|
1
|
Lobo N, Hensley PJ, Bree KK, Nogueras-Gonzalez GM, Navai N, Dinney CP, Kamat AM. Should patients with non-muscle-invasive bladder cancer discontinue fibrin clot inhibitors during bacille Calmette-Guérin? BJU Int 2022; 130:463-469. [PMID: 34854189 PMCID: PMC11902302 DOI: 10.1111/bju.15665] [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] [Indexed: 11/30/2022]
Abstract
OBJECTIVE To determine the impact of fibrin clot inhibitor (FCI) use on oncological outcomes in a large contemporary cohort of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adequate bacille Calmette-Guérin (BCG). PATIENTS AND METHODS We performed an Institutional Review Board-approved review of patients with NMIBC treated with adequate intravesical BCG, at our institution between 2000 and 2018. FCI use at the time of BCG therapy was recorded for each patient. Patients were stratified according to use of FCI medication. Recurrence- and progression-free survival were analysed using Kaplan-Meier methods and Cox proportional hazard models. RESULTS Overall, 226 of 526 patients (43.0%) used a FCI: aspirin (205), clopidogrel (38), warfarin (18) and novel oral anticoagulant (NOAC; seven). The use of FCIs did not adversely affect either recurrence- or progression-free survival (P = 0.385 and P = 0.131, respectively). These results did not change when the impact of aspirin, clopidogrel or warfarin/NOAC use on recurrence and progression was evaluated separately. On multivariate analysis, FCI use was neither associated with tumour recurrence nor progression. CONCLUSION The use of FCIs was not associated with adverse oncological outcomes in a large contemporary cohort of patients receiving adequate intravesical BCG for NMIBC. Based on these results, FCIs may be safely continued during BCG immunotherapy.
Collapse
Affiliation(s)
- Niyati Lobo
- Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Patrick J. Hensley
- Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kelly K. Bree
- Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Neema Navai
- Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Colin P. Dinney
- Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ashish M. Kamat
- Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| |
Collapse
|
|
2
|
NFκB-Activated COX2/PGE 2/EP4 Axis Controls the Magnitude and Selectivity of BCG-Induced Inflammation in Human Bladder Cancer Tissues. Cancers (Basel) 2021; 13:cancers13061323. [PMID: 33809455 PMCID: PMC7998891 DOI: 10.3390/cancers13061323] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/01/2021] [Accepted: 03/12/2021] [Indexed: 01/03/2023] Open
Abstract
Simple Summary The clinical effectiveness of Bacillus Calmette-Guérin (BCG) is limited to patients with early stages of bladder cancer (BlCa) and its effects are often transient. To understand the mechanisms limiting the effectiveness of BCG, we evaluated its impact on the human BlCa tumor microenvironment (TME) and the feasibility of its pharmacologic modulation. We observed that BCG non-selectively induces both CTL-attracting chemokines and Treg/MDSC attractants and suppressive factors in human BlCa tissue explants, in a mechanism involving NFκB-induced PGE2 synthesis and EP4 signaling. In contrast to non-selective impact of NFκB blockade on BCG-induced inflammation, the PGE2 antagonism selectively enhanced the BCG-driven production of CTL attractants but eliminated the induction of Treg/MDSC attractants and suppressive factors, enhancing the CTL migration but reducing Treg attraction to BCG-treated BlCa. Since intratumoral CTL accumulation predicts long term patient outcomes and the effectiveness of cancer immunotherapies, our data indicates the feasibility of targeting the PGE2-chemokine interplay to enhance the therapeutic effects of BCG. Abstract Bacillus Calmette-Guérin (BCG) is commonly used in the immunotherapy of bladder cancer (BlCa) but its effectiveness is limited to only a fraction of patients. To identify the factors that regulate the response of human BlCa tumor microenvironment (TME) to BCG, we used the ex vivo whole-tissue explant model. The levels of COX2 in the BCG-activated explants closely correlated with the local production of Treg- and MDSCS attractants and suppressive factors, while the baseline COX2 levels did not have predictive value. Accordingly, we observed that BCG induced high levels of MDSC- and Treg-attracting chemokines (CCL22, CXCL8, CXCL12) and suppressive factors (IDO1, IL-10, NOS2). These undesirable effects were associated with the nuclear translocation of phosphorylated NFκB, induction of COX2, the key enzyme controlling PGE2 synthesis, and elevation of a PGE2 receptor, EP4. While NFκB blockade suppressed both the desirable and undesirable components of BCG-driven inflammation, the inhibitors of PGE2 synthesis (Celecoxib or Indomethacin) or signaling (EP4-selective blocker, ARY-007), selectively eliminated the induction of MDSC/Treg attractants and immunosuppressive factors but enhanced the production of CTL attractants, CCL5, CXCL9 and CXCL10. PGE2 blockade allowed for the selectively enhanced migration of CTLs to the BCG-treated BlCa samples and eliminated the enhanced migration of Tregs. Since the balance between the CTLs and suppressive cells in the TME predicts the outcomes in patients with BlCa and other diseases, our data help to elucidate the mechanisms which limit the effectiveness of BCG therapies and identify new targets to enhance their therapeutic effects.
