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1
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Singh J, Hussain Y, Meena A, Sinha RA, Luqman S. Asiatic acid impedes NSCLC progression by inhibiting COX-2 and modulating PI3K signaling. FEBS Lett 2024; 598:3036-3052. [PMID: 39394402 DOI: 10.1002/1873-3468.15027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 07/16/2024] [Accepted: 08/06/2024] [Indexed: 10/13/2024]
Abstract
Non-small cell lung cancer comprises up to 85% of lung cancer cases and has a poor prognosis. At present, there are still no effective treatments for this illness. Evidence suggests that the prostaglandin [cyclooxygenase-2 (COX-2)] and leukotriene [lipoxygenase-5 (5-LOX)] pathways are involved in lung cancer carcinogenesis. Therefore, novel agents that target COX-2 and 5-LOX may have therapeutic potential. In the present study, we examined the role of asiatic acid (AA), a triterpenoid saponin, in targeting the protein kinases responsible for lung cancer proliferation and mobility. The experimental data revealed that AA inhibited the growth of lung cancer cells (> 50%) and it significantly impeded the proliferation of lung cancer cells by inhibiting COX-2, which results in downregulation of the phosphotidyl inositol-3 kinase/protein kinase B/mammalian target of rapamycin signaling pathway, leading to an induction of cytotoxic autophagy-mediated apoptosis. Mechanistically, the expression of mitogen-activated protein kinase/extracellular signal-regulated kinase, hypoxia-inducible factor-1 and vascular endothelial growth factor is downregulated by AA, thereby reducing cell mobility and invasion. It also shows negative osmotic fragility on healthy human erythrocytes. It is concluded that AA may be a viable therapeutic drug for non-small cell lung cancer treatment, which opens new opportunities for synthesizing analogues.
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Affiliation(s)
- Jyoti Singh
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India
- Jawaharlal Nehru University, New Delhi, India
| | - Yusuf Hussain
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Abha Meena
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Rohit Anthony Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Suaib Luqman
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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2
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Ortiz-Placín C, Castillejo-Rufo A, Estarás M, González A. Membrane Lipid Derivatives: Roles of Arachidonic Acid and Its Metabolites in Pancreatic Physiology and Pathophysiology. Molecules 2023; 28:4316. [PMID: 37298790 PMCID: PMC10254454 DOI: 10.3390/molecules28114316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/17/2023] [Accepted: 05/19/2023] [Indexed: 06/12/2023] Open
Abstract
One of the most important constituents of the cell membrane is arachidonic acid. Lipids forming part of the cellular membrane can be metabolized in a variety of cellular types of the body by a family of enzymes termed phospholipases: phospholipase A2, phospholipase C and phospholipase D. Phospholipase A2 is considered the most important enzyme type for the release of arachidonic acid. The latter is subsequently subjected to metabolization via different enzymes. Three enzymatic pathways, involving the enzymes cyclooxygenase, lipoxygenase and cytochrome P450, transform the lipid derivative into several bioactive compounds. Arachidonic acid itself plays a role as an intracellular signaling molecule. Additionally, its derivatives play critical roles in cell physiology and, moreover, are involved in the development of disease. Its metabolites comprise, predominantly, prostaglandins, thromboxanes, leukotrienes and hydroxyeicosatetraenoic acids. Their involvement in cellular responses leading to inflammation and/or cancer development is subject to intense study. This manuscript reviews the findings on the involvement of the membrane lipid derivative arachidonic acid and its metabolites in the development of pancreatitis, diabetes and/or pancreatic cancer.
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Affiliation(s)
| | | | | | - Antonio González
- Instituto de Biomarcadores de Patologías Moleculares, Departamento de Fisiología, Universidad de Extremadura, 10003 Cáceres, Spain; (C.O.-P.); (A.C.-R.); (M.E.)
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3
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Xu F, Zhou X, Lin L, Xu J, Feng Y, He Y, Hao H. BML-111, the agonist of lipoxin A4, suppresses epithelial-mesenchymal transition and migration of MCF-7 cells via regulating the lipoxygenase pathway. Int J Immunopathol Pharmacol 2023; 37:3946320231223826. [PMID: 38134963 DOI: 10.1177/03946320231223826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2023] Open
Abstract
Introduction: Aberrant epithelial-mesenchymal transition (EMT) and migration frequently occur during tumour progression. BML-111, an analogue of lipoxin A4, has been implicated in inflammation in cancer research. Methods: 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, western blot, Reverse Transcription Polymerase Chain Reaction (RT-PCR), transwell assay, immunofluorescence, and immunohistochemistry were conducted in this study. Results: In vitro experiments revealed that BML-111 inhibited EMT and migration in CoCl2-stimulated MCF-7 cells. These effects were achieved by inhibiting MMP-2 and MMP-9, which are downregulated by 5-lipoxygenase (5-LOX). Moreover, BML-111 inhibited EMT and migration of breast cancer cells in BALB/c nude mice inoculated with MCF-7 cells. Conclusion: Our results suggest that BML-111 may be a potential therapeutic drug for breast cancer and that blocking the 5-LOX pathway could be a possible approach for mining effective drug targets.
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Affiliation(s)
- Fen Xu
- Department of General Medicine, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xiaoyan Zhou
- Department of Pathophysiology, Medical College of Nanchang University, Nanchang, China
| | - Lan Lin
- Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jing Xu
- Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yu Feng
- Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yuanqiao He
- Department of Laboratory Animal Science, Medical College of Nanchang University, Nanchang, China
| | - Hua Hao
- Department of Pathology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
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Channar PA, Alharthy RD, Ejaz SA, Saeed A, Iqbal J. Synthesis, Biological Evaluation, and Molecular Dynamics of Carbothioamides Derivatives as Carbonic Anhydrase II and 15-Lipoxygenase Inhibitors. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27248723. [PMID: 36557863 PMCID: PMC9785969 DOI: 10.3390/molecules27248723] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 11/28/2022] [Accepted: 12/02/2022] [Indexed: 12/13/2022]
Abstract
A series of hydrazine-1-carbothioamides derivatives (3a-3j) were synthesized and analyzed for inhibitory potential towards bovine carbonic anhydrase II (b-CA II) and 15-lipoxygenase (15-LOX). Interestingly, four derivatives, 3b, 3d, 3g, and 3j, were found to be selective inhibitors of CA II, while other derivatives exhibited CA II and 15-LOX inhibition. In silico studies of the most potent inhibitors of both b-CA II and 15-LOX were carried out to find the possible binding mode of compounds in their active site. Furthermore, MD simulation results confirmed that these ligands are stably bound to the two targets, while the binding energy further confirmed the inhibitory effects of the 3h compound. As these compounds may have a role in particular diseases, the reported compounds are of great relevance for future applications in the field of medicinal chemistry.
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Affiliation(s)
- Pervaiz Ali Channar
- Department of Basic sciences and Humanities, Faculty of Information Sciences and Humanities, Dawood University of Engineering and Technology, Karachi 74800, Pakistan
| | - Rima D. Alharthy
- Chemistry Department, Faculty of Science and Arts, King Abdulaziz University, Rabigh 21911, Saudi Arabia
| | - Syeda Abida Ejaz
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan
| | - Aamer Saeed
- Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan
- Correspondence: (A.S.); or (J.I.)
| | - Jamshed Iqbal
- Center for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan
- Correspondence: (A.S.); or (J.I.)
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Anticancer effects of herbal medicines in pancreatic ductal adenocarcinoma through modulation of steroid hormone response proteins. Sci Rep 2022; 12:9910. [PMID: 35701649 PMCID: PMC9198029 DOI: 10.1038/s41598-022-14174-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 05/17/2022] [Indexed: 11/20/2022] Open
Abstract
Many individual herbs and herbal formulae have been demonstrated to provide safe and effective treatment for pancreatic ductal adenocarcinoma (PDAC); however, the therapeutic mechanisms underlying their effects have not been fully elucidated. A total of 114 herbal formulae comprising 216 single herbal medicines used to treat PDAC were identified. Cluster analysis revealed a core prescription including four herbs [Glycyrrhizae Radix et Rhizome (Gan Cao), Codonopsis Radix (Dang Shen), Citri Reticulatae Pericarpium (Chen Pi), and Pinelliae Rhizoma (Ban Xia)] in combination to treat PDAC, and 295, 256, 141, and 365 potential targets were screened for each of these four herbs, respectively. PDAC-related proteins (n = 2940) were identified from the DisGeNET database. Finally, 44 overlapping targets of herbs and PDAC were obtained, representing potential targets of the herbal medicines for PDAC treatment. GO enrichment analysis indicated that targets common to herbs and PDAC primarily functioned in response to steroid hormones. KEGG pathway enrichment analysis indicated that the herbs may prevent PDAC by influencing apoptotic, p53, and PI3K/Akt signaling pathways. Further, molecular docking analysis indicated that of identified bioactive compounds, stigmasterol, phaseol, perlolyrine, shinpterocarpin, and licopyranocoumarin have good binding ability with proteins involved in responses to steroid hormones, while stigmasterol, phaseol, perlolyrine, and DIOP have good binding ability with PTGS2(also known as COX-2), ESR1, ESR2, AR, and PGR. The anti-PDAC activity of herbal medicines may be mediated via regulation of proteins with roles in responses to steroid hormones. This study provides further evidence supporting the potential for use of herbal medicines to treat PDAC.
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Bose D, Chaudhary A, Padmavati M, Chatterjee J, Banerjee R. In vitro evaluation of anti-proliferative activity of protein from Litchi chinensis honey against human cervical cancer cell line (HeLa). J Herb Med 2022. [DOI: 10.1016/j.hermed.2021.100518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Kwong SC, Abd Jamil AH, Rhodes A, Taib NA, Chung I. Fatty acid binding protein 7 mediates linoleic acid-induced cell death in triple negative breast cancer cells by modulating 13-HODE. Biochimie 2020; 179:23-31. [PMID: 32931863 DOI: 10.1016/j.biochi.2020.09.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 08/11/2020] [Accepted: 09/07/2020] [Indexed: 01/01/2023]
Abstract
Different fatty acids have distinct effects on the survival of breast cancer cells, which could be mediated by fatty acid binding proteins (FABPs), a family of lipid chaperones. Due to the diverse structures of the members of FABP family, each FABP demonstrates distinct binding affinities to different fatty acids. Of note, FABP7 is predominantly expressed in triple negative breast cancer (TNBC), the most aggressive subtype of breast cancer. Yet, the role of FABP7 in modulating the effects of fatty acids on TNBC survival was unclear. In contrast to the high expression of FABP7 in human TNBC tumours, FABP7 protein was undetectable in TNBC cell lines. Hence, a FABP7 overexpression model was used for this study, in which the transduced TNBC cell lines (MDA-MB-231 and Hs578T) were treated with various mono- and polyunsaturated fatty acids. Oleic acid (OA), docosahexaenoic acid (DHA) and arachidonic acid (AA) inhibited TNBC cell growth at high concentrations, with no differences resulted from FABP7 overexpression. Interestingly, overexpression of FABP7 augmented linoleic acid-induced cell death in MDA-MB-231 cells. The increased cell death may be explained by a decrease in 13-HODE, a pro-tumorigenic oxidation product of linoleic acid. The phenotype was, however, attenuated with a rescue treatment using 25 nM 13-HODE. The decrease in 13-HODE was potentially due to fatty acid partitioning modulated by FABP7, as demonstrated by a 3-fold increase in fatty acid oxidation. Our findings suggest that linoleic acid could be a potential therapeutic strategy for FABP7-overexpressing TNBC patients.
