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Pancreatic Neoplasms: HELP
Articles by Ana Maria Moro
Based on 18 articles published since 2010
(Why 18 articles?)
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Between 2010 and 2020, Ana Moro wrote the following 18 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Deficiency in hormone-sensitive lipase accelerates the development of pancreatic cancer in conditional KrasG12D mice. 2018

Xu, Mu / Chang, Hui-Hua / Jung, Xiaoman / Moro, Aune / Chou, Caroline Ei Ne / King, Jonathan / Hines, O Joe / Sinnett-Smith, James / Rozengurt, Enrique / Eibl, Guido. ·Departments of Surgery, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Ave, CHS 72-236, Los Angeles, CA, 90095, USA. · CURE: Digestive Diseases Research Center, University of California at Los Angeles, Los Angeles, USA. · Departments of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. · Departments of Surgery, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Ave, CHS 72-236, Los Angeles, CA, 90095, USA. GEibl@mednet.ucla.edu. · CURE: Digestive Diseases Research Center, University of California at Los Angeles, Los Angeles, USA. GEibl@mednet.ucla.edu. ·BMC Cancer · Pubmed #30086728.

ABSTRACT: BACKGROUND: Hormone sensitive lipase (HSL) is a neutral lipase that preferentially catalyzes the hydrolysis of diacylglycerol contributing to triacylglycerol breakdown in the adipose tissue. HSL has been implicated to play a role in tumor cachexia, a debilitating syndrome characterized by progressive loss of adipose tissue. Consequently, pharmacological inhibitors of HSL have been proposed for the treatment of cancer-associated cachexia. In the present study we used the conditional KrasG12D (KC) mouse model of pancreatic ductal adenocarcinoma (PDAC) with a deficiency in HSL to determine the impact of HSL suppression on the development of PDAC. METHODS: KC;Hsl RESULTS: Compared to KC;Hsl CONCLUSIONS: HSL deficiency is associated with adipose tissue and pancreatic inflammation and accelerates PDAC development in the KC mouse model.

2 Article Metformin Decreases the Incidence of Pancreatic Ductal Adenocarcinoma Promoted by Diet-induced Obesity in the Conditional KrasG12D Mouse Model. 2018

Chang, Hui-Hua / Moro, Aune / Chou, Caroline Ei Ne / Dawson, David W / French, Samuel / Schmidt, Andrea I / Sinnett-Smith, James / Hao, Fang / Hines, O Joe / Eibl, Guido / Rozengurt, Enrique. ·Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Freiburg, Freiburg, Germany. · Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. GEibl@mednet.ucla.edu. ·Sci Rep · Pubmed #29651002.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a particularly deadly disease. Chronic conditions, including obesity and type-2 diabetes are risk factors, thus making PDAC amenable to preventive strategies. We aimed to characterize the chemo-preventive effects of metformin, a widely used anti-diabetic drug, on PDAC development using the Kras

3 Article Incidence of pancreatic cancer is dramatically increased by a high fat, high calorie diet in KrasG12D mice. 2017

Chang, Hui-Hua / Moro, Aune / Takakura, Kazuki / Su, Hsin-Yuan / Mo, Allen / Nakanishi, Masako / Waldron, Richard T / French, Samuel W / Dawson, David W / Hines, O Joe / Li, Gang / Go, Vay Liang W / Sinnett-Smith, James / Pandol, Stephen J / Lugea, Aurelia / Gukovskaya, Anna S / Duff, Michael O / Rosenberg, Daniel W / Rozengurt, Enrique / Eibl, Guido. ·Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America. · Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America. · Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States of America. · Pancreatic Research Group, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America. · Center for Molecular Oncology, UCONN Health, Farmington, CT, United States of America. · Department of Pathology, Harbor-UCLA Medical Center, Torrance, CA, United States of America. · Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States of America. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America. · Department of Biostatistics, School of Public Health at UCLA, Los Angeles, CA, United States of America. · Department of Genetics and Genome Sciences, UCONN Health, Farmington, CT, United States of America. ·PLoS One · Pubmed #28886117.

