bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1587: AMPK-mTOR axis as key target for chemoprevention of UV-induced skin cancer by the bioflavonoid apigenin
Authors: Tong Xin , Bridgeman Bryan B. , Smith Kimberly A. , Avram Michael J. , Pelling Jill C. 
Published: August 2012

Abstract
Over two million new cases of UV-induced non-melanoma skin cancer are diagnosed yearly in the USA, making it the most common form of cancer in this country. Apigenin, a nonmutagenic, naturally occurring flavonoid found in a variety of fruits and leafy vegetables, inhibits UV-induced skin cancer in mice. Our laboratory and others have shown that apigenin treatment of cells results in a wide variety of antitumorigenic and chemopreventive actions, including suppression of COX-2 expression, enhancement of p53 expression, and induction of cell cycle arrest and apoptosis. However, the primary target(s) responsible for apigenin's chemopreventive function remains elusive. For the first time, we have demonstrated that apigenin activated AMP-activated protein kinase (AMPK) in keratinocytes (mouse and human keratinocyte cell lines, primary normal human epidermal keratinocytes (NHEKs) and mouse epidermis in vivo). The activation of AMPK resulted in inhibition of mTOR signaling, which relieved the block to the autophagy pathway, further inducing autophagy in human keratinocytes. At early stages of tumorigenesis, autophagy acts as a tumor suppressor by removing damaged organelles, proteins, reducing chromosome instability, and inducing type II programmed cell death. Therefore, pharmacological induction of autophagy provides a new strategy for cancer chemoprevention. We have further demonstrated that UV radiation also induced moderate AMPK activation, suggesting that there is a protective cellular response after UV radiation alone, providing limited protection through modest AMPK activation. More intriguingly, pretreatment of keratinocytes or skin with apigenin prior to UV radiation induced AMPK activation dramatically (both in vitro and in vivo). In addition, UV markedly increased mTOR phosphorylation in SKH-1 mice epidermis, and apigenin completely inhibited UV-mediated mTOR activation. Taken together, our results demonstrate that the AMPK/mTOR axis is involved in chemoprevention of UV-induced skin cancer by apigenin, and mechanistically the activation of AMPK further induces autophagy to suppress UV-induced tumorigenesis. Identifying AMPK-mTOR axis as a key target of apigenin and targeting the autophagy pathway for cancer chemoprevention would provide a new target and strategy for the development of better treatment and prevention of skin cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1587. doi:1538-7445.AM2012-1587
Abstract 159: Macrophage Migration Inhibitory Factor (MIF) enhances proliferation and expression of tumorigenic cytokines in a bladder cancer cell line
Authors: Choudhary Shilpa , Pruitt James R. , Sielecki Thais M. , Pilbeam Carol , Taylor John Arthur 
Published: August 2012