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Affiliation(s)
- Soke Chee Kwong
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Amira Hajirah Abd Jamil
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Anthony Rhodes
- Department of Pathology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia; School of Health Sciences, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia
| | - Nur Aishah Taib
- Department of Surgery, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia; University of Malaya Cancer Research Institute, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Ivy Chung
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia; University of Malaya Cancer Research Institute, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
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Mi S, Qu Y, Chen X, Wen Z, Chen P, Cheng Y. Radiotherapy Increases 12-LOX and CCL5 Levels in Esophageal Cancer Cells and Promotes Cancer Metastasis via THP-1-Derived Macrophages. Onco Targets Ther 2020; 13:7719-7733. [PMID: 32801779 PMCID: PMC7415441 DOI: 10.2147/ott.s257852] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Accepted: 07/15/2020] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Dioxygenase 12-lipoxygenase (12-LOX) plays an important role in tumorigenesis and promotes angiogenesis and proliferation in several tumors, including prostate and breast tumors. Radiotherapy enhances the expression of 12-LOX in esophageal squamous cell carcinoma (ESCC). Two types of macrophages can be found in the tumor microenvironment. The M2 subtype accelerates tumor progression; however, the relationship between 12-LOX and macrophages is not well established. Here, we explore this interaction and its effect on ESCC to induce tumor progression. METHODS AND RESULTS RT-qPCR and Western blot analyses were used to evaluate the mRNA and protein expression levels of 12-LOX and chemokine (C-C motif) ligand 5 (CCL5) in ESCC after radiotherapy. CCL5 expression was increased by 12-LOX upregulation but was suppressed by the well-established 12-LOX inhibitor, baicalein. Furthermore, CCL5 attracted and repolarized human myeloid leukemia mononuclear cells (THP-1)-derived macrophages. Finally, ESCC co-culture with THP-1-derived macrophages led to a strong cancer migratory capacity. CONCLUSION Radiation-induced 12-LOX overexpression in ESCC upregulates CCL5 expression, thereby attracting THP-1-derived macrophages and promoting their polarization to the M2 subtype, which enhances cellular metastasis.
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Affiliation(s)
- Si Mi
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of China
| | - Yan Qu
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of China
| | - Xue Chen
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of China
| | - Zhihua Wen
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of China
| | - Pengxiang Chen
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of China
| | - Yufeng Cheng
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of China
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Jiang T, Zhou B, Li YM, Yang QY, Tu KJ, Li LY. ALOX12B promotes carcinogenesis in cervical cancer by regulating the PI3K/ERK1 signaling pathway. Oncol Lett 2020; 20:1360-1368. [PMID: 32724378 PMCID: PMC7377187 DOI: 10.3892/ol.2020.11641] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Accepted: 04/03/2020] [Indexed: 12/28/2022] Open
Abstract
Cervical cancer is a malignant disease and a threat to women's health worldwide. Surgical resection followed by radiotherapy or chemotherapy is the main treatment strategy for cervical cancer; however, patients with cervical cancer, especially those with late-stage disease, may not benefit from these traditional therapies, which results in poor clinical outcome. ALOX12B is a gene encoding lipoxygenase, and a mutation in ALOX12B was detected in lung and breast cancer. Furthermore, ALOX12B is essential to the proliferation of epidermoid carcinoma cells; however, the role of ALOX12B in cervical cancer has not been studied thus far, to the best of our knowledge. In the present study, the expression levels of ALOX12B were reduced in cervical cancer cells by lentiviral transfection, and it was found that both cell proliferation and clone formation ability were significantly reduced, and the cell cycle was blocked at G1 phase. Tumor growth was also suppressed in vivo in a xenograft tumor model, but the migration of tumor cells was not affected by ALOX12B. Subsequently, using western blotting, it was demonstrated that knockdown of ALOX12B decreased the expression levels of PI3K, MEK1, ERK1, C-fos and cdc25. Meanwhile, overexpression of ALOX12B increased the expression levels of these five molecules. Conclusively, ALOX12B promoted cell proliferation in cervical cancer via regulation of the PI3K/ERK1 signaling pathway. The present study may improve our understanding of the molecular mechanisms underlying the function of ALOX12B in cervical cancer and inform new therapeutic strategies.
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Affiliation(s)
- Tao Jiang
- Department of Gynecological Oncology, Jiangxi Medical College of Nanchang University, Nanchang, Jiangxi 330031, P.R. China.,Department of Gynecology, The Affiliated Jiujiang Hospital of Nanchang University, Jiujiang, Jiangxi 332000, P.R. China
| | - Bing Zhou
- Department of Pathology, The Affiliated Jiujiang Hospital of Nanchang University, Jiujiang, Jiangxi 332000, P.R. China
| | - Yuan Meng Li
- Department of Gynecology, The Affiliated Jiujiang Hospital of Nanchang University, Jiujiang, Jiangxi 332000, P.R. China
| | - Qui Ying Yang
- Department of Gynecology, The Affiliated Jiujiang Hospital of Nanchang University, Jiujiang, Jiangxi 332000, P.R. China
| | - Kai Jia Tu
- Department of Gynecological Oncology, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, P.R. China
| | - Long Yu Li
- Department of Gynecological Oncology, Jiangxi Medical College of Nanchang University, Nanchang, Jiangxi 330031, P.R. China.,Department of Gynecological Oncology, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, P.R. China
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Chang J, Tang N, Fang Q, Zhu K, Liu L, Xiong X, Zhu Z, Zhang B, Zhang M, Tao J. Inhibition of COX-2 and 5-LOX regulates the progression of colorectal cancer by promoting PTEN and suppressing PI3K/AKT pathway. Biochem Biophys Res Commun 2019; 517:1-7. [PMID: 29339153 DOI: 10.1016/j.bbrc.2018.01.061] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 01/09/2018] [Indexed: 01/18/2023]
Abstract
For colorectal cancer (CRC) patients, local and systemic inflammatory responses have been extensively reported to closely associate with patient survival. However, the specific signaling pathways responsible for carcinogenic responses are unclear. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of PI3K/AKT pathway that is gradually inactivated in cancers through mutation, loss of heterozygosity and others epigenetic mechanisms. In addition, COX and LOX metabolic pathways of arachidonic acid (AA) play a crucial role in promoting adenoma development. The aim of this study is to clarify the relationship of COX, LOX and PTEN/PI3K/AKT pathway. Results showed that the over-expressed COX and LOX in cancer cells can be targeted to decrease the expression of PTEN. After using corresponding inhibitors, this condition was significantly improved and promoted apoptosis, inhibited invasion, proliferation and the production of reactive oxygen species. And for COX-2-/- or 5-LOX-/- ApcMin/+ mice, the PI3K/AKT pathway was further inhibited via promoting PTEN. Furthermore, weakened oxidative stress, inhibited adenoma growth, and improved survival rate. All findings indicated that PTEN was indirectly targeted by these enzyme inhibitors and acted as the potential therapeutic target for colorectal cancer therapy. In short, COX-2 or 5-LOX deletion and its inhibitors enhanced activity of PTEN and suppressed cell and adenoma progression through PI3K/AKT pathway in colorectal cancer.
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Affiliation(s)
- Jian Chang
- Department of Pancreatic Surgery, Renmin Hospital of Wuhan University, China; Department of Hepatobiliary Surgery, Wuhan First Hospital, China
| | - Nan Tang
- Department of Neurosurgery, Union Hospital Tongji Medical College, Huazhong University of Science and Technology, China
| | - Qi Fang
- Department of Pancreatic Surgery, Renmin Hospital of Wuhan University, China
| | - Kongfan Zhu
- Department of Pancreatic Surgery, Renmin Hospital of Wuhan University, China
| | - Lei Liu
- Department of Pancreatic Surgery, Renmin Hospital of Wuhan University, China
| | - Xingcheng Xiong
- Department of Pancreatic Surgery, Renmin Hospital of Wuhan University, China
| | - Zhongchao Zhu
- Department of Pancreatic Surgery, Renmin Hospital of Wuhan University, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, China
| | - Mingzhi Zhang
- Department of Medicine, Vanderbilt University, Nashville, TN, USA
| | - Jing Tao
- Department of Pancreatic Surgery, Renmin Hospital of Wuhan University, China.
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Leung HH, Yau YF, Leung KS, Lee YY, Oger C, Durand T, Galano J, Loke WM, Lee JC. Garlic Supplementation Modified Enzymatic Omega‐6 Polyunsaturated Fatty Acid Oxidation in Mild Hypercholesterolemia. EUR J LIPID SCI TECH 2019. [DOI: 10.1002/ejlt.201900069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- Ho Hang Leung
- School of Biological SciencesThe University of Hong KongHong Kong SAR
| | - Yu Fung Yau
- School of Biological SciencesThe University of Hong KongHong Kong SAR
| | - Kin Sum Leung
- School of Biological SciencesThe University of Hong KongHong Kong SAR
| | - Yiu Yiu Lee
- School of Biological SciencesThe University of Hong KongHong Kong SAR
| | - Camille Oger
- Institut des Biomolécules Max MousseronUniversité de MontpellierUMR 5247 CNRS, ENSCMFrance
| | - Thierry Durand
- Institut des Biomolécules Max MousseronUniversité de MontpellierUMR 5247 CNRS, ENSCMFrance
| | - Jean‐Marie Galano
- Institut des Biomolécules Max MousseronUniversité de MontpellierUMR 5247 CNRS, ENSCMFrance
| | - Wai Mun Loke
- School of Chemical and Life SciencesCentre for Functional Food & Human NutritionNanyang PolytechnicSingapore 569830Singapore
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Simijonović D, Vlachou EE, Petrović ZD, Hadjipavlou-Litina DJ, Litinas ΚE, Stanković N, Mihović N, Mladenović MP. Dicoumarol derivatives: Green synthesis and molecular modelling studies of their anti-LOX activity. Bioorg Chem 2018; 80:741-752. [PMID: 30077781 DOI: 10.1016/j.bioorg.2018.07.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 07/17/2018] [Accepted: 07/18/2018] [Indexed: 12/28/2022]
Abstract
Dicoumarol derivatives were synthesized in the InCl3 catalyzed pseudo three-component reactions of 4-hydroxycoumarin with aromatic aldehydes in excellent yields. The reactions were performed in water under microwave irradiation. All synthesized compounds were characterized using NMR, IR, and UV-Vis spectroscopy, as well as with TD-DFT. Obtained dicoumarols were subjected to evaluation of their in vitro lipid peroxidation and soybean lipoxygenase inhibition activities. It was shown that five of ten examined compounds (3e, 3h, 3b, 3d, 3f) possess significant potential of antilipid peroxidation (84-97%), and that compounds 3b, 3e, 3h provided the highest soybean lipoxygenase (LOX-Ib) inhibition (IC50 = 52.5 µM) and 3i somewhat lower activity (IC50 = 55.5 µM). The bioactive conformations of the best LOX-Ib inhibitors were obtained by means of molecular docking and molecular dynamics. It was shown that, within the bioactive conformations interior to LOX-Ib active site, the most active compounds form the pyramidal structure made of two 4-hydroxycoumarin cores and a central phenyl substituent. This form serves as a spatial barrier which prevents LOX-Ib Fe2+/Fe3+ ion activity to generate the coordinative bond with the C13 hydroxyl group of the α-linoleate. It is worth pointing out that the most active compounds 3b, 3e, 3h and 3i can be candidates for further examination of their in vitro and in vivo anti-inflammatory activity and that molecular modeling study results provide possibility to screen bioactive conformations and elucidate the mechanism of dicoumarols anti-LOX activity.