ABSTRACT: Epidemiologic data has linked obesity to a higher risk of pancreatic cancer, but the underlying mechanisms are poorly understood. To allow for detailed mechanistic studies in a relevant model mimicking diet-induced obesity and pancreatic cancer, a high-fat, high-calorie diet (HFCD) was given to P48+/Cre;LSL-KRASG12D (KC) mice carrying a pancreas-specific oncogenic Kras mutation. The mice were randomly allocated to a HFCD or control diet (CD). Cohorts were sacrificed at 3, 6, and 9 months and tissues were harvested for further analysis. Compared to CD-fed mice, HFCD-fed animals gained significantly more weight. Importantly, the cancer incidence was remarkably increased in HFCD-fed KC mice, particularly in male KC mice. In addition, KC mice fed the HFCD showed more extensive inflammation and fibrosis, and more advanced PanIN lesions in the pancreas, compared to age-matched CD-fed animals. Interestingly, we found that the HFCD reduced autophagic flux in PanIN lesions in KC mice. Further, exome sequencing of isolated murine PanIN lesions identified numerous genetic variants unique to the HFCD. These data underscore the role of sustained inflammation and dysregulated autophagy in diet-induced pancreatic cancer development and suggest that diet-induced genetic alterations may contribute to this process. Our findings provide a better understanding of the mechanisms underlying the obesity-cancer link in males and females, and will facilitate the development of interventions targeting obesity-associated pancreatic cancer.

4 Article Evaluation of the Influence of the Conjugation Site of the Chelator Agent HYNIC to GLP1 Antagonist Radiotracer for Insulinoma Diagnosis. 2017

Faintuch, Bluma Linkowski / Seo, Daniele / de Oliveira, Erica Aparecida / Targino, Roselaine Campos / Moro, Ana Maria. ·Institute of Energy and Nuclear Research Radiopharmacy Center Av. Prof. Lineu Prestes, 2242 São Paulo, Brazil. · Radiopharmacy Center, Institute of Energy and Nuclear Research, São Paulo, Brazil. · Laboratory of Biopharmacology in Animal Cells, Butantan Institute, Sao Paulo, Brazil. ·Curr Radiopharm · Pubmed #28164753.

ABSTRACT: BACKGROUND AND OBJECTIVE: Radiotracer diagnosis of insulinoma, can be done using somatostatin or glucagon-like peptide 1 (GLP-1). Performance of GLP-1 antagonists tends to be better than of agonists. METHODS: We investigated the uptake of the antagonist exendin (9-39), radiolabeled with technetium- 99m. Two different sites of the biomolecule were selected for chelator attachment. RESULTS: HYNIC-βAla chelator attached to serine (C- terminus) of exendin, was associated with higher tumor uptake than to aspartate (N- terminus). CONCLUSION: The chelator position in the biomolecule influenced receptor uptake.

5 Article Robust Early Inflammation of the Peripancreatic Visceral Adipose Tissue During Diet-Induced Obesity in the KrasG12D Model of Pancreatic Cancer. 2016

Hertzer, Kathleen M / Xu, Mu / Moro, Aune / Dawson, David W / Du, Lin / Li, Gang / Chang, Hui-Hua / Stark, Alexander P / Jung, Xiaoman / Hines, Oscar Joe / Eibl, Guido. ·From the Departments of *Surgery and †Pathology and Laboratory Medicine,David Geffen School of Medicine at UCLA, Los Angeles, CA; and ‡Department of Biostatistics, Fielding School of Public Health at UCLA, Los Angeles, CA. ·Pancreas · Pubmed #26495779.

ABSTRACT: OBJECTIVES: Obesity increases the incidence of multiple types of cancer. Our previous work has shown that a high-fat, high-calorie diet (HFCD) leads to visceral obesity, pancreatic inflammation, and accelerated pancreatic neoplasia in KrasG12D (KC) mice. In this study, we aimed to investigate the effects of an HFCD on visceral adipose inflammation with emphasis on potential differences between distinct visceral adipose depots. METHODS: We examined the weight and visceral obesity in both wild-type and KC mice on either control diet (CD) or HFCD. After 3 months, mice were killed for histological examination. Multiplex assays were also performed to obtain cytokine profiles between different adipose depots. RESULTS: Both wild-type and KC mice on an HFCD exhibited significantly increased inflammation in the visceral adipose tissue, particularly in the peripancreatic fat (PPF), compared with animals on a CD. This was associated with significantly increased inflammation in the pancreas. Cytokine profiles were different between visceral adipose depots and between mice on the HFCD and CD. CONCLUSIONS: Our results clearly demonstrate that an HFCD leads to obesity and inflammation in the visceral adipose tissue, particularly the PPF. These data suggest that obesity-associated inflammation in PPF may accelerate pancreatic neoplasia in KC mice.