Collapse
|
|
3
|
Lin C, Yuan H, Wang W, Zhu Z, Lu Y, Wang J, Feng F, Wu J. Importance of PNO1 for growth and survival of urinary bladder carcinoma: Role in core-regulatory circuitry. J Cell Mol Med 2019; 24:1504-1515. [PMID: 31800162 PMCID: PMC6991670 DOI: 10.1111/jcmm.14835] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Accepted: 10/20/2019] [Indexed: 02/06/2023] Open
Abstract
PNO1 (partner of Nob1) was known as a RNA‐binding protein in humans, and its ortholog PNO1 was reported to participate ribosome and proteasome biogenesis in yeasts. Yet there have been few studies about its functions in mammalian cells, and so far its role in human cells has never been reported, especially in urinary bladder cancer (UBC).We interrogated the cellular functions and clinical significance of PNO1 in, and its molecular mechanism through microarrays and bioinformatics analysis. Our findings support that PNO1 participates in promoting proliferation and colonogenesis, while reducing apoptosis of UBC cells, and is also predicted to be associated with the migration and metastasis of UBC PNO1 knockdown (KD) attenuated the tumorigenesis ability of UBC in mouse. PNO1 KD led to the altered expression of 1543 genes that are involved in a number of signalling pathways, biological functions and regulation networks. CD44, PTGS2, cyclin D1, CDK1, IL‐8, FRA1, as well as mTOR, p70 S6 kinase, p38 and Caspase‐3 proteins were all down‐regulated in PNO1 KD cells, suggesting the involvement of PNO1 in inflammatory responses, cell cycle regulation, chemotaxis, cell growth and proliferation, apoptosis, cell migration and invasiveness. This study will enhance our understanding of the molecular mechanism of UBC and may eventually provide novel targets for individualized cancer therapy.
Collapse
Affiliation(s)
- Chunhua Lin
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Hejia Yuan
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Wenting Wang
- The Central Laboratory, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Zhe Zhu
- Division of Regenerative Medicine, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Youyi Lu
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Jiahui Wang
- The Central Laboratory, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Fan Feng
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Jitao Wu
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| |
Collapse
|
|
4
|
ROS Generation and Antioxidant Defense Systems in Normal and Malignant Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:6175804. [PMID: 31467634 PMCID: PMC6701375 DOI: 10.1155/2019/6175804] [Citation(s) in RCA: 478] [Impact Index Per Article: 79.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 06/24/2019] [Indexed: 02/08/2023]
Abstract
Reactive oxygen species (ROS) are by-products of normal cell activity. They are produced in many cellular compartments and play a major role in signaling pathways. Overproduction of ROS is associated with the development of various human diseases (including cancer, cardiovascular, neurodegenerative, and metabolic disorders), inflammation, and aging. Tumors continuously generate ROS at increased levels that have a dual role in their development. Oxidative stress can promote tumor initiation, progression, and resistance to therapy through DNA damage, leading to the accumulation of mutations and genome instability, as well as reprogramming cell metabolism and signaling. On the contrary, elevated ROS levels can induce tumor cell death. This review covers the current data on the mechanisms of ROS generation and existing antioxidant systems balancing the redox state in mammalian cells that can also be related to tumors.
Collapse
|
|
5
|
Bourn J, Cekanova M. Cyclooxygenase inhibitors potentiate receptor tyrosine kinase therapies in bladder cancer cells in vitro. DRUG DESIGN DEVELOPMENT AND THERAPY 2018; 12:1727-1742. [PMID: 29942116 PMCID: PMC6005335 DOI: 10.2147/dddt.s158518] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Purpose Receptor tyrosine kinase inhibitors (RTKIs) are used as targeted therapies for patients diagnosed with cancer with highly expressed receptor tyrosine kinases (RTKs), including the platelet-derived growth factor receptor (PDGFR) and c-Kit receptor. Resistance to targeted therapies is partially due to the activation of alternative pro-survival signaling pathways, including cyclooxygenase (COX)-2. In this study, we validated the effects of two RTKIs, axitinib and AB1010, in combination with COX inhibitors on the V-akt murine thymoma oncogene homolog 1 (Akt) and COX-2 signaling pathways in bladder cancer cells. Methods The expression of several RTKs and their downstream signaling targets was analyzed by Western blot (WB) analysis in human and canine bladder transitional cell carcinoma (TCC) cell lines. The effects of RTKIs and COX inhibitors in bladder TCC cells were assessed by MTS for cell viability, by Caspase-3/7 and Annexin V assay for apoptosis, by WB analysis for detection of COX-2 and Akt signaling pathways, and by enzyme-linked immunosorbent assay for detection of prostaglandin E2 (PGE2) levels. Results All tested TCC cells expressed the c-Kit and PDGFRα receptors, except human 5637 cells that had low RTKs expression. In addition, all tested cells expressed COX-1, COX-2, Akt, extracellular signal regulated kinases 1/2, and nuclear factor kappa-light-chain-enhance of activated B cells proteins, except human UM-UC-3 cells, where no COX-2 expression was detected by WB analysis. Both RTKIs inhibited cell viability and increased apoptosis in a dose-dependent manner in tested bladder TCC cells, which positively correlated with their expression levels of the PDGFRα and c-Kit receptors. RTKIs increased the expression of COX-2 in h-5637 and K9TCC#1Lillie cells. Co-treatment of indomethacin inhibited AB1010-induced COX-2 expression leading to an additive effect in inhibition of cell viability and PGE2 production in tested TCC cells. Conclusion Co-treatment of RTKIs with indomethacin inhibited cell viability and AB1010-induced COX-2 expression resulting in decreased PGE2 production in tested TCC cells. Thus, COX inhibition may further potentiate RTKIs therapies in bladder cancer.