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Affiliation(s)
- Dušica Simijonović
- University of Kragujevac, Faculty of Science, Department of Chemistry, Radoja Domanovića 12, 34000 Kragujevac, Serbia.
| | - Evangelia-Eirini Vlachou
- Laboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
| | - Zorica D Petrović
- University of Kragujevac, Faculty of Science, Department of Chemistry, Radoja Domanovića 12, 34000 Kragujevac, Serbia
| | - Dimitra J Hadjipavlou-Litina
- Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
| | - Κonstantinos E Litinas
- Laboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
| | - Nevena Stanković
- Kragujevac Center for Computational Biochemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, 34000 Kragujevac, P.O. Box 60, Serbia
| | - Nezrina Mihović
- Kragujevac Center for Computational Biochemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, 34000 Kragujevac, P.O. Box 60, Serbia
| | - Milan P Mladenović
- Kragujevac Center for Computational Biochemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, 34000 Kragujevac, P.O. Box 60, Serbia
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In vitro study of iron coordination properties, anti-inflammatory potential, and cytotoxic effects of N-salicylidene and N-vanillidene anil Schiff bases. CHEMICAL PAPERS 2018. [DOI: 10.1007/s11696-018-0419-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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14
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Perán M, López-Ruiz E, García MÁ, Nadaraia-Hoke S, Brandt R, Marchal JA, Kenyon J. A formulation of pancreatic pro-enzymes provides potent anti-tumour efficacy: a pilot study focused on pancreatic and ovarian cancer. Sci Rep 2017; 7:13998. [PMID: 29070896 PMCID: PMC5656641 DOI: 10.1038/s41598-017-14571-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 10/12/2017] [Indexed: 12/13/2022] Open
Abstract
Proteolytic enzymes have shown efficacy in cancer therapy. We present a combination of the two pro-enzymes Trypsinogen and Chymotrypsinogen A with potent in vitro and in vivo anti-tumour efficacy. A synergetic anti-tumour effect for Trypsinogen and Chymotrypsinogen A was determined at a ratio 1:6 (named PRP) using 24 human cancer cell lines. The antiangiogenic effect of PRP was analysed by matrigel-based tube formation and by fibrous capsule formation assays. Furthermore, cell invasion and wound healing assays together with qRT-PCR determination of epithelial-to-mesenchymal transition (EMT) markers were performed on human cancer cells treated with PRP. Additionally, in vivo pharmacokinetic studies were implemented and the PRP's anti-tumour efficacy was explored against orthotopic pancreatic and ovarian cancer tumours. PRP formulation was proven to inhibit in vitro angiogenesis, tumour growth, cancer cell migration and invasiveness; and to be an effective and well tolerated in vivo anti-tumour treatment. Finally, the clinical efficacy of a suppository formulation containing both pancreatic pro-enzymes in the context of a UK Pharmaceuticals Special Scheme was evaluated in advanced cancer patients. Consequently, PRP could have relevant oncological clinical applications for the treatment of advanced or metastatic pancreatic adenocarcinoma and advanced epithelial ovarian cancer.
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Affiliation(s)
- Macarena Perán
- Department of Health Sciences, University of Jaén, Jaén, Spain.
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain.
| | - Elena López-Ruiz
- Department of Health Sciences, University of Jaén, Jaén, Spain
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain
| | - María Ángel García
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain
- Department of Oncology, University Hospital Virgen de las Nieves, Granada, Spain
- Biosanitary Research Institute of Granada (ibs.GRANADA), University Hospitals of Granada-University of Granada, Granada, Spain
| | | | - Ralf Brandt
- vivoPharm LLC, 1214 Research Boulevard 17036, Hummelstown PA, United States
| | - Juan A Marchal
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain
- Biosanitary Research Institute of Granada (ibs.GRANADA), University Hospitals of Granada-University of Granada, Granada, Spain
- Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, Spain
| | - Julian Kenyon
- The Dove Clinic for Integrated Medicine, Twyford, SO21 1RG, UK.
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15
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Khan S, Ferguson Bennit H, Asuncion Valenzuela MM, Turay D, Diaz Osterman CJ, Moyron RB, Esebanmen GE, Ashok A, Wall NR. Localization and upregulation of survivin in cancer health disparities: a clinical perspective. Biologics 2015; 9:57-67. [PMID: 26185415 PMCID: PMC4501680 DOI: 10.2147/btt.s83864] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Survivin is one of the most important members of the inhibitors of apoptosis protein family, as it is expressed in most human cancers but is absent in normal, differentiated tissues. Lending to its importance, survivin has proven associations with apoptosis and cell cycle control, and has more recently been shown to modulate the tumor microenvironment and immune evasion as a result of its extracellular localization. Upregulation of survivin has been found in many cancers including breast, prostate, pancreatic, and hematological malignancies, and it may prove to be associated with the advanced presentation, poorer prognosis, and lower survival rates observed in ethnically diverse populations.
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Affiliation(s)
- Salma Khan
- Department of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA ; Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Heather Ferguson Bennit
- Department of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA ; Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Malyn May Asuncion Valenzuela
- Department of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA ; Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - David Turay
- Department of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA ; Department of Anatomy, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Carlos J Diaz Osterman
- Department of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA ; Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Ron B Moyron
- Department of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA ; Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Grace E Esebanmen
- Department of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA ; Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Arjun Ashok
- Department of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA ; Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Nathan R Wall
- Department of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA ; Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
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16
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Saeki T, Inui H, Fujioka S, Fukuda S, Nomura A, Nakamura Y, Park EY, Sato K, Kanamoto R. Staurosporine synergistically potentiates the deoxycholate-mediated induction of COX-2 expression. Physiol Rep 2014; 2:2/8/e12143. [PMID: 25168879 PMCID: PMC4246598 DOI: 10.14814/phy2.12143] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Colorectal cancer is a major cause of cancer‐related death in western countries, and thus there is an urgent need to elucidate the mechanism of colorectal tumorigenesis. A diet that is rich in fat increases the risk of colorectal tumorigenesis. Bile acids, which are secreted in response to the ingestion of fat, have been shown to increase the risk of colorectal tumors. The expression of cyclooxygenase (COX)‐2, an inducible isozyme of cyclooxygenase, is induced by bile acids and correlates with the incidence and progression of cancers. In this study, we investigated the signal transduction pathways involved in the bile‐acid‐mediated induction of COX‐2 expression. We found that staurosporine (sts), a potent protein kinase C (PKC) inhibitor, synergistically potentiated the deoxycholate‐mediated induction of COX‐2 expression. Sts did not increase the stabilization of COX‐2 mRNA. The sts‐ and deoxycholate‐mediated synergistic induction of COX‐2 expression was suppressed by a membrane‐permeable Ca2+ chelator, a phosphoinositide 3‐kinase inhibitor, a nuclear factor‐κB pathway inhibitor, and inhibitors of canonical and stress‐inducible mitogen‐activated protein kinase pathways. Inhibition was also observed using PKC inhibitors, suggesting the involvement of certain PKC isozymes (η, θ, ι, ζ, or μ). Our results indicate that sts exerts its potentiating effects via the phosphorylation of p38. However, the effects of anisomycin did not mimic those of sts, indicating that although p38 activation is required, it does not enhance deoxycholate‐induced COX‐2 expression. We conclude that staurosporine synergistically enhances deoxycholate‐induced COX‐2 expression in RCM‐1 colon cancer cells. e12143 The expression of COX‐2, an inducible isozyme of cyclooxygenase, correlates with the incidence and progression of cancers, and bile acids have been shown to induce COX‐2 expression. We investigated the signal transduction pathways involved in the bile‐acid‐mediated induction of COX‐2 expression, and we found that staurosporine, a potent PKC inhibitor, synergistically potentiated the deoxycholate‐mediated induction of COX‐2 expression. Staurosporine exerted its potentiating effects via the phosphorylation of p38, and the involvement of certain PKC isozymes was suggested.
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Affiliation(s)
- Tohru Saeki
- Laboratory of Molecular Nutrition, Kyoto Prefectural University, Kyoto, Japan
| | - Haruka Inui
- Laboratory of Molecular Nutrition, Kyoto Prefectural University, Kyoto, Japan
| | - Saya Fujioka
- Laboratory of Molecular Nutrition, Kyoto Prefectural University, Kyoto, Japan
| | - Suguru Fukuda
- Laboratory of Molecular Nutrition, Kyoto Prefectural University, Kyoto, Japan
| | - Ayumi Nomura
- Laboratory of Molecular Nutrition, Kyoto Prefectural University, Kyoto, Japan
| | - Yasushi Nakamura
- Laboratory of Food Science, Kyoto Prefectural University, Kyoto, Japan
| | - Eun Young Park
- Laboratory of Food Science, Kyoto Prefectural University, Kyoto, Japan
| | - Kenji Sato
- Laboratory of Food Science, Kyoto Prefectural University, Kyoto, Japan
| | - Ryuhei Kanamoto
- Laboratory of Molecular Nutrition, Kyoto Prefectural University, Kyoto, Japan
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17
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Rödl CB, Vogt D, Kretschmer SBM, Ihlefeld K, Barzen S, Brüggerhoff A, Achenbach J, Proschak E, Steinhilber D, Stark H, Hofmann B. Multi-dimensional target profiling of N,4-diaryl-1,3-thiazole-2-amines as potent inhibitors of eicosanoid metabolism. Eur J Med Chem 2014; 84:302-11. [PMID: 25036790 DOI: 10.1016/j.ejmech.2014.07.025] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 07/05/2014] [Accepted: 07/08/2014] [Indexed: 11/28/2022]
Abstract
Eicosanoids like leukotrienes and prostaglandins play a considerable role in inflammation. Produced within the arachidonic acid (AA) cascade, these lipid mediators are involved in the pathogenesis of pain as well as acute and chronic inflammatory diseases like rheumatoid arthritis and asthma. With regard to the lipid cross-talk within the AA pathway, a promising approach for an effective anti-inflammatory therapy is the development of inhibitors targeting more than one enzyme of this cascade. Within this study, thirty N-4-diaryl-1,3-thiazole-2-amine based compounds with different substitution patterns were synthesized and tested in various cell-based assays to investigate their activity and selectivity profile concerning five key enzymes involved in eicosanoid metabolism (5-, 12-, 15-lipoxygenase (LO), cyclooxygenase-1 and -2 (COX-1/-2)). With compound 7, 2-(4-phenyl)thiazol-2-ylamino)phenol (ST-1355), a multi-target ligand targeting all tested enzymes is presented, whereas compound 9, 2-(4-(4-chlorophenyl)thiazol-2-ylamino)phenol (ST-1705), represents a potent and selective 5-LO and COX-2 inhibitor with an IC50 value of 0.9 ± 0.2 μM (5-LO) and a residual activity of 9.1 ± 1.1% at 10 μM (COX-2 product formation). The promising characteristics and the additional non-cytotoxic profile of both compounds reveal new lead structures for the treatment of eicosanoid-mediated diseases.