6 Article Prostaglandin E2 activates the mTORC1 pathway through an EP4/cAMP/PKA- and EP1/Ca2+-mediated mechanism in the human pancreatic carcinoma cell line PANC-1. 2015

Chang, Hui-Hua / Young, Steven H / Sinnett-Smith, James / Chou, Caroline Ei Ne / Moro, Aune / Hertzer, Kathleen M / Hines, Oscar Joe / Rozengurt, Enrique / Eibl, Guido. ·Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California; and. · Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California. · Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California; and GEibl@mednet.ucla.edu. ·Am J Physiol Cell Physiol · Pubmed #26310818.

ABSTRACT: Obesity, a known risk factor for pancreatic cancer, is associated with inflammation and insulin resistance. Proinflammatory prostaglandin E2 (PGE2) and elevated insulin-like growth factor type 1 (IGF-1), related to insulin resistance, are shown to play critical roles in pancreatic cancer progression. We aimed to explore a potential cross talk between PGE2 signaling and the IGF-1/Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway in pancreatic cancer, which may be a key to unraveling the obesity-cancer link. In PANC-1 human pancreatic cancer cells, we showed that PGE2 stimulated mTORC1 activity independently of Akt, as evaluated by downstream signaling events. Subsequently, using pharmacological and genetic approaches, we demonstrated that PGE2-induced mTORC1 activation is mediated by the EP4/cAMP/PKA pathway, as well as an EP1/Ca(2+)-dependent pathway. The cooperative roles of the two pathways were supported by the maximal inhibition achieved with the combined pharmacological blockade, and the coexistence of highly expressed EP1 (mediating the Ca(2+) response) and EP2 or EP4 (mediating the cAMP/PKA pathway) in PANC-1 cells and in the prostate cancer line PC-3, which also robustly exhibited PGE2-induced mTORC1 activation, as identified from a screen in various cancer cell lines. Importantly, we showed a reinforcing interaction between PGE2 and IGF-1 on mTORC1 signaling, with an increase in IL-23 production as a cellular outcome. Our data reveal a previously unrecognized mechanism of PGE2-stimulated mTORC1 activation mediated by EP4/cAMP/PKA and EP1/Ca(2+) signaling, which may be of great importance in elucidating the promoting effects of obesity in pancreatic cancer. Ultimately, a precise understanding of these molecular links may provide novel targets for efficacious interventions devoid of adverse effects.

7 Article E-cadherin expression in obesity-associated, Kras-initiated pancreatic ductal adenocarcinoma in mice. 2015

Stark, Alexander P / Chang, Hui-Hua / Jung, Xiaoman / Moro, Aune / Hertzer, Kathleen / Xu, Mu / Schmidt, Andrea / Hines, O Joe / Eibl, Guido. ·Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA. · Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA. Electronic address: Geibl@mednet.ucla.edu. ·Surgery · Pubmed #26297056.

ABSTRACT: BACKGROUND: The epithelial-mesenchymal transition (EMT) is critical in the development of invasive epithelial malignancies. EMT is accelerated by inflammation and results in decreased E-cadherin expression. Diet-induced obesity is an inflammatory state that accelerates pancreatic carcinogenesis; its effect on EMT and E-cadherin expression in the development of pancreatic ductal adenocarcinoma is unclear. METHODS: Conditional Kras(G12D) mice were fed a control diet or a high-fat, high-calorie diet for 3 or 9 months (n = 10 each). Immunohistochemistry with anti-E-cadherin antibody was performed. E-cadherin expression was characterized by staining intensity, location, and proportion of positive cells. In vitro expression of E-cadherin and Slug in primary pancreatic intraepithelial neoplasia (PanIN) and cancer cells was determined by Western blot. RESULTS: The HFCD led to increased weight gain in both 3- (15.8 vs 5.6 g, P < .001) and 9-month (19.8 vs 12.9 g, P = .007) mice. No differences in E-cadherin expression among various stages of preinvasive PanIN lesions were found--regardless of age or diet. In invasive cancer, E-cadherin expression was aberrant, with loss of membranous staining and prominent cytoplasmic staining, associated with strong, cytoplasmic expression of β-catenin. In vitro expression of E-cadherin was greatest in primary PanIN cells, accompanied by absent Slug expression. Cancer cell lines demonstrated significantly decreased E-cadherin expression in the presence of upregulated Slug. CONCLUSION: Despite increased pancreatic inflammation and accelerated carcinogenesis, the high-fat, high-calorie diet did not induce changes in E-cadherin expression in PanIN lesions of all stages. Invasive lesions demonstrated aberrant cytoplasmic E-cadherin staining. Loss of normal membranous localization may reflect a functional loss of E-cadherin.