Collapse
Affiliation(s)
- Jennifer Bourn
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA.,UT-ORNL Graduate School of Genome Science and Technology, The University of Tennessee, Knoxville, TN, USA
| | - Maria Cekanova
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA.,UT-ORNL Graduate School of Genome Science and Technology, The University of Tennessee, Knoxville, TN, USA
| |
Collapse
|
|
6
|
Wang J, Zou K, Feng X, Chen M, Li C, Tang R, Xuan Y, Luo M, Chen W, Qiu H, Qin G, Li Y, Zhang C, Xiao B, Kang L, Kang T, Huang W, Yu X, Wu X, Deng W. Downregulation of NMI promotes tumor growth and predicts poor prognosis in human lung adenocarcinomas. Mol Cancer 2017; 16:158. [PMID: 29025423 PMCID: PMC5639741 DOI: 10.1186/s12943-017-0705-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Accepted: 07/12/2017] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND N-myc (and STAT) interactor (NMI) plays vital roles in tumor growth, progression, and metastasis. In this study, we identified NMI as a potential tumor suppressor in lung cancer and explored its molecular mechanism involved in lung cancer progression. METHODS Human lung cancer cell lines and a mouse xenograft model was used to study the effect of NMI on tumor growth. The expression of NMI, COX-2 and relevant signaling proteins were examined by Western blot. Tissue microarray immunohistochemical analysis was performed to assess the correlation between NMI and COX-2 expression in lung cancer patients. RESULTS NMI was highly expressed in normal lung cells and tissues, but lowly expressed in lung cancer cells and tissues. Overexpression of NMI induced apoptosis, suppressed lung cancer cell growth and migration, which were mediated by up-regulation of the cleaved caspase-3/9 and down-regulation of phosphorylated PI3K/AKT, MMP2/MMP9, β-cadherin, and COX-2/PGE2. In contrast, knockdown of NMI promoted lung cancer cell colony formation and migration, which were correlated with the increased expression of phosphorylated PI3K/AKT, MMP2/MMP9, β-cadherin and COX-2/PGE2. Further study showed that NMI suppressed COX-2 expression through inhibition of the p50/p65 NF-κB acetylation mediated by p300. The xenograft lung cancer mouse models also confirmed the NMI-mediated suppression of tumor growth by inhibiting COX-2 signaling. Moreover, tissue microarray immunohistochemical analysis of lung adenocarcinomas also demonstrated a negative correlation between NMI and COX-2 expression. Kaplan-Meier analysis indicated that the patients with high level of NMI had a significantly better prognosis. CONCLUSIONS Our study showed that NMI suppressed tumor growth by inhibiting PI3K/AKT, MMP2/MMP9, COX-2/PGE2 signaling pathways and p300-mediated NF-κB acetylation, and predicted a favorable prognosis in human lung adenocarcinomas, suggesting that NMI was a potential tumor suppressor in lung cancer.
Collapse
Affiliation(s)
- Jingshu Wang
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.,Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Kun Zou
- The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xu Feng
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Miao Chen
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Cong Li
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Ranran Tang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Yang Xuan
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Meihua Luo
- Shunde Hospital, Southern Medical University, Foshan, China
| | - Wangbing Chen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huijuan Qiu
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Ge Qin
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Yixin Li
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Changlin Zhang
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Binyi Xiao
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Lan Kang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Tiebang Kang
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Wenlin Huang
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.,State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China
| | - Xinfa Yu
- Shunde Hospital, Southern Medical University, Foshan, China.
| | - Xiaojun Wu
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
| | - Wuguo Deng
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China. .,State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China.
| |
Collapse
|
|
7
|
Bladder Cancer Stem-Like Cells: Their Origin and Therapeutic Perspectives. Int J Mol Sci 2015; 17:ijms17010043. [PMID: 26729098 PMCID: PMC4730288 DOI: 10.3390/ijms17010043] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Revised: 12/14/2015] [Accepted: 12/24/2015] [Indexed: 12/22/2022] Open
Abstract
Bladder cancer (BC), the most common cancer arising from the human urinary tract, consists of two major clinicopathological phenotypes: muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). MIBC frequently metastasizes and is associated with an unfavorable prognosis. A certain proportion of patients with metastatic BC can achieve a remission with systemic chemotherapy; however, the disease relapses in most cases. Evidence suggests that MIBC comprises a small population of cancer stem cells (CSCs), which may be resistant to these treatments and may be able to form new tumors in the bladder or other organs. Therefore, the unambiguous identification of bladder CSCs and the development of targeted therapies are urgently needed. Nevertheless, it remains unclear where bladder CSCs originate and how they are generated. We review recent studies on bladder CSCs, specifically focusing on their proposed origin and the possible therapeutic options based on the CSC theory.
Collapse
|
|
8
|
McBeth L, Grabnar M, Selman S, Hinds TD. Involvement of the Androgen and Glucocorticoid Receptors in Bladder Cancer. Int J Endocrinol 2015; 2015:384860. [PMID: 26347776 PMCID: PMC4546983 DOI: 10.1155/2015/384860] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 07/25/2015] [Accepted: 07/27/2015] [Indexed: 12/15/2022] Open
Abstract
Bladder cancer is encountered worldwide having been associated with a host of environmental and lifestyle risk factors. The disease has a male to female prevalence of 3 : 1. This disparity has raised the possibility of the androgen receptor (AR) pathway being involved in the genesis of the disease; indeed, research has shown that AR is involved in and is likely a driver of bladder cancer. Similarly, an inflammatory response has been implicated as a major player in bladder carcinogenesis. Consistent with this concept, recent work on anti-inflammatory glucocorticoid signaling points to a pathway that may impact bladder cancer. The glucocorticoid receptor- (GR-) α isoform has an important role in suppressing inflammatory processes, which may be attenuated by AR in the development of bladder cancer. In addition, a GR isoform that is inhibitory to GRα, GRβ, is proinflammatory and has been shown to induce cancer growth. In this paper, we review the evidence of inflammatory mediators and the relationship of AR and GR isoforms as they relate to the propensity for bladder cancer.