Abstract
Background: MIF is a proinflammatory cytokine with regulatory properties over tumor suppressor proteins involved in bladder cancer. We have previously reported that the absence of MIF in transgenic mice or the use of a small molecule oral inhibitor of MIF (CPSI-1306, Cytokine PharmaSciences, Inc, King of Prussia, PA) leads to decreased angiogenesis and invasive potential in the BBN mouse model of bladder cancer. The objective of this study was to evaluate potential pathways of MIF activity in a cell culture model. Methods: High grade, metastatic HTB-5 bladder cancer cells were treated with rhMIF 1-100 ng/ml (CPSI). Measurements included cell counts, proliferation by 3H-thymidine incorporation (TdR), phosphorylated and total ERK by Western analysis and mRNA expression of TNF-α, IL-6, VEGF and CD74 (putative receptor for MIF) by real time PCR. CPSI-1306 (0.5-500 nM) was tested for its ability to decrease ERK phosphorylation. Results: MIF 100 ng/ml increased cell counts 2-fold (p&lt;0.01) on culture days 2-4. MIF increased TdR, normalized to cell numbers, 30% (p&lt;0.01). MIF (1-100 ng/ml) stimulated ERK phosphorylation in a dose dependent manner, which was abrogated by the addition of CPSI-1306 at doses above 5 nM. A specific inhibitor of ERK (PD98059, 50 μm) blocked the MIF stimulated increase in cell number. MIF treatment for 24 hrs increased mRNA expression of the agiogenic factor VEGF and the cytokine TNF-α 2-fold (p&lt;0.01). IL-6 mRNA was unchanged. mRNA levels for the putative MIF receptor, CD74, increased 1.3 fold with treatment (p=0.01). Conclusion: MIF increased ERK phosphorylation, which was blocked by CPSI-1306, a small molecule inhibitor of MIF. MIF also increased cell proliferation via an ERK pathway. These data, along with the increased cytokine expression, provide a potential explanation for the decreased angiogenesis and invasion seen in our in vivo murine models using global knockout of MIF or CPSI-1306. This study is the first to begin to elucidate mechanistic pathways involved in MIFs role in bladder cancer and possible pathways involved in CPSI-1306 inhibition. Funding Source: ACS MRSG-08-270-01-CCE, NIH RO1DK48361
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 159. doi:1538-7445.AM2012-159
Abstract 1590: Taxifolin suppresses UV-induced skin carcinogenesis by targeting EGFR and PI3-K
Authors: Oi Naomi , Chen Hanyong , Kim Myoung Ok , Bode Ann M. , Dong Zigang 
Published: August 2012

Abstract
Skin cancer is one of the most commonly diagnosed cancers in United States. Taxifolin (3, 3′, 4′, 5, 7-pentahydroxy-flavanone, (2R,3R)-dihydroquercetin), which is found in many citrus fruits such as grapefruits and oranges, has been studied for multiple biological effects. However, the molecular mechanisms and direct target of taxifolin in skin cancer chemoprevention are unclear. Here we show that taxifolin suppresses UV-induced skin carcinogenesis by directly targeting epidermal growth factor receptor (EGFR) and phosphoinositide 3-kinase (PI3-K). In silico computer screening results suggest that EGFR and PI3-K are potential targets for taxifolin. In vitro and ex vivo pull-down assay data revealed that taxifolin indeed directly interacts with EGFR and PI3-K at the ATP-binding pocket, and inhibited their kinase activities in vitro. UVB-induced phosphorylation of EGFR and Akt were substantially suppressed by taxifolin in mouse skin epidermal JB6 P+ cells. Taxifolin also suppressed UVB-induced phosphorylation of mitogen-activated protein kinases (MAPKs) and cyclooxygenase-2 (COX-2) expression. Importantly, topical treatment with taxifolin to the dorsal skin significantly suppressed tumor incidence, multiplicity and volume in a solar UV-induced skin carcinogenesis mouse model. Further analysis of the solar UV-exposed mouse skin showed that the taxifolin-treated group had a substantial reduction in solar UV-induced phosphorylation of EGFR and Akt. These results suggest that taxifolin exerts potent chemopreventive activity against UV-induced skin carcinogenesis by targeting EGFR and PI3-K.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1590. doi:1538-7445.AM2012-1590
Abstract 1593: Sulforaphane protects melanocytes and skin from individuals at increased risk for melanoma from the effects of UV radiation: Role of thioredoxin reductase 1.
Authors: Cassidy Pamela B. , Quackenbush John , Campbell Jennifer , Moos Philip J. , Leachman Sancy A. 
Published: August 2012