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Affiliation(s)
- Carmen B Rödl
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany
| | - Dominik Vogt
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany
| | - Simon B M Kretschmer
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany
| | - Katja Ihlefeld
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany
| | - Sebastian Barzen
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany
| | - Astrid Brüggerhoff
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany
| | - Janosch Achenbach
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany
| | - Ewgenij Proschak
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany
| | - Dieter Steinhilber
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany
| | - Holger Stark
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany; Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany.
| | - Bettina Hofmann
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
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18
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The role of inflammation in pancreatic cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 816:129-51. [PMID: 24818722 DOI: 10.1007/978-3-0348-0837-8_6] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an extremely poor prognosis. Inflammatory processes have emerged as key mediators of pancreatic cancer development and progression. In genetically engineered mouse models, induction of pancreatitis accelerates PDAC development, and patients with chronic pancreatitis are known to have a higher risk of developing pancreatic cancer. In recent years, much effort has been given to identify the underlying mechanisms that contribute to inflammation-induced tumorigenesis. Many inflammatory pathways have been identified and inhibitors have been developed in order to prevent cancer development and progression. In this chapter, we discuss the role of inflammatory pathways in the initiation and progression of pancreatic cancer as well as the role of inhibitors used in treatment and prevention of pancreatic cancer.
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19
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The Kaposi's sarcoma-associated herpesvirus (KSHV)-induced 5-lipoxygenase-leukotriene B4 cascade plays key roles in KSHV latency, monocyte recruitment, and lipogenesis. J Virol 2013; 88:2131-56. [PMID: 24335295 DOI: 10.1128/jvi.02786-13] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). KS lesions are characterized by endothelial cells with multiple copies of the latent KSHV episomal genome, lytic replication in a low percentage of infiltrating monocytes, and inflammatory cytokines plus growth factors. We demonstrated that KSHV utilizes inflammatory cyclooxygenase 2/prostaglandin E2 to establish and maintain latency (Sharma-Walia, N., A. G. Paul, V. Bottero, S. Sadagopan, M. V. Veettil, N. Kerur, and B. Chandran, PLoS Pathog 6:e1000777, 2010 [doi:10.1371/journal.ppat.1000777]). Here, we evaluated the role of 5-lipoxygenase (5LO) and its chemotactic metabolite leukotriene B4 (LTB4) in KSHV biology. Abundant staining of 5LO was detected in human KS tissue sections. We observed elevated levels of 5LO and high levels of secretion of LTB4 during primary KSHV infection of endothelial cells and in PEL B cells (BCBL-1 and BC-3 cells). Blocking the 5LO/LTB4 cascade inhibited viral latent ORF73, immunomodulatory K5, viral macrophage inflammatory protein 1 (MIP-1), and viral MIP-2 gene expression, without much effect on lytic switch ORF50, immediate early lytic K8, and viral interferon-regulatory factor 2 gene expression. 5LO inhibition significantly downregulated latent viral Cyclin and latency-associated nuclear antigen 2 levels in PEL cells. 5LO/LTB4 inhibition downregulated TH2-related cytokine secretion, elevated TH1-related cytokine secretion, and reduced human monocyte recruitment, adhesion, and transendothelial migration. 5LO/LTB4 inhibition reduced fatty acid synthase (FASN) promoter activity and its expression. Since FASN, a key enzyme required in lipogenesis, is important in KSHV latency, these findings collectively suggest that 5LO/LTB4 play important roles in KSHV biology and that effective inhibition of the 5LO/LTB4 pathway could potentially be used in treatment to control KS/PEL.
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20
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Ferreiro-Vera C, Priego-Capote F, Mata-Granados JM, Luque de Castro MD. Short-term comparative study of the influence of fried edible oils intake on the metabolism of essential fatty acids in obese individuals. Food Chem 2012; 136:576-84. [PMID: 23122100 DOI: 10.1016/j.foodchem.2012.08.081] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2011] [Revised: 03/01/2012] [Accepted: 08/31/2012] [Indexed: 11/28/2022]
Abstract
The effect of breakfast intake of fried oils containing natural antioxidants or a synthetic autooxidation inhibitor on the metabolism of essential fatty acids focused on obese individuals. Serum levels of eicosanoids were compared in individuals before and after intake of different breakfasts. Univariate descriptive analysis was used to characterise the cohort selected for this study and multivariate analysis to reveal statistical differences of normalised eicosanoids concentrations (determined by solid-phase extraction coupled to LC-MS/MS) depending on the edible oil used for breakfast preparation. The results showed that the intake of breakfast prepared with pure sunflower oil subjected to deep frying causes an effect over the eicosanoids profile that enables discrimination versus the rest of individuals. The effect was a significant increase in the concentration of hydroxyoctadecadienoic acid (HODE) metabolites, indicative markers of the intake of fried oils. The concentration of HODE metabolites was lower when the oil contained either natural antioxidants from olive-oil pomace or a synthetic autooxidation inhibitor as dimethylsiloxane. The comparison of the effect of fried sunflower oils with fried extra virgin olive oil shows the benefits associated to the consumption of the latter.
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Affiliation(s)
- Carlos Ferreiro-Vera
- Department of Analytical Chemistry, Annex C-3, Campus of Rabanales, University of Córdoba, E-14071 Córdoba, Spain
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21
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Al-Wadei HAN, Al-Wadei MH, Ullah MF, Schuller HM. Celecoxib and GABA cooperatively prevent the progression of pancreatic cancer in vitro and in xenograft models of stress-free and stress-exposed mice. PLoS One 2012; 7:e43376. [PMID: 22916251 PMCID: PMC3420877 DOI: 10.1371/journal.pone.0043376] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2012] [Accepted: 07/23/2012] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and is associated with high levels of psychological distress. We have shown that beta-adrenergic receptors (β-ARs), which are activated by stress neurotransmitters, regulate PDAC cells via cyclic AMP (cAMP)-dependent signaling in vitro, that social stress promotes PDAC progression in mouse xenografts and that γ-aminobutyric acid (GABA) inhibits these responses in vitro and in vivo. The targeted inhibition of stress-induced regulatory pathways may abolish the potentially negative impact of psychological stress on clinical outcomes. Our current data show that chronic exposure of PDAC cell lines Panc-1 (activating point mutations in K-ras) and BXPC-3 (no mutations in K-ras) in vitro to the stress neurotransmitter epinephrine at the concentration (15 nM) previously measured in the serum of mice exposed to social stress significantly increased proliferation and migration. These responses were inhibited in a concentration-dependent manner by celecoxib. The effects of celecoxib alone and in combination with γ-aminobutyric acid (GABA) on the progression of subcutaneous mouse xenografts from the cell line (BXPC-3) most responsive to epinephrine were then investigated in the presence and absence of social stress. Cancer-stimulating factors (VEGF & prostaglandin E(2) [PGE(2)]) and levels of cAMP were measured by immunoassays in blood and xenograft tissue. Phosphorylation of the signaling proteins ERK, CREB, Src, and AKT was assessed by ELISA assays and Western blotting. Expression of COX-2, 5-lipoxygenase, and p-5-LOX were determined by semi-quantitative Western blotting. Celecoxib alone significantly inhibited xenograft progression and decreased systemic and tumor VEGF, PGE2, and cAMP as well as phosphorylated signaling proteins in stress-exposed and stress-free mice. These responses were significantly enhanced by co-treatment with GABA. The celecoxib-induced downregulation of COX-2 protein and p-5-LOX was also significantly enhanced by GABA under both experimental conditions. Our findings identify the targeted inhibition of stress-induced pathways as a promising area for more effective cancer intervention in pancreatic cancer.
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Affiliation(s)
- Hussein A. N. Al-Wadei
- Experimental Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee, United States of America
- Department of Preventive Medicine, Sana’a University, Sana’a, Yemen
| | - Mohammed H. Al-Wadei
- Experimental Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee, United States of America
| | - Mohammad F. Ullah
- Experimental Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee, United States of America
| | - Hildegard M. Schuller
- Experimental Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee, United States of America
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22
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Hillion J, Smail SS, Di Cello F, Belton A, Shah S, Huso T, Schuldenfrei A, Nelson DM, Cope L, Campbell N, Karikari C, Aderinto A, Maitra A, Huso DL, Resar LMS. The HMGA1-COX-2 axis: a key molecular pathway and potential target in pancreatic adenocarcinoma. Pancreatology 2012; 12:372-9. [PMID: 22898640 PMCID: PMC3466102 DOI: 10.1016/j.pan.2012.05.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
CONTEXT Although pancreatic cancer is a common, highly lethal malignancy, the molecular events that enable precursor lesions to become invasive carcinoma remain unclear. We previously reported that the high-mobility group A1 (HMGA1) protein is overexpressed in >90% of primary pancreatic cancers, with absent or low levels in early precursor lesions. METHODS Here, we investigate the role of HMGA1 in reprogramming pancreatic epithelium into invasive cancer cells. We assessed oncogenic properties induced by HMGA1 in non-transformed pancreatic epithelial cells expressing activated K-RAS. We also explored the HMGA1-cyclooxygenase (COX-2) pathway in human pancreatic cancer cells and the therapeutic effects of COX-2 inhibitors in xenograft tumorigenesis. RESULTS HMGA1 cooperates with activated K-RAS to induce migration, invasion, and anchorage-independent cell growth in a cell line derived from normal human pancreatic epithelium. Moreover, HMGA1 and COX-2 expression are positively correlated in pancreatic cancer cell lines (r(2) = 0.93; p < 0.001). HMGA1 binds directly to the COX-2 promoter at an AT-rich region in vivo in three pancreatic cancer cell lines. In addition, HMGA1 induces COX-2 expression in pancreatic epithelial cells, while knock-down of HMGA1 results in repression of COX-2 in pancreatic cancer cells. Strikingly, we also discovered that Sulindac (a COX-1/COX-2 inhibitor) or Celecoxib (a more specific COX-2 inhibitor) block xenograft tumorigenesis from pancreatic cancer cells expressing high levels of HMGA1. CONCLUSIONS Our studies identify for the first time an important role for the HMGA1-COX-2 pathway in pancreatic cancer and suggest that targeting this pathway could be effective to treat, or even prevent, pancreatic cancer.
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Affiliation(s)
- Joelle Hillion
- Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Shamayra S. Smail
- Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Pathobiology Graduate Program, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Francescopaolo Di Cello
- Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Amy Belton
- Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Sandeep Shah
- Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Tait Huso
- Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Andrew Schuldenfrei
- Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Dwella Moton Nelson
- Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Leslie Cope
- Oncology Center-Biostatistics/Bioinformatics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Nathaniel Campbell
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Collins Karikari
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Abimbola Aderinto
- Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Anirban Maitra
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - David L. Huso
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Linda M. S. Resar
- Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Pathobiology Graduate Program, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
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23
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Hogendorf P, Durczyński A, Kumor A, Strzelczyk J. Prostaglandin E2 (PGE2) in portal blood in patients with pancreatic tumor--a single institution series. J INVEST SURG 2012; 25:8-13. [PMID: 22272632 DOI: 10.3109/08941939.2011.592569] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Cyclooxygenase-2 (COX-2) may play a significant role in the development of pancreatic cancer. One of COX-2 main metabolites is prostaglandin E2 (PGE2), which is involved both in inflammation and carcinogenesis. As PGE2 is inactivated in the lungs and the liver we assumed that the best medium to assess the level of PGE2 is not peripheral but portal blood. PATIENTS AND METHODS Fifty-seven patients with pathologically verified diagnosis of pancreatic ductal adenocarcinoma (PDAC group, n = 38) and chronic pancreatitis (CP group, n = 19) were enrolled in this study. Sample of blood from central line was collected before surgery. Intraoperatively portal vein was identified and sampled. PGE2 levels were determined using ELISA test. All the patients were followed-up for 1-35 months. RESULTS PGE2 portal blood levels in patients with PDAC were higher than in patients with CP (190.55 ± 149.86 versus 120.23 ± 132.60; p = .04). PGE2 concentration at a cut-off value of 94.46 pg/ml had a sensitivity of 91.67%, specificity of 50%, AUC = 0.631 (95% CI, 0.489-0.758). CONCLUSION The PGE2 portal blood levels in PDAC patients are higher than in those with CP. The PGE2 portal concentration cannot be a single marker in diagnosing PDAC due to low specificity.