Collapse
Affiliation(s)
- Lucien McBeth
- Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614, USA
| | - Maria Grabnar
- Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614, USA
| | - Steven Selman
- Department of Urology, University of Toledo College of Medicine, Toledo, OH 43614, USA
| | - Terry D. Hinds
- Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614, USA
| |
Collapse
|
|
9
|
Gakis G. The role of inflammation in bladder cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 816:183-96. [PMID: 24818724 DOI: 10.1007/978-3-0348-0837-8_8] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The aim of this book chapter is to present the latest basic research developments on the role of inflammation in bladder cancer and provide insights into their future clinical significance in preventing bladder carcinogenesis and progression. Bladder cancer is a highly immunogenic malignancy. Urothelial cancer cells aim to manipulate the immune system by inhibiting its cytotoxic function while stimulating the secretion of growth promoting factors. Cytokine-induced imbalances in the distribution and differentiation of tumor-infiltrating cytotoxic cells can boost bladder cancer cell proliferation. Tumor-induced release of excessive amount of cytokines causes an "inflammatory storm" which drives metastasis formation via degradation of extracellular matrix proteins. Tumor-related selective cyclooxygenase-2 (COX-2) upregulation suppresses the cell-mediated immune response via aberrant prostaglandin metabolism resulting in failure of differentiation of myeloid cell progenitors into mature antigen-presenting cells. T cells are capable of increasing the oxidative stress on bladder cancer cells via induction of COX-2 and STEAP expression. Some evidence also suggests that COX-2 activation may be also involved in inflammation-mediated cancer stem cell proliferation. Antibodies against the VEGF-co-receptor neuropilin decrease the angiogenetic potential of bladder cancer cells. Inflammation-based predictive bladder cancer models have demonstrated to accurately predict response to treatment both in the curative and palliative setting. While randomized trials do not support a clinical benefit for the use of anti-inflammatory drugs (i.e., celecoxib, atorvastatin) in preventing recurrence of low-grade bladder cancer, further investigations are warranted in the setting of high-grade tumors since the immune response to cancer stimuli is most probably more pronounced in advanced stages.
Collapse
Affiliation(s)
- Georgios Gakis
- Department of Urology, University Hospital Tübingen, Eberhard-Karls University, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany,
| |
Collapse
|
|
10
|
Lipsky MJ, Badalato GM, Motamedinia P, Hruby GW, McKiernan JM. The Effect of Fibrin Clot Inhibitors on the Immunomodulatory Efficacy of Bacillus Calmette-Guérin Therapy for Non–muscle-invasive Bladder Cancer. Urology 2013; 81:1273-8. [DOI: 10.1016/j.urology.2012.09.065] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Revised: 09/16/2012] [Accepted: 09/28/2012] [Indexed: 02/07/2023]
|
|
11
|
Bailey KA, Wallace K, Smeester L, Thai SF, Wolf DC, Edwards SW, Fry RC. Transcriptional Modulation of the ERK1/2 MAPK and NF-κB Pathways in Human Urothelial Cells After Trivalent Arsenical Exposure: Implications for Urinary Bladder Cancer. JOURNAL OF CANCER RESEARCH UPDATES 2012; 1:57-68. [PMID: 23487506 PMCID: PMC3593739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Chronic exposure to drinking water contaminated with inorganic arsenic (iAs) is associated with an increased risk of urinary bladder (UB) cancers in humans. The exact role of specific iAs metabolite(s) in As-mediated carcinogenesis remains largely unknown. Experimental evidence suggests that trivalent arsenicals, namely arsenite (iAsIII) and two of its metabolites, monomethylarsonous acid (MMAIII) and dimethylarsinous acid (DMAIII), are possible proximate UB carcinogens. Here, we used a transcriptomics approach to examine perturbed molecular pathways in a human urothelial cell line (UROtsa) after short-term exposure to iAsIII, MMAIII and DMAIII. Molecular pathways containing genes that encode proteins implicated in UB cancer development were perturbed by both MMAIII and DMAIII. These pathways included those of the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (ERK 1/2 MAPK) and nuclear factor kappa beta (NF-κB). Together, these results may inform the current understanding of effects in the UB induced by acute As exposure and the relationship of these effects with As-mediated carcinogenesis.
Collapse
Affiliation(s)
- Kathryn A. Bailey
- Department of Environmental Sciences and Engineering, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Kathleen Wallace
- National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA
| | - Lisa Smeester
- Department of Environmental Sciences and Engineering, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Sheau-Fung Thai
- National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA
| | - Douglas C. Wolf
- National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA
| | - Stephen W. Edwards
- National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA
| | - Rebecca C. Fry
- Department of Environmental Sciences and Engineering, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC 27599, USA
| |
Collapse
|
|
12
|
Dobek GL, Zhang X, Balazs DA, Godbey WT. Analysis of promoters and expression-targeted gene therapy optimization based on doubling time and transfectability. FASEB J 2011; 25:3219-28. [PMID: 21602450 DOI: 10.1096/fj.11-185421] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Genes under the control of the cyclooxygenase-2 (Cox-2), human epidermal growth factor receptor 2 (Her-2), and survivin promoters were constructed and delivered to murine and human carcinoma cells. It was found that (P)Cox-2-driven reporter expression was strong and correlated well with endogenous Cox-2 levels, while (P)Her-2 and (P)survivin yielded poor results, consistent with the three distinct expression mechanisms used by cancer cells to overexpress the endogenous versions of the selected genes. The (P)Cox-2 was then used to drive the expression of caspase genes both in vitro and in vivo to bring about targeted apoptosis of carcinoma cells successfully. The results led to the following conclusions. 1) When selecting a promoter/enhancer for expression-targeted gene delivery, it is not enough to perform a microarray on some tumor tissue and select the control element associated with the greatest amount of gene up-regulation vs. normal controls. The mechanism of expression for the particular gene should be taken into account to prevent lengthy and costly research trials. 2) When overexpression is due to activator binding, a predictive model based on endogenous gene expression levels, overall cell transfectability, and cell doubling rates can be used to predict expression-targeted gene delivery outcomes with significant accuracy.