8 Article Determination of Rottlerin, a Natural Protein Kinases C Inhibitor, in Pancreatic Cancer Cells and Mouse Xenografts by RP-HPLC Method. 2013

Lu, Qing-Yi / Zhang, Lifeng / Lugea, Aurelia / Moro, Aune / Edderkaoui, Mouad / Eibl, Guido / Pandol, Stephen J / Go, Vay-Liang W. ·Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. · Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA ; Veterans Affairs Greater Los Angeles Healthcare System, University of California, Los Angeles, CA, USA. · Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. ·J Chromatogr Sep Tech · Pubmed #24482742.

ABSTRACT: Rottlerin is a natural polyphenolic ketone isolated from the pericarps of Mallotus phillippinensis. In previous studies we showed that parenteral administration of rottlerin reduced tumor growth in murine xenograft models of pancreatic cancer. The aim of this study was to develop a simple and validated method for the quantitative determination of rottlerin in plasma and tumor tissues of mice fed a rottlerin diet. A xenograft model of pancreatic cancer was prepared by injection of 2×10

9 Article Ellagic acid and embelin affect key cellular components of pancreatic adenocarcinoma, cancer, and stellate cells. 2013

Edderkaoui, Mouad / Lugea, Aurelia / Hui, Hongxiang / Eibl, Guido / Lu, Qing-Yi / Moro, Aune / Lu, Xuyang / Li, Gang / Go, Vay-Liang / Pandol, Stephen J. ·a Veterans Affairs Greater Los Angeles Healthcare System , Los Angeles , California , USA. ·Nutr Cancer · Pubmed #24127740.

ABSTRACT: Ellagic acid is a polyphenolic phytochemical present in many fruits and nuts with anticancer properties demonstrated in experimental tumor studies. Embelin is a benzoquinone phytochemical isolated from the Japanese herb Ardisiae Japonicae and has been shown to induce apoptosis in cancer cells. We found that ellagic acid and embelin each dose-dependently increased apoptosis and inhibited proliferation in human pancreatic cancer cells, MIA PaCa-2 and HPAF-II cells, and in pancreatic stellate cells, which are progenitors of pancreatic cancer desmoplasia. In each of these cell types, combinations of ellagic acid and embelin at low micromolar concentrations (0.5-3 μM) induced synergistic increases in apoptosis and decreases in proliferation. Ellagic acid decreased NF-κB transcriptional activity, whereas embelin decreased STAT-3 phosphorylation and protein expression of its downstream target survivin in cancer cells. In vivo dietary ellagic acid alone or in combination with embelin decreased tumor size and tumor cellularity in a subcutaneous xenograft mouse model of pancreatic cancer. These results show that ellagic acid and embelin interact with divergent intracellular signaling pathways resulting in augmentation of apoptosis and inhibition of proliferation at low micromolar concentrations for the key cellular components of pancreatic adenocarcinoma.

10 Article miR-143 decreases COX-2 mRNA stability and expression in pancreatic cancer cells. 2013

Pham, Hung / Rodriguez, C Ekaterina / Donald, Graham W / Hertzer, Kathleen M / Jung, Xiaoman S / Chang, Hui-Hua / Moro, Aune / Reber, Howard A / Hines, O Joe / Eibl, Guido. ·Department of Surgery, UCLA Center of Excellence in Pancreatic Diseases, UCLA David Geffen School of Medicine, University of California - Los Angeles, Los Angeles, CA 90095, United States; Department of Medicine, Veterans Affair Greater Los Angeles Healthcare System, Los Angeles, CA 90073, United States. ·Biochem Biophys Res Commun · Pubmed #23973710.