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Affiliation(s)
- Piotr Hogendorf
- Department of General and Transplant Surgery, Norbert Barlicki Memorial Teaching Hospital, Medical University of Łódź, Poland.
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Ding X, Zhu C, Qiang H, Zhou X, Zhou G. Enhancing antitumor effects in pancreatic cancer cells by combined use of COX-2 and 5-LOX inhibitors. Biomed Pharmacother 2011; 65:486-90. [PMID: 21993002 DOI: 10.1016/j.biopha.2011.06.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2011] [Accepted: 06/05/2011] [Indexed: 10/17/2022] Open
Abstract
Cyclooxygenase (COX)-2 and lipoxygenase (LOX)-5 are involved in carcinogenesis of pancreatic cancer. COX-2 inhibitor celecoxib displays inhibitory effects in pancreatic cancer cell growth. Recently, it has been reported that COX-2 inhibitor may not be able to suppress pancreatic tumor growth in vivo and its application is further limited by untoward side effects. The present study provides evidence that combined use of celecoxib and 5-LOX inhibitor MK886 markedly suppresses pancreatic tumor cell growth in vitro. Compared to the single inhibitor treatment, dual treatment with celecoxib and MK886 exerted additive antitumor effects in pancreatic tumor cells. We found that MK886 reversed celecoxib-induced increases in 5-LOX gene expression and Erk1/2 activation in pancreatic tumor cells. Moreover, Dual treatment of pancreatic tumor cells with celecoxib and MK886 inhibited the levels of LBT4 receptor BLT1 and vascular endothelial growth factor. Our results imply that combined use of celecoxib and MK886 might be an effective way to treat clinical patients with pancreatic cancer.
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Affiliation(s)
- Xiaoling Ding
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nangtong, Jiangsu 226001, China
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25
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Mainetti LE, Rozados VR, Rossa A, Bonfil RD, Scharovsky OG. Antitumoral and antimetastatic effects of metronomic chemotherapy with cyclophosphamide combined with celecoxib on murine mammary adenocarcinomas. J Cancer Res Clin Oncol 2011; 137:151-63. [PMID: 20349084 DOI: 10.1007/s00432-010-0869-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2009] [Accepted: 03/12/2010] [Indexed: 12/16/2022]
Abstract
PURPOSE Metronomic chemotherapy (MCT) refers to the chronic and equally spaced administration of low doses of different chemotherapy drugs, without extended interruptions. Previously, we demonstrated the antitumor effect of MCT with cyclophosphamide (Cy) in a mouse mammary adenocarcinoma model. Herein, we investigated the therapeutic efficacy of metronomic Cy combined with celecoxib (Cel) in two murine mammary adenocarcinoma models. METHODS Mice were s.c. challenged with M-234 p or M-406 mammary tumors and from day 5 or 8 on, respectively, treated with: (I) no treatment (controls); (II) Cy in the drinking water (25-30 mg/kg body weight/day); (III) Cel (30 mg/kg p.o.), five times/week; (IV) treated as II + III. Mice challenged i.v. with M-234 p or M-406 tumor cells received, on day 3, the same treatments. RESULTS We found that MCT with Cy plus Cel inhibited tumor growth decreased lung metastases, and increased the median survival time, in both tumor models, having very low toxicity. MCT with Cy combined with Cel was more effective than each monotherapy. CONCLUSIONS The therapeutic benefits of combined MCT with cyclophosphamide plus celecoxib on mammary adenocarcinomas together with its very low toxicity profile warrant further study in an attempt to make the translation into the clinic.
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Affiliation(s)
- Leandro E Mainetti
- Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Santa Fe 3100, 2000 Rosario, Argentina
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Caballero J, Fernández M, Coll D. Quantitative structure-activity relationship of organosulphur compounds as soybean 15-lipoxygenase inhibitors using CoMFA and CoMSIA. Chem Biol Drug Des 2010; 76:511-7. [PMID: 21040497 DOI: 10.1111/j.1747-0285.2010.01039.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Three-dimensional quantitative structure-activity relationship studies were carried out on a series of 28 organosulphur compounds as 15-lipoxygenase inhibitors using comparative molecular field analysis and comparative molecular similarity indices analysis. Quantitative information on structure-activity relationships is provided for further rational development and direction of selective synthesis. All models were carried out over a training set including 22 compounds. The best comparative molecular field analysis model only included steric field and had a good Q² = 0.789. Comparative molecular similarity indices analysis overcame the comparative molecular field analysis results: the best comparative molecular similarity indices analysis model also only included steric field and had a Q² = 0.894. In addition, this model predicted adequately the compounds contained in the test set. Furthermore, plots of steric comparative molecular similarity indices analysis field allowed conclusions to be drawn for the choice of suitable inhibitors. In this sense, our model should prove useful in future 15-lipoxygenase inhibitor design studies.
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Affiliation(s)
- Julio Caballero
- Centro de Bioinformática y Simulación Molecular, Facultad de Ingeniería en Bioinformática, Universidad de Talca, 2 Norte 685, Casilla 721, Talca, Chile.
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Agarwal S, Reddy GV, Reddanna P. Eicosanoids in inflammation and cancer: the role of COX-2. Expert Rev Clin Immunol 2010; 5:145-65. [PMID: 20477063 DOI: 10.1586/1744666x.5.2.145] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Eicosanoids, a family of oxygenated metabolites of eicosapolyenoic fatty acids, such as arachidonic acid, formed via the lipoxygenase, cyclooxygenase (COX) and epoxygenase pathways, play an important role in the regulation of various pathophysiological processes, including inflammation and cancer. COX-2, the inducible isoform of COX, has emerged as the key enzyme regulating inflammation, and promises to play a considerable role in cancer. Although NSAIDs have been in use for centuries, the COX-2 selective inhibitors - coxibs - have emerged as potent anti-inflammatory drugs with fewer gastric side effects. As COX-2 plays a major role in neoplastic transformation and cancer growth, by downregulating apoptosis and promoting angiogenesis, invasion and metastasis, coxibs have a potential role in the prevention and treatment of cancer. Recent studies indicate their possible application in overcoming drug resistance by downregulating the expression of MDR-1. However, the cardiac side effects of some of the coxibs have limited their application in treating various inflammatory disorders and warrant the development of COX-2 inhibitors without side effects. This review will focus on the role of COX-2 in inflammation and cancer, with an emphasis on novel approaches to the development of COX-2 inhibitors without side effects.
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Affiliation(s)
- Smita Agarwal
- Department of Animal Sciences, School of Life Sciences, University of Hyderabad, Hyderabad 500 046, India.
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28
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Khan AN, Perveen S, Malik A, Afza N, Iqbal L, Latif M, Saleem M. Conferin, potent antioxidant and anti-inflammatory isoflavone from Caragana conferta Benth. J Enzyme Inhib Med Chem 2010. [DOI: 10.3109/14756360903179484] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Amna Nisar Khan
- International Center for Chemical Sciences, HEJ Research Institute of Chemistry, University of Karachi, Karachi, Pakistan
| | - Shagufta Perveen
- International Center for Chemical Sciences, HEJ Research Institute of Chemistry, University of Karachi, Karachi, Pakistan
| | - Abdul Malik
- International Center for Chemical Sciences, HEJ Research Institute of Chemistry, University of Karachi, Karachi, Pakistan
| | - Nighat Afza
- Pharmaceutical Research Center, PCSIR Laboratories Complex, Karachi, Pakistan
| | - Lubna Iqbal
- Pharmaceutical Research Center, PCSIR Laboratories Complex, Karachi, Pakistan
| | - Mehreen Latif
- Pharmaceutical Research Center, PCSIR Laboratories Complex, Karachi, Pakistan
| | - Muhammad Saleem
- Pharmaceutical Research Center, PCSIR Laboratories Complex, Karachi, Pakistan
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Buchholz M, Gress TM. Molecular changes in pancreatic cancer. Expert Rev Anticancer Ther 2009; 9:1487-97. [PMID: 19828010 DOI: 10.1586/era.09.107] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
As with many human malignancies, pancreatic cancer is a complex genetic disorder. Several thousand disease-associated alterations on the DNA, mRNA, miRNA and protein levels have been reported to date. Some of these alterations, including a number of gatekeeper mutations, which are of pre-eminent importance for the onset and progression of the disease, have been extensively studied in primary tissues, in vitro experiments and transgenic mouse models. For the vast majority of alterations, however, data about the functional significance are lacking. The situation is complicated by the fact that no certainty exists concerning the identity of the cells that originally undergo malignant transformation nor about the precise nature and fate of premalignant lesions that are observed in pancreatic tissues.
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Affiliation(s)
- Malte Buchholz
- Klinik f. Innere Medizin, SP Gastroenterologie, Universitätsklinikum Marburg, Baldingerstrasse 35043 Marburg, Germany.
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Petrović ZD, Hadjipavlou-Litina D, Pontiki E, Simijonović D, Petrović VP. Diethanolamine Pd(II) complexes in bioorganic modeling as model systems of metallopeptidases and soybean lipoxygenase inhibitors. Bioorg Chem 2009; 37:162-6. [PMID: 19679328 DOI: 10.1016/j.bioorg.2009.07.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2009] [Revised: 07/10/2009] [Accepted: 07/13/2009] [Indexed: 11/29/2022]
Abstract
The reaction of PdCl(2) with diethanolammonium chloride (DEAxHCl), in the molar ratio 1:2, affords the [HDEA](2)[PdCl(4)] complex (1). The hydrolytic activity of the novel Pd(II) complex 1 was tested in reaction with N-acetylated L-histidylglycine dipeptide (AcHis-Gly). Complex 1, as well as earlier prepared trans-[PdCl(2)(DEA)(2)] complex (2), and DEA, as their precursor, were tested for their in vitro free radical scavenging activity. UV absorbance-based enzyme assays were done in order to evaluate their inhibitory activity of soybean lipoxygenase (LOX). Also, assays with superoxide anion radical were done. The scavenging activities of the complexes were measured and compared with those of their precursors and caffeic acid. Complex 2 exhibits the highest antioxidant activity and the highest inhibitory effect against the soybean LOX.
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Affiliation(s)
- Zorica D Petrović
- Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12, 34000 Kragujevac, Serbia.
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Adrian TE, Hennig R, Friess H, Ding X. The Role of PPARgamma Receptors and Leukotriene B(4) Receptors in Mediating the Effects of LY293111 in Pancreatic Cancer. PPAR Res 2009; 2008:827096. [PMID: 19190780 PMCID: PMC2631651 DOI: 10.1155/2008/827096] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2008] [Accepted: 10/22/2008] [Indexed: 11/25/2022] Open
Abstract
Pancreatic cancer is a devastating disease in which current therapies are inadequate. Separate lines of research have identified the 5-lipoxygenase/leukotriene B(4) receptor pathway and the PPARgamma pathway as potential targets for prevention or treatment of this disease. LY293111 was originally designed as a potent leukotriene B(4) receptor antagonist for treatment of inflammatory conditions. LY293111 was also known to have inhibitory effects on 5-lipoxygenase, which is upstream of the production of leukotrienes. LY293111 was shown to have potent anticancer effects in pancreatic cancer and several other solid malignancies, where it caused cell cycle arrest and marked apoptosis. Subsequently, it came to light that LY293111 exhibited PPARgamma agonist activity in addition to its effects on the 5-lipoxygenase pathway. This raises the question of which of the two targets is of greatest importance with regard to the anticancer effects of this agent. The evidence to date is not conclusive, but suggests that the effects of LY293111 may be mediated by both LTB(4) receptors and PPARgamma.