Collapse
Affiliation(s)
- Georgina L Dobek
- Department of Comparative Medicine, Tulane University, New Orleans, LA 70118, USA.
| | | | | | | |
Collapse
|
|
13
|
Zhang X, Turner C, Godbey WT. Comparison of Caspase Genes for the Induction of Apoptosis Following Gene Delivery. Mol Biotechnol 2008; 41:236-46. [DOI: 10.1007/s12033-008-9133-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2008] [Accepted: 11/23/2008] [Indexed: 10/21/2022]
|
|
14
|
Saxena A, Prasad KN, Ghoshal UC, Bhagat MR, Krishnani N, Husain N. Polymorphism of -765G > C COX-2 is a risk factor for gastric adenocarcinoma and peptic ulcer disease in addition to H pylori infection: A study from northern India. World J Gastroenterol 2008; 14:1498-503. [PMID: 18330937 PMCID: PMC2693741 DOI: 10.3748/wjg.14.1498] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [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 investigate -765G > C COX-2 polymorphism and H pylori infection in patients with gastric adenocarcinoma, peptic ulcer disease (PUD) and non-ulcer dyspepsia (NUD).
METHODS: We enrolled 348 adult patients (62 gastric adenocarcinoma, 45 PUD and 241 NUD) undergoing upper gastrointestinal endoscopy at two referral centers between September, 2002 and May, 2007. H pylori infection was diagnosed when any of the four tests (RUT, culture, histopathology and PCR) were positive. Genotyping for -765G > C polymorphism of COX-2 was performed by PCR-RFLP analysis.
RESULTS: Frequency of C carrier had significant association with gastric adenocarcinoma as compared to NUD [77.4% vs 29%, P < 0.001, odds ratio (OR) 8.20; 95% confidence interval (95% CI), 4.08-16.47] and PUD (77.4% vs 31.1%, P < 0.001; OR 8.04; 95% CI, 3.25-19.90). Risk of gastric adenocarcinoma was significantly higher in patients having C carrier with (OR 7.83; 95% CI 3.09-19.85) and without H pylori infection (OR 7.06; 95% CI, 2.61-19.09). Patients with C carrier and H pylori infection had significant risk for the development of PUD (P < 0.001; OR 5.65; 95% CI, 2.07-15.34).
CONCLUSION: -765G > C COX-2 polymorphism with or without H pylori could be a marker for genetic susceptibility to gastric adenocarcinoma. COX-2 polymorphism in presence of H pylori infection might be useful in predicting the risk of PUD.
Collapse
|
|
15
|
Expression-targeted gene therapy for the treatment of transitional cell carcinoma. Cancer Gene Ther 2008; 15:543-52. [PMID: 18323852 DOI: 10.1038/cgt.2008.7] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Targeted gene delivery for induced apoptosis of transitional cell carcinomas was carried out in vivo in mice via utilization of the murine cyclooxygenase type 2 (Cox-2) promoter (Tis10). MB49 cells, which constitutively overexpress Cox-2 like numerous other carcinomas, selectively expressed delivered genes that utilized this transcriptional control element. The products of the delivered genes were artificially inducible forms of caspases 3 and 9, which remained inactive until a chemical inducer of dimerization was later injected intraperitoneally. The genes were delivered intravesically as plasmids complexed with poly(ethylenimine). Significant improvements, in the form of reduced bladder mass, reduced tumor volume, anti-angiogenesis and inhibition of tumor growth were seen versus untreated or unactivated controls. In some instances, tumors were seen to go into complete remission. There were no apparent bystander effects associated with the treatments. This targeted gene therapy regimen could have wide applicability to numerous cancers due to constitutive overexpression of Cox-2.
Collapse
|
|
16
|
Pereira C, Sousa H, Ferreira P, Fragoso M, Moreira-Dias L, Lopes C, Medeiros R, Dinis-Ribeiro M. -765G > C COX-2 polymorphism may be a susceptibility marker for gastric adenocarcinoma in patients with atrophy or intestinal metaplasia. World J Gastroenterol 2006; 12:5473-8. [PMID: 17006983 PMCID: PMC4088228 DOI: 10.3748/wjg.v12.i34.5473] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To investigate the relationship between the -765G > C COX-2 polymorphism and the development of different gastric lesions: atrophy or intestinal metaplasia and gastric adenocarcinoma.
METHODS: A cross-sectional study was performed involving 320 Portuguese individuals (210 without evidence of neoplastic disease, 73 patients with gastric adenocarcinomas and 37 with atrophy or intestinal metaplasia) using a PCR-RFLP method.
RESULTS: -765C allele was overrepresented in the patients with gastric adenocarcinoma (51%) when compared either with the control group (38%) or patients with atrophy or intestinal metaplasia (27%). Callele was found to be very common in our population (0.22), and a multivariate logistic regression analysis revealed nearly 3-fold increased risk for the progression to gastric adenocarcinoma in patients with atrophy or intestinal metaplasia carrying the -765C allele (OR = 2.67, 95% CI = 1.03-6.93; P = 0.04).