Abstract
Our interest in the natural product sulforaphane (SF) began with studies of patients at high risk for melanoma. Germline loss-of-function (LOF) mutations in the highly polymorphic melanocortin-1 receptor gene (MC1R), confers a 4-fold increased risk for melanoma. Much of this increase arises from the loss of MC1R-mediated upregulation of antioxidant, pigment synthesis, DNA repair and anti-apoptotic pathways that protect epidermal melanocytes from the mutagenic effects of UV radiation. We have found that SF (likely due to its antioxidant activity) protects both normal human melanocytes, and the skin of human subjects with LOF MC1R mutations, from the harmful effects of UV light. Shave biopsies were harvested from donors with either wild-type MC1R or two LOF alleles. The epidermal tissues were treated ex vivo with UV and/or SF then analyzed histologically and by qPCR. Our results showed that SF provides significant protection from UV to both melanocytes and skin. We found also that the antioxidant protein thioredoxin reductase 1 (TR1) was significantly induced by SF. In order to explore the role of TR1 in protecting melanocytes from UV-induced damage, we have created a human melanocyte cell line that expresses a micro RNA which targets TR1. These cells display increased sensitivity to the effects of UV and differential processing of the pigment synthesis protein tyrosinase. This study demonstrates the promise of SF as an agent for protection of human skin in individuals with high-risk MC1R genotypes from the effects of UV light, and highlights the role of TR1 in this process.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1593. doi:1538-7445.AM2012-1593
Abstract 1600: Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch carcinogenesis by topical garcinol through inhibition of 5-lipoxygenase
Authors: Zhang Xinyan , Chen Xin , Lu Ye , Shim Joong-Youn , Sang Shengmin , Sun Zheng , Chen Xiaoxin Luke 
Published: August 2012

Abstract
Oral cancer is a common malignancy occurring in developing countries, and remains problematic due to lack of effective strategies of prevention and treatment. Our previous studies have shown that aberrant arachidonic acid metabolism, especially the 5-lipoxygenase (5-Lox) pathway, is involved in oral carcinogenesis, and can be targeted for cancer prevention. In order to develop potent topical agents for oral cancer chemoprevention, five known 5-Lox inhibitors from dietary and synthetic sources were evaluated for their potential efficacy when topically applied on the oral epithelium. Garcinol, a polyisoprenylated benzophenone from the fruit rind of Garcinia spp., was found to be the most promising agent based on our calculation of a theoretical activity index. In a short-term study on 7,12-dimethylbenz[a]anthracene (DMBA)-treated hamster cheek pouch, topical garcinol suppressed leukotriene B4 (LTB4) biosynthesis and inhibited inflammation and cell proliferation in the oral epithelium. In a long-term carcinogenesis study, topical garcinol significantly reduced the size of visible tumors, the number of cancer lesions, cell proliferation, and LTB4 biosynthesis. Furthermore, computer modeling showed that garcinol well fit the active site of 5-Lox, and inhibited enzyme activity through possible interactions between the phenolic hydroxyl groups and the non-heme catalytic iron. These results demonstrated that topical garcinol exerts its chemopreventive effect on DMBA-induced hamster cheek pouch carcinogenesis by inhibiting 5-Lox, inflammation and cell. Chemical modifications of garcinol may produce more potent 5-Lox inhibitors for topical use in oral cancer chemoprevention.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1600. doi:1538-7445.AM2012-1600
Abstract 1610A: Chromatin modifying agents improve the anticancer activity of resveratrol in prostate cancer cells
Authors: Savva Christiana G. , Papageorgis Panos , Constantinou Andreas I. 
Published: August 2012

