M.
Published: January 2014

Since the discovery of miR-15a and miR-16-1 deletions in CLL15, many laboratories around the world have shown miRNA dysregulation in all tumors studied, including the most common, such as lung, breast, prostate and gastrointestinal cancers. Such dysregulation, like the dysregulation of oncogenes and tumor suppressor genes, can be caused by multiple mechanisms, such as deletion, amplification, mutation, transcriptional dysregulation and epigenetic changes.

As miRNAs have multiple targets, their function in tumorigenesis could be due to their regulation of a few specific targets, possibly even one, or many targets. A future challenge will be to identify all of the targets of the miRNAs involved in cancer and establish their contribution to malignant transformation. An additional challenge will be the identification of all of the miRNAs that are dysregulated by pathways that are consistently dysregulated in various types of human cancers. This point is of particular importance, as instead of focusing on specific alterations in protein-coding oncogenes or tumor suppressor genes — which may be difficult to treat — we could focus on their downstream miRNA targets. If these miRNA targets are crucial for the expression of the malignant phenotype and the cancer cells depend on their dysregulation for proliferation and survival, we can expect that the use of miRNAs or anti-miRNAs will result in tumor regression. Genomic analyses for alteration in miRNA genes or for copy number alterations in various human tumors by deep sequencing is in progress but has not been completed. These studies could provide additional information concerning the involvements of miRNAs in cancer and in many other diseases.

Over the past few years, we have observed a shift from conventional chemotherapy to targeted therapies, and miRNAs and anti-miRNAs will contribute extensively to the latter.

Citation Format: Carlo M. Croce. microRNAs and cancer progression. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr ED06-02.
Abstract ED06-03: Circulating microRNAs as cancer biomarkers
Authors: Tewari Muneesh
Published: January 2014

The discovery of circulating microRNAs (e.g., cell-free microRNAs present in plasma and/or serum) has created new opportunities for improving early detection, prevention and treatment of cancer. My presentation will cover basic mechanisms and clinical applications of circulating microRNA biomarkers, as well as potential pitfalls and key future directions in this nascent but promising research area.

Citation Format: Muneesh Tewari. Circulating microRNAs as cancer biomarkers. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr ED06-03.
Abstract FO01-01: Estimating how many prostate cancers are overdiagnosed: Overcoming challenges and avoiding mistakes
Authors: Etzioni Ruth
Published: January 2014

Despite the promise of the PSA test for early detection of prostate cancer, it is now clear that PSA screening can be costly, generating harms alongside benefits. Overdiagnosis, or the detection of cancers that would never have been detected clinically, is perhaps the harm of greatest concern in PSA screening. However, different studies provide widely varying assessments of the magnitude of the overdiagnosis problem. A report from the European prostate screening trial estimated that 48 men would have to be overdiagnosed to prevent one prostate cancer death, and a report based on US incidence trends estimated that more than one million men had been overdiagnosed and overtreated by 2005. These statistics are alarming but dramatically overstate the problem. In this presentation I will demonstrate how different definitions, methods and even populations can produce very different, and sometimes inaccurate, assessments of the frequency of overdiagnosis associated with PSA screening. I will present results from two studies of the US population that showed that about one in four men over 50 detected by PSA screening prior to 2000 was overdiagnosed. I will also present personalized estimates of the likelihood of overdiagnosis that vary from from 3 to 80% depending on age, grade and PSA. These estimates can be used in designing population screening programs that reduce costs and harms while preserving benefit.

Citation Format: Ruth Etzioni. Estimating how many prostate cancers are overdiagnosed: Overcoming challenges and avoiding mistakes. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr FO01-01.
Abstract FO03-02: Worldwide collaborations: The experience of EPIC
Authors: Key Timothy
Published: January 2014

Worldwide collaborations are essential for advancing cancer epidemiology. EPIC – the European Prospective Investigation into Cancer and Nutrition – was established in 1992 as a collaboration between epidemiologists in 10 European countries. Thus from the beginning EPIC has developed approaches to gain the maximum scientific benefit from international collaboration. Beyond Europe, EPIC now participates in several worldwide collaborations with the contribution of both scientific expertise and epidemiological data, including: the Breast and Prostate Cancer Cohort Consortium (BPC3) and the Pancreatic Cancer Cohort Consortium (PANSCAN) as part of the NCI Cohort Consortium; the Harvard Pooling Project of Prospective Studies of Diet and Cancer (Pooling Project); the Endogenous Hormones and Breast cancer Collaborative Group; and the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group. These worldwide collaborations provide the large numbers of cancer cases needed to produce definitive findings on risk factors for cancer.

Citation Format: Timothy Key. Worldwide collaborations: The experience of EPIC. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr FO03-02.