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Affiliation(s)
- Thomas E. Adrian
- Department of Physiology, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611-3008, USA
| | - Rene Hennig
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611-3008, USA
- Department of Surgery, Technische Universitaet Muenchen, 81675 Munich, Germany
| | - Helmut Friess
- Department of Surgery, Technische Universitaet Muenchen, 81675 Munich, Germany
| | - Xianzhong Ding
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611-3008, USA
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Wang J, John EM, Ingles SA. 5-lipoxygenase and 5-lipoxygenase-activating protein gene polymorphisms, dietary linoleic acid, and risk for breast cancer. Cancer Epidemiol Biomarkers Prev 2008; 17:2748-54. [PMID: 18843019 DOI: 10.1158/1055-9965.epi-08-0439] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The n-6 polyunsaturated fatty acid 5-lipoxygenase pathway has been shown to play a role in the carcinogenesis of breast cancer. We conducted a population-based case-control study among Latina, African-American, and White women from the San Francisco Bay area to examine the association of the 5-lipoxygenase gene (ALOX5) and 5-lipoxygenase-activating protein gene (ALOX5AP) with breast cancer risk. Three ALOX5AP polymorphisms [poly(A) microsatellite, -4900 A>G (rs4076128), and -3472 A>G (rs4073259)] and three ALOX5 polymorphisms [Sp1-binding site (-GGGCGG-) variable number of tandem repeat polymorphism, -1279 G>T (rs6593482), and 760 G>A (rs2228065)] were genotyped in 802 cases and 888 controls. We did not find significant main effects of ALOX5 and ALOX5AP genotypes on breast cancer risk that were consistent across race or ethnicity; however, there was a significant interaction between the ALOX5AP -4900 A>G polymorphism and dietary linoleic acid intake (P=0.03). Among women consuming a diet high in linoleic acid (top quartile of intake, >17.4 g/d), carrying the AA genotype was associated with higher breast cancer risk (age- and race-adjusted odds ratio, 1.8; 95% confidence interval, 1.2-2.9) compared with carrying genotypes AG or GG. Among women consuming <or=17.4 g/d of linoleic acid, ALOX5AP -4900 genotype was not associated with breast cancer risk (age- and race-adjusted odds ratio, 0.9; 95% confidence interval, 0.7-1.2). These results support a role for n-6 polyunsaturated fatty acids in breast carcinogenesis and suggest that epidemiologic studies on dietary fat and breast cancer should take into account genetic predisposition related to n-6 polyunsaturated fatty acid metabolism.
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Affiliation(s)
- Jun Wang
- Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
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AHMAD IJAZ, CHEN SHILIN, PENG YONG, CHEN SIBAO, XU LIJIA. Lipoxygenase inhibiting and antioxidant iridoids from Buddleja crispa. J Enzyme Inhib Med Chem 2008; 23:140-3. [DOI: 10.1080/14756360701342532] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Affiliation(s)
- IJAZ AHMAD
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100094, China
- Medicinal Botanic Centre, PCSIR Laboratories Complex Peshawar, N.W.F.P, Pakistan
| | - SHILIN CHEN
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100094, China
| | - YONG PENG
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100094, China
| | - SIBAO CHEN
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology, Shenzhen, 518057, China
| | - LIJIA XU
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100094, China
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Zhou H, Huang L, Sun Y, Rigas B. Nitric oxide-donating aspirin inhibits the growth of pancreatic cancer cells through redox-dependent signaling. Cancer Lett 2008; 273:292-9. [PMID: 18805632 DOI: 10.1016/j.canlet.2008.08.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2008] [Revised: 06/27/2008] [Accepted: 08/08/2008] [Indexed: 11/15/2022]
Abstract
The novel chemopreventive nitric oxide-donating aspirin (NO-ASA) prevents nearly 90% of ductal adenocarcinomas in a animal tumor model. To decipher the mechanism of this effect, we studied in BxPC-3 human pancreatic cancer cells the sequence of signaling events leading from NO-ASA treatment to cell growth inhibition. NO-ASA inhibited the growth of BxPC-3 cells (IC(50) =13 microM), by inhibiting proliferation modestly and inducing apoptosis, necrosis and G(1)/S cell cycle block. At 15 min of treatment with NO-ASA, the intracellular levels of reactive oxygen species (ROS) began increasing (peak at 8h, baseline levels by 24h). ROS activated almost immediately in a time- and concentration-dependent manner the MAPK pathways p38, ERK and JNK (their activation was abrogated by the antioxidant N-acetylcysteine). MAPK activation induced p21(cip-1), which suppressed the levels of cyclin D1 that controls the G(1)/S cell cycle transition. NO-ASA induced COX-2 expression starting 90 min after p21(cip-1) was induced. When COX-2 expression was knocked down using siRNA against cox-2, the expression of p21(cip-1) was induced by NO-ASA, regardless of the level of expression of COX-2, suggesting a marginal, if any, role for COX-2 in the growth inhibitory effect of NO-ASA. These findings along with the temporal sequence of individual changes indicate a signaling sequence that involves ROS-->MAPKs-->p21(cip-1)-->cyclin D1-->cell death. Our findings establish the critical role of ROS as proximal signaling molecules in the action of anticancer compounds and may be useful in designing mechanism-driven approaches to cancer control.
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Affiliation(s)
- Hui Zhou
- Division of Cancer Prevention, Stony Brook University, Life Sciences Building, Room 006, Stony Brook, NY 11794-5200, USA
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Zhang B, Wang CL, Zhao WH, Lv M, Wang CY, Zhong WX, Zhou WY, Yu WS, Zhang Y, Li S. Effect of 5-LOX/COX-2 common inhibitor DHDMBF30 on pancreatic cancer cell Capan2. World J Gastroenterol 2008; 14:2494-500. [PMID: 18442195 PMCID: PMC2708359 DOI: 10.3748/wjg.14.2494] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the effect of 5-lipoxygenase/cyclooxy-genase-2 (5-LOX/COX-2) dual inhibitor 7-tert-butyl-2, 3-dihydro-3, 3-dimethyl substituted dihydrofuran 30 (DHDMBF30) on proliferation and apoptosis of the pancreatic cancer cell line Capan-2 and the effect of DHDMBF30 on human pancreatic cancer in a nude mouse model.
METHODS: Investigate the effect of 5-LOX/COX-2 dual inhibitor DHDMBF30 on proliferation and apoptosis of the pancreatic cancer cell line Capan-2 by RT-PCR, MTT assay, FCM and electron microscope. Cell line Capan-2 was inoculated percutaneously on the outer thigh of 12 nude mice. The VEGF mRNA of transplantation tumor was detected by RT-PCR.
RESULTS: DHDMBF30 inhibits the proliferation of cell line Capan2, reduces the expression of 5-LOX, COX-2 and VEGF. After Capan2 was treated with DHDMBF30, we found that the apoptosis peak of the experimental group was significantly higher than that of the contrast group (3.08 ± 1.89 vs 27.67 ± 0.52, P < 0.001). The tumor weight of the DHDMBF30 group was significantly lower than PBS control groups (1.35 ± 0.47 vs 2.92 ± 0.73, P < 0.01). Expression of VEGF in the DHDMBF30 group was significantly decreased.
CONCLUSION: DHDMBF30 inhibits the proliferation of the pancreatic cell line Capan2, and induces apoptosis and inhibits the growth of pancreatic cancer in nude mice.
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Zhang Y, Chen AY, Li M, Chen C, Yao Q. Ginkgo biloba extract kaempferol inhibits cell proliferation and induces apoptosis in pancreatic cancer cells. THE JOURNAL OF SURGICAL RESEARCH 2008. [PMID: 18570926 DOI: 10.1016/j.jss.2008.02.036s0022-4804(08)00140-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Kaempferol is one of the most important constituents in ginkgo flavonoids. Recent studies indicate kaempferol may have antitumor activities. The objective of this study was to determine the effect and mechanisms of kaempferol on pancreatic cancer cell proliferation and apoptosis. MATERIALS AND METHODS Pancreatic cancer cell lines MIA PaCa-2 and Panc-1 were treated with kaempferol, and the inhibitory effects of kaempferol on pancreatic cancer cell proliferation were examined by direct cell counting, 3H-thymidine incorporation, and MTS assay. Lactate dehydrogenase release from cells was determined as an index of cytotoxicity. Apoptosis was analyzed by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay. RESULTS Upon the treatment with 70 microm kaempferol for 4 days, MIA PaCa-2 cell proliferation was significantly inhibited by 79% and 45.7% as determined by direct cell counting and MTS assay, respectively, compared with control cells (P < 0.05). Similarly, the treatment with kaempferol significantly inhibited Panc-1 cell proliferation. Kaempferol treatment also significantly reduced 3H-thymidine incorporation in both MIA PaCa-2 and Panc-1 cells. Combination treatment of low concentrations of kaempferol and 5-fluorouracil showed an additive effect on the inhibition of MIA PaCa-2 cell proliferation. Furthermore, kaempferol had significantly less cytotoxicity than 5-fluorouracil in normal human pancreatic ductal epithelial cells (P = 0.029). In both MIA PaCa-2 and Panc-1 cells, apoptotic cell population was increased when treated with kaempferol in a concentration-dependent manner. CONCLUSIONS Ginkgo biloba extract kaempferol effectively inhibits pancreatic cancer cell proliferation and induces cancer cell apoptosis, which may sensitize pancreatic tumor cells to chemotherapy. Kaempferol may have clinical applications as adjuvant therapy in the treatment of pancreatic cancer.
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Affiliation(s)
- Yuqing Zhang
- Molecular Surgeon Research Center, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA
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Ginkgo biloba extract kaempferol inhibits cell proliferation and induces apoptosis in pancreatic cancer cells. J Surg Res 2008; 148:17-23. [PMID: 18570926 DOI: 10.1016/j.jss.2008.02.036] [Citation(s) in RCA: 123] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2007] [Revised: 02/12/2008] [Accepted: 02/20/2008] [Indexed: 12/26/2022]
Abstract
BACKGROUND Kaempferol is one of the most important constituents in ginkgo flavonoids. Recent studies indicate kaempferol may have antitumor activities. The objective of this study was to determine the effect and mechanisms of kaempferol on pancreatic cancer cell proliferation and apoptosis. MATERIALS AND METHODS Pancreatic cancer cell lines MIA PaCa-2 and Panc-1 were treated with kaempferol, and the inhibitory effects of kaempferol on pancreatic cancer cell proliferation were examined by direct cell counting, 3H-thymidine incorporation, and MTS assay. Lactate dehydrogenase release from cells was determined as an index of cytotoxicity. Apoptosis was analyzed by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay. RESULTS Upon the treatment with 70 microm kaempferol for 4 days, MIA PaCa-2 cell proliferation was significantly inhibited by 79% and 45.7% as determined by direct cell counting and MTS assay, respectively, compared with control cells (P < 0.05). Similarly, the treatment with kaempferol significantly inhibited Panc-1 cell proliferation. Kaempferol treatment also significantly reduced 3H-thymidine incorporation in both MIA PaCa-2 and Panc-1 cells. Combination treatment of low concentrations of kaempferol and 5-fluorouracil showed an additive effect on the inhibition of MIA PaCa-2 cell proliferation. Furthermore, kaempferol had significantly less cytotoxicity than 5-fluorouracil in normal human pancreatic ductal epithelial cells (P = 0.029). In both MIA PaCa-2 and Panc-1 cells, apoptotic cell population was increased when treated with kaempferol in a concentration-dependent manner. CONCLUSIONS Ginkgo biloba extract kaempferol effectively inhibits pancreatic cancer cell proliferation and induces cancer cell apoptosis, which may sensitize pancreatic tumor cells to chemotherapy. Kaempferol may have clinical applications as adjuvant therapy in the treatment of pancreatic cancer.