Abstract
Resveratrol (Rsv), a dietary compound from grapes gained considerable attention as a cancer chemopreventive agent in several preclinical rodent models of prostate carcinogenesis. However, the poor bioavailability of Rsv in human plasma raised reservations about the potential health benefits of dietary Rsv. The objective of the present study was to combine Rsv with other agents, that can be given at non-toxic concentrations, in order to produce strong anticancer effects at low Rsv concentrations. For this purpose, we choose the histone deacetylase inhibitor (HDAC) suberoyl-anilide hydroxamic acid (SAHA), and the demethylating agent, 5-aza-2′-deoxycytidine (5-aza) which we evaluated in PC-3 prostate cancer cells. We found that Rsv at relatively low concentrations (2.5 μM) inhibited only marginally cell growth (&lt;15 %). Similarly, the selected concentration of SAHA (0.5 μM) or 5-aza (0.05 μM) also produced minimal inhibition of cell growth (&lt;17 % and &lt;15 % inhibition respectively). A substantial decrease (&gt; 50 %) in cellular proliferation was evident when Rsv was combined with either one of the chromatin modifying agents. Concomitant analysis of cell proliferation and apoptosis revealed that pre-treatment with SAHA or 5-aza followed by Rsv administration suspended cell growth. Cell cycle arrest was also evident which was associated with p53-indepented up-regulation of p21 and accompanied by an increase in the ratio of Bax/Bcl-2. Treatment with the pan-caspase inhibitor, z-vad.fmk did not restore cell growth, indicating that the mechanism by which these compounds trigger apoptosis is independed of caspase activation. These data suggest that the growth-inhibitory effect is mediated via upregulation of p21, down regulation of key cell cycle activators, and followed by apoptotic cell death. This combined action of Rsv might be the result of transcriptional alterations of specific genes that participate in the apoptotic and survival pathways due to the chromatin remodeling effects of SAHA and 5-aza. Our results show conclusively that, in a highly invasive prostate cancer cell line, the combination of Rsv with an HDAC inhibitor or a demethylaying agent, increases Rsv's anticancer activity. These new insights, in enhancing the anticancer effect of Rsv, may be applied to new and innovative strategies in the treatment or prevention of prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1610A. doi:1538-7445.AM2012-1610A
Abstract 1613: Delta-tocotrienol delays the progression of pancreatic intraepithelial neoplasia (PanIN) lesions in a conditional KrasG12D mouse model
Authors: Husain Kazim , Centeno Barbara , Perez Marta , Lee Guo , Kazim Sabiha , Chen Dung-Tsa , Sebti Said , Malafa Mokenge 
Published: August 2012

Abstract
Background: We have shown that natural vitamin E γ-tocotrienol is the most bioactive tocotrienols in inhibiting the cell proliferation and induction of apoptosis in pancreatic cancer cells as well as in xenograft models. Therefore in this study we evaluated the chronic 12-month feeding of γ-tocotrienol on the prevention of the progression of PanIN lesions in a conditional KrasG12D mouse model. Methods: Offspring of LSLKRASG12D x PDX-1-Cre intercrosses (double positive by genotyping) were randomized to three groups: 1) No treatment (NT), 2) Vehicle (ethanol extracted olive oil, 1.0 ml/kg x 2/ day, PO) and 3) γ-tocotrienol (200 mg/kg x 2/day, PO). The treatment was started at the age of 10 weeks and continued for 12 months. The survival of the mice in three groups was plotted by Kaplan-Meir graph. The pancreas of KRASG12D; PDX-1-Cre mice was analyzed for the presence of murine PanINs. The apoptosis, cell cycle and signaling markers were determined by Western blotting and immunostaining. Results: No significant difference in food intake and body weight gain between γ-tocotrienol and control groups was observed during 12 months feeding. γ-tocotrienol treatment significantly increased survival of mice compared to control groups (p&lt;0.025). Mice fed γ-tocotrienol had a significant delay in the progression of mPanIN lesions. The proportion of mPanIN-3 lesion was significantly decreased (P&lt;0.001), whereas the relative numbers of all other lesions combined were slightly increased in the γ-tocotrienol-fed animals. γ-tocotrienol feeding also inhibited the pMEK and pERK signaling and increased p27Kip1 expression in the pancreatic tumor tissues. The apoptosis markers such as caspase-3, PARP1 cleavage, and Bax expression were increased in tumor tissues of mice treated with γ-tocotrienol compared to controls. NF-κB/p65 and the NF-κB transcriptional targets Bcl-XL was down-regulated by γ-tocotrienol treatment. The ratio of the proapoptotic (Bax) and antiapoptotic (Bcl-XL) proteins was increased almost 4-folds in the pancreatic tumor tissues compared to controls. Conclusion: γ-tocotrienol delays the progression of pancreatic cancer precursor lesions in a preclinical animal model hence warrant it's clinical use for the prevention and treatment of pancreatic cancer in high-risk patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1613. doi:1538-7445.AM2012-1613
Abstract 1618: Synergistic growth inhibition of human hepatocellular carcinoma cells by acyclic retinoid and GW4064, a farnesoid X receptor ligand
Authors: Ohno Tomohiko , Shimizu Masahito , Kubota Masaya , Sakai Hiroyasu , Moriwaki Hisataka 
Published: August 2012