CONCLUSION: -765C carrier status should be considered as another susceptibility marker for gastric adenocarcinoma development in patients with atrophy or intestinal metaplasia.
Collapse
Affiliation(s)
- Carina Pereira
- Serviço de Gastrenterologia, Instituto Português de Oncologia do Porto FG EPE, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal
| | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Moussa O, Yordy JS, Abol-Enein H, Sinha D, Bissada NK, Halushka PV, Ghoneim MA, Watson DK. Prognostic and functional significance of thromboxane synthase gene overexpression in invasive bladder cancer. Cancer Res 2006; 65:11581-7. [PMID: 16357168 DOI: 10.1158/0008-5472.can-05-1622] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Thromboxane synthase (TXAS) is one of the enzymes downstream from cyclooxygenase-2 and catalyzes the synthesis of thromboxane A(2) (TXA(2)). TXAS was among the genes we identified based on its overexpression in invasive bladder tumors. TXAS is overexpressed in common forms of bladder tumors: 69 of 97 (71.1%) transitional cell carcinoma (TCC), 38 of 53 (71.6%) squamous cell carcinoma, and 5 of 11 (45.5%) adenocarcinoma relative to nontumor tissue. Overall, 112 of 161 (69.5%) invasive tumors exhibited elevated expression. Significantly, patients with tumors having >4-fold levels of TXAS expression showed significant statistical evidence of lower overall survival expressed by the estimated hazard ratio of 2.74 with P = 0.009 in Cox's regression analysis. TXAS mRNA expression was found to be an independent prognostic marker for patients with bladder cancer. Treatment of bladder cancer cell lines (T24 and TCC-SUP) with TXAS inhibitors and TXA(2) (TP) receptor antagonists reduced cell growth, migration, and invasion, whereas TP agonists stimulated cell migration and invasion. The positive correlation between elevated TXAS expression and shorter patient survival supports a potential role for TXAS-regulated pathways in tumor invasion and metastases and suggests that modulation of the TXAS pathway may offer a novel therapeutic approach.
Collapse
MESH Headings
- Adenocarcinoma/enzymology
- Adenocarcinoma/genetics
- Adenocarcinoma/pathology
- Adult
- Carcinoma, Squamous Cell/enzymology
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/pathology
- Carcinoma, Transitional Cell/enzymology
- Carcinoma, Transitional Cell/genetics
- Carcinoma, Transitional Cell/pathology
- Cell Movement
- Cell Proliferation
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Male
- Middle Aged
- Neoplasm Invasiveness
- Neoplasm Staging
- Prognosis
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptors, Thromboxane/agonists
- Receptors, Thromboxane/antagonists & inhibitors
- Receptors, Thromboxane/metabolism
- Survival Rate
- Thromboxane-A Synthase/antagonists & inhibitors
- Thromboxane-A Synthase/genetics
- Thromboxane-A Synthase/metabolism
- Urinary Bladder Neoplasms/enzymology
- Urinary Bladder Neoplasms/genetics
- Urinary Bladder Neoplasms/pathology
Collapse
Affiliation(s)
- Omar Moussa
- Department of Pathology and Laboratory Medicine, Biochemistry Medical University of South Carolina, Charleston, 29425, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
18
|
Borzacchiello G, Paciello O, Papparella S. Expression of cyclooxygenase-1 and -2 in canine nasal carcinomas. J Comp Pathol 2004; 131:70-6. [PMID: 15144801 DOI: 10.1016/j.jcpa.2004.01.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2003] [Accepted: 01/12/2004] [Indexed: 11/16/2022]
Abstract
Cyclooxygenase-1 (COX-1) and cyclooxygenase -2 (COX-2) are known to play a role in the carcinogenesis of many human and animal primary epithelial tumours. However, expression of COX-1 and -2 has not been investigated in canine nasal epithelial carcinoma, a rare form of neoplasia. COX-1 immunolabelling was demonstrated in normal canine nasal mucosa and in a minority of neoplastic specimens. Cytoplasmic COX-2, however, was strongly expressed in the majority of canine nasal carcinomas. In addition, COX-2 expression was demonstrated in dysplastic epithelium and in a proportion of stromal cells. Co-expression of both enzyme isoforms was revealed by confocal laser scanning microscopy. The results indicate that COX-2 is overexpressed in a proportion of naturally occurring canine nasal carcinomas, suggesting its possible role in canine nasal tumorigenesis.
Collapse
Affiliation(s)
- G Borzacchiello
- Universita degli Studi di Napoli Federico II, Dipartimento di Patologia e Sanita Animale, Via F. Delpino, 1, Napoli 80137, Italy
| | | | | |
Collapse
|
|
19
|
Pruthi RS, Derksen E, Gaston K, Wallen EM. Rationale for use of cyclooxygenase-2 inhibitors in prevention and treatment of bladder cancer. Urology 2004; 64:637-42. [PMID: 15491687 DOI: 10.1016/j.urology.2004.04.047] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2004] [Accepted: 04/26/2004] [Indexed: 11/17/2022]
Affiliation(s)
- Raj S Pruthi
- Division of Urologic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | | | | | | |
Collapse
|
|
20
|
Abstract
Selective cyclooxygenase (COX)-2-inhibiting and other nonsteroidal anti-inflammatory drugs (NSAIDs) show promise for preventing and treating bladder and prostate cancers. In contrast to the strong NSAID epidemiology in colorectal cancer, the epidemiologic data on NSAIDs and genitourinary (GU) cancers are limited and mixed. However, a substantial body of preclinical in vitro and in vivo animal model data shows consistent NSAID activity in treating, and in some cases preventing, GU cancers and begins to address the mechanisms behind this activity (eg, involving Akt and ERK2 in the prostate). Many preclinical and clinical NSAID studies currently under way are helping to resolve the best type (selective or nonselective COX inhibitors or non-COX inhibitors), dose and duration of NSAID treatment for prevention in the GU setting. Future studies likely will focus on clarifying the NSAID mechanisms behind and developing NSAID combinations for both treating and preventing GU cancers.