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Stoeltzing O, Liu W, Fan F, Wagner C, Stengel K, Somcio RJ, Reinmuth N, Parikh AA, Hicklin DJ, Ellis LM. Regulation of cyclooxygenase-2 (COX-2) expression in human pancreatic carcinoma cells by the insulin-like growth factor-I receptor (IGF-IR) system. Cancer Lett 2007; 258:291-300. [PMID: 17950526 DOI: 10.1016/j.canlet.2007.09.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2007] [Revised: 09/15/2007] [Accepted: 09/17/2007] [Indexed: 01/18/2023]
Abstract
Both the insulin-like growth factor-I receptor (IGF-IR) and cyclooxygenase-2 (COX-2) are frequently overexpressed in pancreatic cancer. We hypothesized that IGF-IR is directly involved in induction of COX-2 and sought to investigate signaling pathways mediating this effect. Pancreatic cancer cells (L3.6pl) were stably transfected with a dominant-negative receptor (IGF-IR DN) construct or empty vector (pcDNA). Cells were stimulated with IGF-I to determine activated signaling intermediates and induction of COX-2. Signaling pathways mediating COX-2 induction were identified using signaling inhibitors. IGF-I up-regulated COX-2 selectively via the MAPK/(Erk-1/2) pathway. In addition, IGF-IR DN cells showed a marked decrease in constitutive COX-2 and a blunted response to IGF-I. Similarly, treatment with an anti-IGF-IR antibody effectively inhibited IGF-IR and MAPK/Erk activation and decreased COX-2 in parental cells. In conclusion, activation of IGF-IR mediates COX-2 expression in human pancreatic cancer cells.
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Affiliation(s)
- Oliver Stoeltzing
- Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77230-1402, USA
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Loo WTY, Sasano H, Chow LWC. Effects of capecitabine and vinorelbine on cell proliferation, metabolism and COX2 and p16 expression in breast cancer cell lines and solid tumour tissues. Biomed Pharmacother 2007; 61:596-600. [PMID: 17904787 DOI: 10.1016/j.biopha.2007.08.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
BACKGROUND Capecitabine is a recently developed oral antineoplastic prodrug of 5-fluorouracil. It has demonstrated a favorable tolerability profile, with low incidence of myelosuppression. Vinorelbine, a third generation vinca alkaloid, works by inhibiting mitosis and interfering with cells' ability to synthesize DNA and RNA. The present study investigates the therapeutic value of single use capecitabine on solid tumour tissues in vitro using breast cancer cell lines and as reference. The data is to be compared with the use of vinorelbine which is a conventionally applied drug for advanced breast cancer patients. METHODS The trucut biopsies of 35 metastatic breast tumour patients were obtained. The tissues were cultured for 24h. Capecitabine and vinorelbine were added according to the corresponding groups to be cultured by another 24h. Plain medium was added for control group. The two cell lines chosen were BT-783 and MB-MDA-231 to act as a reference group. The metabolic rate of the tissues and cell lines were measured by ATP bioluminescence assay and the proliferation rate was measured by WST-1. The level of COX2 and p16 after capecitabine and vinorelbine treatment was assessed with immunohistochemical methods. RESULTS One-way ANOVA revealed lower metabolic rate in test groups than control in cell lines and tumour tissues. WST-1 showed similar trend in both cell lines. COX2 and p16 staining showed decreases in cell size and number after drug use. CONCLUSIONS Capecitabine demonstrated similar inhibitory effects as vinorelbine in breast cancer cell lines and solid tumour tissues at decreasing cell proliferation and metabolism as well as decreasing the expression of metabolic proteins and tumor suppressor genes. Capecitabine also has the added benefits of convenient oral administration and lower cost.
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Affiliation(s)
- Wings T Y Loo
- Department of Pathology, Tohuku University School of Medicine, Sendai, Japan
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Covey TM, Edes K, Fitzpatrick FA. Akt activation by arachidonic acid metabolism occurs via oxidation and inactivation of PTEN tumor suppressor. Oncogene 2007; 26:5784-92. [PMID: 17369849 DOI: 10.1038/sj.onc.1210391] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) enzymes are overexpressed during inflammation and multistage tumor progression in many neoplastic disorders including lung, breast and pancreatic cancers. Here we report that the tumor suppressor phosphatase and tensin homolog (PTEN) is oxidized and inactivated during arachidonic acid (AA) metabolism in pancreatic cancer cell lines expressing COX-2 or 5-LOX. Oxidation of PTEN decreases its phosphatase activity, favoring increased phosphatidylinositol 3,4,5-triphosphate production, activation of Akt and phosphorylation of downstream Akt targets including GSK-3beta and S6K. These effects are recapitulated with pancreatic phospholipase A(2), which hydrolyses the release of membrane-bound AA. Interference with PTEN's physiological antagonism of signals from growth factors, insulin and oncogenes may confer risk for hypertrophic or neoplastic diseases associated with chronic inflammation or unwarranted oxidative metabolism of essential fatty acids.
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Affiliation(s)
- T M Covey
- 1Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT, USA
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Ahmad VU, Iqbal S, Nawaz SA, Choudhary MI, Farooq U, Ali ST, Ahmad A, Bader S, Kousar F, Arshad S, Tareen RB. Isolation of four new pterocarpans from Zygophyllum eurypterum (Syn. Z. atriplicoides) with enzyme-inhibition properties. Chem Biodivers 2007; 3:996-1003. [PMID: 17193332 DOI: 10.1002/cbdv.200690109] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Four new pterocarpans, atricarpan A (=(-)-1,2-dihydroxy-4-(hydroxymethyl)-3,9-dimethoxypterocarpan; 1), atricarpan B (=(-)-2,3-ethylenedioxy)-1,4-dihydroxy-9-methoxypterocarpan; 2), atricarpan C (=(-)-1,9-dimethoxypterocarpan-3-carboxylic acid; 3), and atricarpan D (=(-)-2,9-dimethoxy-4-(5-oxohexyl)pterocarpan; 4) were isolated from the BuOH extract of the whole plant of Zygophyllum eurypterum. The structure elucidations of those compounds were based primarily on 1D- and 2D-NMR analysis, including COSY, HMBC, and HMQC correlations. Compounds 1-4 also inhibited butyrylcholinesterase (BChE; EC 3.1.1.8) enzyme in a concentration-dependent manner with IC(50) values between 12.5-65.0 microM. Similarly, compounds 1 and 4 inhibited lipoxygenase (LOX; EC 1.13.11.12) and acetylcholinesterase (AChE; EC 3.1.1.7) enzymes with IC50 values of 13.5 and 20.5 muM, respectively.
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Affiliation(s)
- Viqar Uddin Ahmad
- H.E.J. Research Institute of Chemistry, International Center for Chemical Sciences, University of Karachi, Karachi-75270, Pakistan
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Al-Waili NS, Saloom KY, Al-Waili T, Al-Waili A, Al-Waili H. Modulation of prostaglandin activity, part 1: prostaglandin inhibition in the management of nonrheumatologic diseases: immunologic and hematologic aspects. Adv Ther 2007; 24:189-222. [PMID: 17526477 DOI: 10.1007/bf02850008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Prostaglandins (PGs) are active biologic substances that are involved in a wide range of physiologic processes; when their production is out of balance, they are factors in the pathogenesis of illness. Modulation of PGs by inhibition or stimulation is promising for the management of various conditions. PG inhibitors are widely used to relieve pain and inflammation in patients with rheumatologic disease. Interest in the use of PG inhibitors to prevent cancer and cardiovascular events is growing. More than 27 y ago, investigators found that PG depresses antibody production in vivo; reduces serum iron, hemoglobin, and leukoid series in bone marrow during acute and chronic blood loss; reduces albumin during antigenic stimulation; suppresses hypercalcemia after bleeding; and reduces fasting blood sugar and hyperglycemia after ether anesthesia and bleeding. Chronic conditions that produce large quantities of PGs are associated with immunosuppression and secondary anemia. Investigators in the present study hypothesized (1) that the overproduction of PGs is responsible for immunosuppression and secondary anemia in conditions associated with increased PG synthesis, such as pathologic inflammation, malignancy, trauma, and injury, and (2) that PG inhibitors reverse immunosuppression and secondary anemia, thereby enhancing the immune response. This is supported by many reports that show the immunosuppressive effects of PGs and their role in the immunosuppression associated with pathologic inflammation, burns, trauma, and tumors. Inhibition of PGs can be achieved through the use of synthetic medicines and natural products. This article reviews the effects of PGs and inhibition of increased synthesis of PGs on the lymphoid system, hematologic indices, and bone marrow elements in trauma, injury, burns, and tumors. The Medline database (1966-2006) was used in this study. Investigators in the present study and others have provided evidence that shows the involvement of PGs in immunosuppression and secondary anemia, as well as the efficacy of inhibited overproduction of PGs in many pathologic conditions other than rheumatologic disease.
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Affiliation(s)
- Noori S Al-Waili
- Al-Waili's Charitable Foundation for Science and Trading, New York City, NY, USA.
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Perveen S, Khan SB, Malik A, Tareen RB, Nawaz SA, Choudhary MI. Phenolic constituents from Perovskia atriplicifolia. Nat Prod Res 2006; 20:347-53. [PMID: 16644529 DOI: 10.1080/14786410500463205] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Perovskoate, an isorinic acid derivative (1) and perovskoside, the catechol derivative (2) have been isolated from the ethyl acetate soluble fraction of the whole plant of Perovskia atriplicifolia and assigned the structure 3(7-hydroxyphenyl)-2-hydroxy propanoic acid; (R)-form, 2-O-(6',7'-dihydroxy-E-cinnamoyl) (1) and 2-methoxy-4-(undecyl-4'-O-beta-D-glucopyranosyl) phenol (2). In addition, caffeic acid (3) and ferulic acid (4) have been reported for the first time from this species. The structures of these compounds were assigned on the basis of 1D and 2D NMR techniques. The compound 1 showed significant inhibitory activity against lipoxygenase and weak to moderate activity against cholinesterases.
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Affiliation(s)
- Shagufta Perveen
- International Centre for Chemical Sciences, H.E.J. Research Institute of Chemistry, University of Karachi, Karachi-75270, Pakistan
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Sharif A, Ahmed E, Malik A, Riaz N, Afza N, Nawaz SA, Arshad M, Shah MR, Choudhary MI. Lipoxygenase inhibitory constituents from Indigofera oblongifolia. Arch Pharm Res 2006; 28:761-4. [PMID: 16114488 DOI: 10.1007/bf02977339] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Indigin, alkylated xanthene (1) and indigoferic acid (2) have been isolated from the chloroform soluble fraction of Indigofera oblongifolia, along with beta-sitosterol (3) and 3-hydroxybenzoic acid (4), which are reported for the first time from this species. Their structures were determined through spectroscopic techniques. Both the new compounds 1 and 2 showed significant activity against enzyme lipoxygenase, while 2 further showed moderate inhibition against BChE.