Abstract
Abnormalities in the expression and function of retinoid X receptor (RXR), a master regulator of the nuclear receptor superfamily, are associated with the development of hepatocellular carcinoma (HCC). Dysfunction of farnesoid X receptor (FXR), one of the nuclear receptors that forms a heterodimer with RXR, also plays a role in liver carcinogenesis. In the present study, we examined the effects of acyclic retinoid (ACR), a synthetic retinoid targeting RXRα, plus GW4064, a ligand for FXR, on the growth of human HCC cells. We found that ACR and GW4064 preferentially inhibited the growth of HLE human HCC cells in comparison with Hc normal hepatocytes. The combination of 1 μM ACR plus 1 μM GW4064 synergistically inhibited the growth of HLE cells by inducing apoptosis and cell cycle arrest in the G0/G1 phase. The combined treatment with these agents acted cooperatively to inhibit the phosphorylation of RXRα, which is regarded as a critical factor for liver carcinogenesis, through inhibition of ERK and Stat3 phosphorylation. This combination also increased the expression levels of p21CIP1 and SHP mRNA, while decreasing the levels of c-myc and cyclin D1 mRNA in HLE cells. In addition, a reporter assay indicated that the FXRE promoter activity was significantly increased by treatment with ACR plus GW4064. Our results suggest that ACR and GW4064 cooperatively inhibit RXRα phosphorylation, modulate the expression of FXR-regulated genes, thus resulting in the growth inhibition of HCC cells. This combination might therefore be effective for the chemoprevention and chemotherapy of HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1618. doi:1538-7445.AM2012-1618
Abstract 1641: Concordance between mutations identified by bar-coded multiplexed sequencing of BRAF, NRAS, and KIT in formalin fixed (FFPE) tissue from melanoma patients using the Ion Torrent Personal Genome Machine (PGM) and a real-time PCR assay
Authors: Watts George S. , Oshiro Marc M. , Cranmer Lee D. 
Published: August 2012

Abstract
The standard chemotherapy for metastatic melanoma is dacarbazine, however, progression free survival with dacarbazine is a dismal two months. Efforts to improve the treatment of melanoma have focused on specific molecular defects following the discovery that the majority of patients have a mutation in one of three members of the BRAF-MAPK signaling pathway: KIT, BRAF, and RAS. Recent clinical trials have shown promise for drugs that target the molecular defects in melanoma, including the recently approved mutant BRAF inhibitor vemurafenib. As new drugs that target specific mutations move through clinical trials, the opportunity to perform precision medicine is becoming a reality. To deliver on the promise shown by the new generation of drugs it will be necessary to detect specific mutations in patients so they can be matched with the right drug. To this end, we have used an Ion Torrent Personal Genome Machine to sequence the six most commonly mutated codons in melanoma (BRAF 600, NRAS 12 and 13, NRAS 61, KIT 576, and KIT 642) from formalin fixed paraffin embedded tissue of late stage melanoma patients. All six codons of interest were sequenced in forty-six patients and mutations identified by comparison to normal controls. The A375 cell line, containing the known mutation V600E in BRAF was used as a positive control. Samples were sequenced in a multiplexed format using bar coding of the amplicons which allowed 14 patients and two controls to be sequenced simultaneously on each chip. Results were confirmed by real time RT-PCR assay specific for the BRAF V600E mutation. We demonstrate the feasibility of using rapid low cost next-generation sequencing to provide robust detection of mutations in fixed patient samples.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1641. doi:1538-7445.AM2012-1641