Collapse
Affiliation(s)
- Anita L Sabichi
- Department of Clinical Cancer Prevention, University of Texas M.D. Amderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | | |
Collapse
|
|
21
|
Mohseni H, Zaslau S, McFadden D, Riggs DR, Jackson BJ, Kandzari S. COX-2 inhibition demonstrates potent anti-proliferative effects on bladder cancer in vitro. J Surg Res 2004; 119:138-42. [PMID: 15145695 DOI: 10.1016/j.jss.2004.03.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2003] [Indexed: 10/26/2022]
Abstract
PURPOSE The purpose of this work was to determine the in vitro effect of Rofecoxib and specific COX 1 and COX 2 inhibitors in regards to cell growth and apoptotic and necrotic activity. INTRODUCTION AND OBJECTIVE Rofecoxib (Vioxx) is a nonsteroidal anti-inflammatory agent (NSAID) that selectively inhibits cyclooxygenase-2 (COX-2). The inducible isoform of COX-2 is overexpressed in many gastrointestinal and genitourinary tract tumors. We hypothesized that in vitro treatment with both COX-1 and COX-2 inhibitors would significantly reduce cellular proliferation of bladder cancer cells by apoptotic pathways. MATERIALS AND METHODS Two human bladder cancer cell lines were grown in culture using standard techniques and treated with Rofecoxib at doses ranging from 125 microg/well serially diluted down to 8.0 microg/well. Catechin (COX 1 inhibitor) and NS398 (COX 2 inhibitor) were used at doses of 50 and 100 microM. Cell viability was measured by MTT at 24 and 72 h. Apoptosis was evaluated by the Annexin V FITC Assay. Statistical analysis was performed by ANOVA. RESULTS Rofecoxib, Catechin, and NS398 all exhibited significant inhibition of cell growth when compared to the nontreated controls. Significant changes in apoptotic activity were observed in all agents tested in both the T24 and the TCCSUP cells. CONCLUSIONS Selective COX-2 inhibition, using the well-tolerated and commercially available Rofecoxib (VIOXX) and specific COX 1 and 2 inhibitors, reduced the growth of human bladder cancer in vitro by apoptotic mechanisms. Further in vivo and human studies are warranted to evaluate the safety and clinical utility of this agent in patients with bladder cancer.
Collapse
Affiliation(s)
- H Mohseni
- Department of Surgery, Robert C. Byrd Health Science Center, West Virginia University, Morgantown, West Virginia 26506, USA
| | | | | | | | | | | |
Collapse
|
|
22
|
St-Germain ME, Gagnon V, Parent S, Asselin E. Regulation of COX-2 protein expression by Akt in endometrial cancer cells is mediated through NF-kappaB/IkappaB pathway. Mol Cancer 2004; 3:7. [PMID: 15016316 PMCID: PMC394342 DOI: 10.1186/1476-4598-3-7] [Citation(s) in RCA: 81] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2003] [Accepted: 03/11/2004] [Indexed: 02/04/2023] Open
Abstract
Background Cyclooxygenase-2 (COX-2) has been shown to be highly expressed in a broad series of primary endometrial tumors and its expression may be closely associated with parameters of tumor aggressiveness. In human endometrial cancer, tumor suppressor phosphatase tensin homologue (PTEN) is frequently mutated. In the presence of a mutated PTEN protein, Akt phosphorylation levels increase leading to the activation of this survival pathway. The nuclear transcription factor κB (NF-κB) is a well establish regulator of genes encoding cytokines, cytokine receptors, and cell adhesion molecules that drive immune and inflammatory responses. More recently, NF-κB activation has been connected with multiple aspects of oncogenesis, including the control of apoptosis, cell cycle, differentiation, and cell migration. It is known that Akt may act through NF-κB pathway and that COX-2 gene has been shown to be regulated at the promoter level by NF-κB. Recently, we showed that Akt regulates COX-2 gene and protein expressions in phospho-Akt expressing endometrial cancer cells. The present study was undertaken to determine the involvement of NF-κB pathway and IκB (an inhibitor of NF-κB) in the regulation of COX-2 expression and to determine more precisely the downstream targets of Akt involved in this process. Results Three different human endometrial cancer cell lines known to have wild type PTEN (HEC 1-A) or a mutated inactive PTEN protein (RL 95-2 and Ishikawa) were used for these studies. Expression IκB and Phospho-IκB were evaluated by Western analysis. The presence of IκB phosphorylation was found in all cell lines studied. There was no difference between cell lines in term of NF-κB abundance. Inhibition of PI 3-K with Wortmannin and LY294002 blocked IκB phosphorylation, reduced NF-κB nuclear activity, reduced COX-2 expression and induced apoptosis. Transfection studies with a dominant negative Akt vector blocked IκB phosphorylation and reduced COX-2 expression. On the opposite, constitutively active Akt transfections resulted in the induction of IκB phosphorylation and up-regulation of COX-2. Conclusion These results demonstrate that Akt signals through NF-κB/IκB pathway to induce COX-2 expression in mutated PTEN endometrial cancer cells.