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Affiliation(s)
- Ahsan Sharif
- International Centre for Chemical Sciences, HEJ Research Institute of Chemistry, University of Karachi, Karachi 75270, Pakistan
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Crowell PL, Schmidt CM, Yip-Schneider MT, Savage JJ, Hertzler DA, Cummings WO. Cyclooxygenase-2 expression in hamster and human pancreatic neoplasia. Neoplasia 2006; 8:437-445. [PMID: 16820089 PMCID: PMC1601471 DOI: 10.1593/neo.04700] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2004] [Revised: 04/27/2006] [Accepted: 05/01/2006] [Indexed: 12/21/2022]
Abstract
Cyclooxygenase-2 (COX-2) has been implicated in the development of gastrointestinal malignancies. The aim of the present study was to determine COX-2 expression/activity throughout stages of experimental and human pancreatic neoplasia. COX-2 immunohistochemistry was performed in pancreata of hamsters subjected to the carcinogen N-nitrosobis-(2-oxopropyl)amine (BOP) and in human pancreatic tumors. COX-2 activity was determined by prostaglandin E2 assay in tumor versus matched normal pancreatic tissues. The activity of the COX inhibitor sulindac was tested in the PC-1 hamster pancreatic cancer model. COX-2 expression was elevated in all pancreatic intraepithelial neoplasias (PanINs) and adenocarcinomas. In BOP-treated hamsters, there were significant progressive elevations in COX-2 expression throughout pancreatic tumorigenesis. In human samples, peak COX-2 expression occurred in PanIN2 lesions and remained moderately elevated in PanIN3 and adenocarcinoma tissues. COX-2 activity was significantly elevated in hamster and human pancreatic cancers compared to pair-matched normal pancreas. Furthermore, hamster pancreatic tumor engraftment/formation in the PC-1 hamster pancreatic cancer model was reduced 4.9-fold by oral administration of sulindac. Increased COX-2 expression is an early event in pancreatic carcinogeneses. The BOP-induced hamster carcinogenesis model is a representative model used to study the role of COX-2 in well-differentiated pancreatic tumorigenesis. COX inhibitors may have a role in preventing tumor engraftment/formation.
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Affiliation(s)
- Pamela L Crowell
- Indiana University Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
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Heirman I, Ginneberge D, Brigelius-Flohé R, Hendrickx N, Agostinis P, Brouckaert P, Rottiers P, Grooten J. Blocking tumor cell eicosanoid synthesis by GP x 4 impedes tumor growth and malignancy. Free Radic Biol Med 2006; 40:285-94. [PMID: 16413410 DOI: 10.1016/j.freeradbiomed.2005.08.033] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2005] [Revised: 08/17/2005] [Accepted: 08/17/2005] [Indexed: 01/18/2023]
Abstract
Using tumor cell-restricted overexpression of glutathione peroxidase 4 (GP x 4), we investigated the contribution of tumor cell eicosanoids to solid tumor growth and malignant progression in two tumor models differing in tumorigenic potential. By lowering cellular lipid hydroperoxide levels, GP x 4 inhibits cyclooxygenase (COX) and lipoxygenase (LOX) activities. GP x 4 overexpression drastically impeded solid tumor growth of weakly tumorigenic L929 fibrosarcoma cells, whereas B16BL6 melanoma solid tumor growth was unaffected. Yet, GP x 4 overexpression did markedly increase the sensitivity of B16BL6 tumors to angio-destructive TNF-alpha therapy and abolished the metastatic lung colonizing capacity of B16BL6 cells. Furthermore, the GP x 4-mediated suppression of tumor cell prostaglandin E(2) (PGE(2)) production impeded the induction of COX-2 expression by the tumor stress conditions hypoxia and inflammation. Thus, our results reflect a PGE(2)-driven positive feedback loop for COX-2 expression in tumor cells. This was further supported by the restoration of COX-2 induction capacity of GP x 4-overexpressing L929 tumor cells when cultured in the presence of exogenous PGE(2). Thus, although COX-2 expression and eicosanoid production may be enabled by PGE(2) from the tumor microenvironment, our results demonstrate the predominant tumor cell origin of protumoral eicosanoids, promoting solid tumor growth of weakly tumorigenic tumors and malignant progression of strongly tumorigenic tumors.
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Affiliation(s)
- Ingeborg Heirman
- Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology and Ghent University, Molecular Immunology Unit, Technologiepark 927, B-9052 Ghent, Belgium
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Ahmad I, Nawaz SA, Afza N, Malik A, Fatima I, Khan SB, Ahmad M, Choudhary MI. Isolation of onosmins A and B, lipoxygenase inhibitors from Onosma hispida. Chem Pharm Bull (Tokyo) 2005; 53:907-10. [PMID: 16079517 DOI: 10.1248/cpb.53.907] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Onosmins A (1) and B (2), lipoxygenase inhibitors, have been isolated from Onosma hispida. Their structures were established as 2-[(4-methylbenzyl)amino]benzoic acid (1) and methyl 2-[(4-methylbenzyl)amino]benzoate (2) through spectroscopic studies, including 2D-NMR. The known compounds apigenin (3), 6,4'-dimethoxy-3,5,7-trihydroxyflavone (4), 6,7-dimethoxy-3,5,4'-trihydroxyflavone (5) and apigenin 7-O-beta-D-glucoside (6) are also reported for the first time from this species. Compounds (1) and (2) inhibited lipoxygenase (LOX, EC 1.13.11.12) enzyme in a concentration-dependent fashion with IC50 values of 24.0 and 36.2 microM, respectively. Lineweaver-Burk as well as Dixon plots and their secondary replots indicated that the nature of inhibition was purely a non-competitive type, with K(i) values 22.0 microM and 31.1, respectively.
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Affiliation(s)
- Ijaz Ahmad
- International Center for Chemical Sciences, HEJ Research Institute of Chemistry, University of Karachi, Karachi-75270, Pakistan
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Chow LWC, Loo WTY, Wai CCY, Lui ELH, Zhu L, Toi M. Study of COX-2, Ki67, and p53 expression to predict effectiveness of 5-flurouracil, epirubicin and cyclophosphamide with celecoxib treatment in breast cancer patients. Biomed Pharmacother 2005; 59 Suppl 2:S298-301. [PMID: 16507397 DOI: 10.1016/s0753-3322(05)80050-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
BACKGROUND Cyclooxygenase-2 (COX-2) affects cell proliferation, apoptosis, and metastasis of breast cancer, and may also be involved in tumor angiogenesis through vascular endothelial growth factor. Ki67 and p53 are common markers of proliferation and apoptosis in tumor cells. This study investigated the change in expression of COX-2, Ki67, and p53 in solid tumors after the administration of chemotherapeutic drugs. MATERIALS AND METHODS Fifty patients were eligible to be treated with preoperative 5-fluorouracil, epirubicin, and cyclophosphamide, with celecoxib (FECC). Tumor tissue samples from 10 patients who, diagnosed with invasive ductal carcinoma, completed chemotherapy were examined immunohistochemically for COX-2, Ki67, and p53. RESULTS From the 60% of patients who expressed COX-2 and 90% who expressed Ki67 and p53 before treatment, 90% of patients revealed a lower intensity staining for each marker after FECC treatment. However, changes in expression of the three markers did not significantly correlate with tumor size, grade, axillary lymph node status. Immunostained slides clearly showed that the diaminobenzidine intensity was markedly reduced after the three-cycle FECC treatment, which implied the combined regimens be effective to the cancer patients. CONCLUSIONS This study demonstrates a novel relationship between COX-2, Ki67, and p53 expression of human breast invasive ductal carcinomas. This functional relationship provides support for a potential therapeutic role of COX-2 inhibitors in human breast cancer.
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Affiliation(s)
- L W C Chow
- Hung Chao Hong Integrated Center for Breast Diseases, Department of Surgery, The University of Hong Kong Medical Center, Queen Mary Hospital, Pokfulam, China.
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Preston IR, Hill NS, Warburton RR, Fanburg BL. Role of 12-lipoxygenase in hypoxia-induced rat pulmonary artery smooth muscle cell proliferation. Am J Physiol Lung Cell Mol Physiol 2005; 290:L367-74. [PMID: 16199435 DOI: 10.1152/ajplung.00114.2005] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The 12-lipoxygenase (12-LO) pathway of arachidonic acid metabolism stimulates cell growth and metastasis of various cancer cells and the 12-LO metabolite, 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], enhances proliferation of aortic smooth muscle cells (SMCs). However, pulmonary vascular effects of 12-LO have not been previously studied. We sought evidence for a role of 12-LO and 12(S)-HETE in the development of hypoxia-induced pulmonary hypertension. We found that 12-LO gene and protein expression is elevated in lung homogenates of rats exposed to chronic hypoxia. Immunohistochemical staining with a 12-LO antibody revealed intense staining in endothelial cells of large pulmonary arteries, SMCs (and possibly endothelial cells) of medium and small-size pulmonary arteries and in alveolar walls of hypoxic lungs. 12-LO protein expression was increased in hypoxic cultured rat pulmonary artery SMCs. 12(S)-HETE at concentrations as low as 10(-5) microM stimulated proliferation of pulmonary artery SMCs. 12(S)-HETE induced ERK 1/ERK 2 phosphorylation but had no effect on p38 kinase expression as assessed by Western blotting. 12(S)-HETE-stimulated SMC proliferation was blocked by the MEK inhibitor PD-98059, but not by the p38 MAPK inhibitor SB-202190. Hypoxia (3%)-stimulated pulmonary artery SMC proliferation was blocked by both U0126, a MEK inhibitor, and baicalein, an inhibitor of 12-LO. We conclude that 12-LO and its product, 12(S)-HETE, are important intermediates in hypoxia-induced pulmonary artery SMC proliferation and may participate in hypoxia-induced pulmonary hypertension.
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Affiliation(s)
- Ioana R Preston
- Pulmonary, Critical Care and Sleep Division, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA.
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Hennig R, Ventura J, Segersvard R, Ward E, Ding XZ, Rao SM, Jovanovic BD, Iwamura T, Talamonti MS, Bell RH, Adrian TE. LY293111 improves efficacy of gemcitabine therapy on pancreatic cancer in a fluorescent orthotopic model in athymic mice. Neoplasia 2005; 7:417-25. [PMID: 15967119 PMCID: PMC1501143 DOI: 10.1593/neo.04559] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2004] [Revised: 01/03/2005] [Accepted: 01/04/2005] [Indexed: 11/18/2022] Open
Abstract
Pancreatic cancer has an abysmal prognosis because of late diagnosis and lack of effective therapeutics. New drugs are desperately needed. The present study determined the effect of the LTB4 receptor antagonist, LY293111, on tumor growth and metastases in a fluorescent orthotopic model of pancreatic cancer. Pancreatic cancer cells (S2-013) with stable expression of enhanced green fluorescent protein were implanted into the duodenal pancreatic lobe of athymic mice. Animals were allocated to four groups (eight mice per group): control (no treatment); LY293111; gemcitabine; and LY293111 + gemcitabine. Monitoring of the surgical procedure and follow-up examinations at 2, 3, and 4 weeks after implantation to monitor tumor growth and metastases were performed using a fluorescence microscope and the reversible skin-flap technique. A staging and scoring system was developed to evaluate tumor progression, based on the TNM classification. Control animals developed end-stage disease with invasive cancer, metastases, and cachexia. Tumor growth and incidence of metastases were significantly reduced in all treated mice. However, combined treatment with LY293111 and gemcitabine was most effective. LY293111 is a novel therapeutic agent for pancreatic cancer, which improves the efficacy of gemcitabine. It is well tolerated and can be administered orally and, therefore, provides a new hope for patients suffering from pancreatic adenocarcinoma.
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Affiliation(s)
- Rene Hennig
- Department of Surgery, University of Heidelberg, Heidelberg, Germany
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