ABSTRACT: Small non-coding RNAs, microRNAs (miRNA), inhibit the translation or accelerate the degradation of message RNA (mRNA) by targeting the 3'-untranslated region (3'-UTR) in regulating growth and survival through gene suppression. Deregulated miRNA expression contributes to disease progression in several cancers types, including pancreatic cancers (PaCa). PaCa tissues and cells exhibit decreased miRNA, elevated cyclooxygenase (COX)-2 and increased prostaglandin E2 (PGE2) resulting in increased cancer growth and metastases. Human PaCa cell lines were used to demonstrate that restoration of miRNA-143 (miR-143) regulates COX-2 and inhibits cell proliferation. miR-143 were detected at fold levels of 0.41 ± 0.06 in AsPC-1, 0.20 ± 0.05 in Capan-2 and 0.10 ± 0.02 in MIA PaCa-2. miR-143 was not detected in BxPC-3, HPAF-II and Panc-1 which correlated with elevated mitogen-activated kinase (MAPK) and MAPK kinase (MEK) activation. Treatment with 10 μM of MEK inhibitor U0126 or PD98059 increased miR-143, respectively, by 187 ± 18 and 152 ± 26-fold in BxPC-3 and 182 ± 7 and 136 ± 9-fold in HPAF-II. miR-143 transfection diminished COX-2 mRNA stability at 60 min by 2.6 ± 0.3-fold in BxPC-3 and 2.5 ± 0.2-fold in HPAF-II. COX-2 expression and cellular proliferation in BxPC-3 and HPAF-II inversely correlated with increasing miR-143. PGE2 levels decreased by 39.3 ± 5.0% in BxPC-3 and 48.0 ± 3.0% in HPAF-II transfected with miR-143. Restoration of miR-143 in PaCa cells suppressed of COX-2, PGE2, cellular proliferation and MEK/MAPK activation, implicating this pathway in regulating miR-143 expression.

11 Article High-fat, high-calorie diet promotes early pancreatic neoplasia in the conditional KrasG12D mouse model. 2013

Dawson, David W / Hertzer, Kathleen / Moro, Aune / Donald, Graham / Chang, Hui-Hua / Go, Vay Liang / Pandol, Steven J / Lugea, Aurelia / Gukovskaya, Anna S / Li, Gang / Hines, Oscar J / Rozengurt, Enrique / Eibl, Guido. ·Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, 10833 LeConte Avenue, 72-236 CHS, Los Angeles, CA 90095. Geibl@mednet.ucla.edu. ·Cancer Prev Res (Phila) · Pubmed #23943783.

ABSTRACT: There is epidemiologic evidence that obesity increases the risk of cancers. Several underlying mechanisms, including inflammation and insulin resistance, are proposed. However, the driving mechanisms in pancreatic cancer are poorly understood. The goal of the present study was to develop a model of diet-induced obesity and pancreatic cancer development in a state-of-the-art mouse model, which resembles important clinical features of human obesity, for example, weight gain and metabolic disturbances. Offspring of Pdx-1-Cre and LSL-KrasG12D mice were allocated to either a high-fat, high-calorie diet (HFCD; ∼4,535 kcal/kg; 40% of calories from fats) or control diet (∼3,725 kcal/kg; 12% of calories from fats) for 3 months. Compared with control animals, mice fed with the HFCD significantly gained more weight and developed hyperinsulinemia, hyperglycemia, hyperleptinemia, and elevated levels of insulin-like growth factor I (IGF-I). The pancreas of HFCD-fed animals showed robust signs of inflammation with increased numbers of infiltrating inflammatory cells (macrophages and T cells), elevated levels of several cytokines and chemokines, increased stromal fibrosis, and more advanced PanIN lesions. Our results show that a diet high in fats and calories leads to obesity and metabolic disturbances similar to humans and accelerates early pancreatic neoplasia in the conditional KrasG12D mouse model. This model and findings will provide the basis for more robust studies attempting to unravel the mechanisms underlying the cancer-promoting properties of obesity, as well as to evaluate dietary- and chemopreventive strategies targeting obesity-associated pancreatic cancer development.

12 Article Role of pancreatic cancer-derived exosomes in salivary biomarker development. 2013

Lau, Chang / Kim, Yong / Chia, David / Spielmann, Nadine / Eibl, Guido / Elashoff, David / Wei, Fang / Lin, Yi-Ling / Moro, Aune / Grogan, Tristan / Chiang, Samantha / Feinstein, Eric / Schafer, Christopher / Farrell, James / Wong, David T W. ·From the Dental Research Institute, UCLA School of Dentistry, Los Angeles, California 90095. ·J Biol Chem · Pubmed #23880764.

ABSTRACT: Recent studies have demonstrated that discriminatory salivary biomarkers can be readily detected upon the development of systemic diseases such as pancreatic cancer, breast cancer, lung cancer, and ovarian cancer. However, the utility of salivary biomarkers for the detection of systemic diseases has been undermined due to the absence of the biological and mechanistic rationale as to why distal diseases from the oral cavity would lead to the development of discriminatory biomarkers in saliva. Here, we examine the hypothesis that pancreatic tumor-derived exosomes are mechanistically involved in the development of pancreatic cancer-discriminatory salivary transcriptomic biomarkers. We first developed a pancreatic cancer mouse model that yielded discriminatory salivary biomarkers by implanting the mouse pancreatic cancer cell line Panc02 into the pancreas of the syngeneic host C57BL/6. The role of pancreatic cancer-derived exosomes in the development of discriminatory salivary biomarkers was then tested by engineering a Panc02 cell line that is suppressed for exosome biogenesis, implanting into the C56BL/6 mouse, and examining whether the discriminatory salivary biomarker profile was ablated or disrupted. Suppression of exosome biogenesis results in the ablation of discriminatory salivary biomarker development. This study supports that tumor-derived exosomes provide a mechanism in the development of discriminatory biomarkers in saliva and distal systemic diseases.

13 Article Metformin inhibits the growth of human pancreatic cancer xenografts. 2013

Kisfalvi, Krisztina / Moro, Aune / Sinnett-Smith, James / Eibl, Guido / Rozengurt, Enrique. ·Department of Medicine, Digestive Diseases Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. ·Pancreas · Pubmed #23462329.

ABSTRACT: OBJECTIVE: Pancreatic ductal adenocarcinoma is a devastating disease, with an overall 5-year survival rate of only 3% to 5%. As the current therapies offer very limited survival benefits, novel therapeutic strategies are urgently required to treat this disease. Here, we determined whether metformin administration inhibits the growth of PANC-1 and MiaPaCa-2 tumor xenografts in vivo. METHODS: Different xenograft models, including orthotopic implantation, were used to determine whether intraperitoneal or oral administration of metformin inhibits the growth of pancreatic cancer in vivo. RESULTS: We demonstrate that metformin given once daily intraperitoneally at various doses (50-250 mg/kg) to nude mice inhibited the growth of PANC-1 xenografts in a dose-dependent manner. A significant effect of metformin was obtained at 50 mg/kg and maximal effect at 200 mg/kg. Metformin administration also caused a significant reduction in the phosphorylation of ribosomal S6 protein and ERK in these xenografts. Metformin also inhibited the growth of pancreatic cancer xenografts when administered orally (2.5 mg/mL) either before or after tumor implantation. Importantly, oral administration of metformin also inhibited the growth of MiaPaCa-2 tumors xenografted orthotopically. CONCLUSIONS: The studies presented here provide further evidence indicating that metformin offers a potential novel approach for pancreatic ductal adenocarcinoma prevention and therapy.

14 Article The flavonoid quercetin inhibits pancreatic cancer growth in vitro and in vivo. 2013

Angst, Eliane / Park, Jenny L / Moro, Aune / Lu, Qing-Yi / Lu, Xuyang / Li, Gang / King, Jonathan / Chen, Monica / Reber, Howard A / Go, Vay Liang W / Eibl, Guido / Hines, Oscar J. ·Department of Surgery, Hirshberg Laboratories for Pancreatic Cancer Research, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. ·Pancreas · Pubmed #23000892.

ABSTRACT: OBJECTIVES: The flavonoid quercetin holds promise as an antitumor agent in several preclinical animal models. However, the efficacy of oral administration of quercetin in a pancreatic cancer mouse model is unknown. METHODS: The antiproliferative effects of quercetin alone or in combination with gemcitabine were tested in 2 human pancreatic cancer cell lines using cell count and MTT assays. Apoptosis was evaluated by flow cytometry. Tumor growth in vivo was investigated in an orthotopic pancreatic cancer animal model using bioluminescence. Quercetin was administered orally in the diet. RESULTS: Quercetin inhibited the growth of pancreatic cancer cell lines, which was caused by an induction of apoptosis. In addition, dietary supplementation of quercetin attenuated the growth of orthotopically transplanted pancreatic xenografts. The combination of gemcitabine and quercetin had no additional effect compared with quercetin alone. In vivo quercetin caused significant apoptosis and reduced tumor cell proliferation. CONCLUSIONS: Our data provide evidence that oral administration of quercetin was capable of inhibiting growth of orthotopic pancreatic tumors in a nude mouse model. These data suggest a possible benefit of quercetin in patients with pancreatic cancer.

15 Article Evidence for activation of mutated p53 by apigenin in human pancreatic cancer. 2012

King, Jonathan C / Lu, Qing-Yi / Li, Gang / Moro, Aune / Takahashi, Hiroki / Chen, Monica / Go, Vay Liang W / Reber, Howard A / Eibl, Guido / Hines, O Joe. ·Department of Surgery, David Geffen School of Medicine at UCLA, 72-107 CHS, 10833 LeConte Ave, Los Angeles, CA 90095, USA. ·Biochim Biophys Acta · Pubmed #22227579.

ABSTRACT: Pancreatic cancer is an exceedingly lethal disease with a five-year survival that ranks among the lowest of gastrointestinal malignancies. Part of its lethality is attributable to a generally poor response to existing chemotherapeutic regimens. New therapeutic approaches are urgently needed. We aimed to elucidate the anti-neoplastic mechanisms of apigenin-an abundant, naturally-occurring plant flavonoid-with a particular focus on p53 function. Pancreatic cancer cells (BxPC-3, MiaPaCa-2) experienced dose and time-dependent growth inhibition and increased apoptosis with apigenin treatment. p53 post-translational modification, nuclear translocation, DNA binding, and upregulation of p21 and PUMA were all enhanced by apigenin treatment despite mutated p53 in both cell lines. Transcription-dependent p53 activity was reversed by pifithrin-α, a specific DNA binding inhibitor of p53, but not growth inhibition or apoptosis suggesting transcription-independent p53 activity. This was supported by immunoprecipitation assays which demonstrated disassociation of p53/BclXL and PUMA/BclXL and formation of complexes with Bak followed by cytochrome c release. Treated animals grew smaller tumors with increased cellular apoptosis than those fed control diet. These results suggest that despite deactivating mutation, p53 retains some of its function which is augmented following treatment with apigenin. Cell cycle arrest and apoptosis induction may be mediated by transcription-independent p53 function via interactions with BclXL and PUMA. Further study of flavonoids as chemotherapeutics is warranted.

16 Article Detection of baicalin metabolites baicalein and oroxylin-a in mouse pancreas and pancreatic xenografts. 2012

Lu, Qing-Yi / Zhang, Lifeng / Moro, Aune / Chen, Monica C / Harris, Diane M / Eibl, Guido / Go, Vay-Liang W. ·Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. ·Pancreas · Pubmed #22158070.

ABSTRACT: OBJECTIVES: Scutellaria baicalensis has been a subject of research interest due to its potential multiple therapeutic benefits. This study was to examine the distribution of baicalein, wogonin, oroxylin A and their glucuronide/sulfate-conjugated metabolites in plasma, colon, small intestine, lung, liver, pancreas, kidney, and prostate tissues and in pancreatic tumor in a xenograft animal model. In addition, we examined metabolic stability of baicalin in these tissues. METHODS: A mouse xenograft model was prepared by injection of 3 × 10 human pancreatic cancer MiaPaCa-2 cells subcutaneously into nude mice. Mice were randomly allocated to control diet (AIN-76A) and 1% S. baicalensis diet (n = 8 per group) for 13 weeks. Levels of baicalein, wogonin, oroxylin A, and their conjugates in mouse tissues were measured by high-pressure liquid chromatography after enzymatic hydrolysis and then extraction. RESULTS: A substantial amount of baicalin (34%-63%) was methylated to oroxylin A and its conjugates in various organs during absorption. Whereas plasma contained predominantly conjugates of baicalein, wogonin, and oroxylin A, both aglycones and conjugates were found in all other tissues investigated and in tumor. CONCLUSIONS: Substantial accumulation of bioactive metabolites are found in target tissues, suggesting strong potential for S. baicalensis use as a preventive or adjuvant supplement for pancreatic cancer.

17 Article Overexpression of CXCL5 is associated with poor survival in patients with pancreatic cancer. 2011

Li, Aihua / King, Jonathan / Moro, Aune / Sugi, Mark D / Dawson, David W / Kaplan, Jeffrey / Li, Gang / Lu, Xuyang / Strieter, Robert M / Burdick, Marie / Go, Vay Liang W / Reber, Howard A / Eibl, Guido / Hines, O Joe. ·Department of Surgery, Hirshberg Laboratories for Pancreatic Cancer Research, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095-6904, USA. ·Am J Pathol · Pubmed #21356384.

ABSTRACT: Epithelial neutrophil-activating peptide-78 (CXCL5), a member of the CXC chemokine family, has been shown to be involved in angiogenesis, tumor growth, and metastasis. The objective of this study was to determine the relationship between CXCL5 expression and tumor progression in human pancreatic cancer and to elucidate the mechanism underlying CXCL5-mediated tumor angiogenesis and cancer growth. We report herein that CXCL5 is overexpressed in human pancreatic cancer compared with paired normal pancreas tissue. Overexpression of CXCL5 is significantly correlated with poorer tumor differentiation, advanced clinical stage, and shorter patient survival. Patients with pancreatic cancer and CXCL5 overexpression who underwent resection of cancer had a mean survival time 25.5 months shorter than that of patients who did not overexpress CXCL5. Blockade of CXCL5 or its receptor CXCR2 by small-interfering RNA knockdown or antibody neutralization attenuated human pancreatic cancer growth in a nude mouse model. Finally, we demonstrated that CXCL5 mediates pancreatic cancer-derived angiogenesis through activation of several signaling pathways, including protein kinase B (Akt), extracellular signal-regulated kinase (ERK), and signal transducer and activator of transcription (STAT) in human endothelial cells. These data suggest that CXCL5 is an important mediator of tumor-derived angiogenesis and that it may serve as a survival factor for pancreatic cancer. Blockade of either CXCL5 or CXCR2 may be a critical adjunct antiangiogenic therapy against pancreatic cancer.

18 Article Quercetin aglycone is bioavailable in murine pancreas and pancreatic xenografts. 2010

Zhang, Lifeng / Angst, Eliane / Park, Jenny L / Moro, Aune / Dawson, David W / Reber, Howard A / Eibl, Guido / Hines, O Joe / Go, Vay-Liang W / Lu, Qing-Yi. ·Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA. ·J Agric Food Chem · Pubmed #20499918.

ABSTRACT: Quercetin is a potential chemopreventive and chemotherapeutic agent for pancreatic and other cancers. This study examined the distribution of quercetin in plasma, lung, liver, pancreas, and pancreatic cancer xenografts in a murine in vivo model and the uptake of quercetin in pancreatic cancer MiaPaCa-2 cells in a cellular in vitro model. Mice were randomly allocated to control or 0.2 and 1% quercetin diet groups utilizing the AIN93G-based diet (n = 12 per group) for 6 weeks. In addition, 6 mice from each group were injected weekly with the chemotherapeutic drug gemcitabine (120 mg/kg mouse, ip). MiaPaCa cells were collected from culture medium after cells were exposed to 30 muM quercetin for 0.5, 1, 2, 4, 8, and 24 h. Levels of quercetin and 3-O'-methylquercetin in mouse tissues and MiaPaCa-2 cells were measured by high-pressure liquid chromatography following enzymatic hydrolysis and then extraction. The study showed that quercetin is accumulated in pancreatic cancer cells and is absorbed in the circulating system, tumors, and tissues of pancreas, liver, and lung in vivo. A higher proportion of total quercetin found in tumors and pancreas is aglycones. Gemcitabine cotreatment with quercetin reduced absorption of quercetin in the mouse circulatory system and liver. Results from the study provide important information on the interpretation of the chemotherapeutic efficacy of quercetin.