Collapse
Affiliation(s)
- Marie-Eve St-Germain
- Department of Chemistry and Biology, Research Group in Molecular and Cellular Biopathology, Medical Biology Section, University of Quebec at Trois-Rivieres, C.P. 500, Trois-Rivieres, Quebec, Canada G9A 5H7
| | - Veronique Gagnon
- Department of Chemistry and Biology, Research Group in Molecular and Cellular Biopathology, Medical Biology Section, University of Quebec at Trois-Rivieres, C.P. 500, Trois-Rivieres, Quebec, Canada G9A 5H7
| | - Sophie Parent
- Department of Chemistry and Biology, Research Group in Molecular and Cellular Biopathology, Medical Biology Section, University of Quebec at Trois-Rivieres, C.P. 500, Trois-Rivieres, Quebec, Canada G9A 5H7
| | - Eric Asselin
- Department of Chemistry and Biology, Research Group in Molecular and Cellular Biopathology, Medical Biology Section, University of Quebec at Trois-Rivieres, C.P. 500, Trois-Rivieres, Quebec, Canada G9A 5H7
| |
Collapse
|
|
23
|
Huguenin S, Vacherot F, Kheuang L, Fleury-Feith J, Jaurand MC, Bolla M, Riffaud JP, Chopin DK. Antiproliferative effect of nitrosulindac (NCX 1102), a new nitric oxide-donating non-steroidal anti-inflammatory drug, on human bladder carcinoma cell lines. Mol Cancer Ther 2004. [DOI: 10.1158/1535-7163.291.3.3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are potent antitumoral agents but their side effects limit their clinical use. A novel class of drugs, nitric oxide-donating NSAIDs (NO-NSAIDs), was found to be safer and more active than classical NSAIDs. This study explored the effect of the NO-donating sulindac derivative, NCX 1102, on three human urothelial epithelial carcinoma cell lines (T24, 647V, and 1207) and primary cultures of normal urothelial cells. Cytotoxicity, antiproliferative effect, cell cycle alterations, morphological changes, and apoptosis were investigated after treatment with NCX 1102 in comparison with the native molecule. After treatment, there was a cytotoxic effect (with IC50 at 48 h of 23.1 μm on 647V, 19.4 μm on T24, and 14.5 μm on 1207) and an antiproliferative effect on all three cell lines with NCX 1102 but not with sulindac. No effect was detected on normal urothelial cells. Flow cytometric analysis showed a differential NCX 1102-induced accumulation of cells in various phases of the cell cycle, depending on cell line and concentration. NCX 1102 induced an occurrence of multinucleated cells in all cell lines and mitotic arrest in 647V and 1207. NCX 1102-treated T24 and 647V cell lines showed a significant difference of apoptotic cell amount when compared to controls. Our results demonstrated a greater antiproliferative potency of NCX 1102 compared to its parent molecule sulindac, and suggested that this new NO-NSAID may have therapeutic impact in the management of bladder cancer.
Collapse
Affiliation(s)
- Sandra Huguenin
- 1Equipe de recherche INSERM E 03-37 Oncogenèse des Tumeurs Respiratoires et Urogénitales, Faculté de Médecine, Créteil, France
| | - Francis Vacherot
- 1Equipe de recherche INSERM E 03-37 Oncogenèse des Tumeurs Respiratoires et Urogénitales, Faculté de Médecine, Créteil, France
| | - Laurence Kheuang
- 1Equipe de recherche INSERM E 03-37 Oncogenèse des Tumeurs Respiratoires et Urogénitales, Faculté de Médecine, Créteil, France
| | - Jocelyne Fleury-Feith
- 1Equipe de recherche INSERM E 03-37 Oncogenèse des Tumeurs Respiratoires et Urogénitales, Faculté de Médecine, Créteil, France
- 2Service d'Histologie et de Biologie Tumorale, Hôpital Tenon, Paris, France; and
| | - Marie-Claude Jaurand
- 1Equipe de recherche INSERM E 03-37 Oncogenèse des Tumeurs Respiratoires et Urogénitales, Faculté de Médecine, Créteil, France
| | | | | | - Dominique K. Chopin
- 1Equipe de recherche INSERM E 03-37 Oncogenèse des Tumeurs Respiratoires et Urogénitales, Faculté de Médecine, Créteil, France
| |
Collapse
|
|
24
|
Godbey WT, Atala A. Directed apoptosis in Cox-2-overexpressing cancer cells through expression-targeted gene delivery. Gene Ther 2003; 10:1519-27. [PMID: 12900768 DOI: 10.1038/sj.gt.3302012] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The principle of promoter-targeted gene delivery was used to direct the expression of reporter genes and inducible caspases to Cox-2-overexpressing cancer cells. The polycation poly(ethylenimine) was used in unmodified form to nonvirally deliver genes into cells, and targeting was achieved at the transcriptional level. Results demonstrated that reporter expression was reduced by an average of 89.8% in normal cells and cell lines not overexpressing Cox-2 when the strong cytomegalovirus promoter was replaced with the human Cox-2 promoter in delivered plasmids. Cocultures of normal and Cox-2-overexpressing cancer cells showed less than 0.5% reporter expression in normal fibroblast cells but over 35% reporter expression in PC3 prostate cancer cells. This targeting method was then used to direct the expression of inducible forms of caspases 3 and 9 to Cox-2-overexpressing cancer cells of the bladder and prostate. Following activation of the resulting caspase pro-forms, cells underwent apoptosis as evidenced by DNA fragmentation and cytoskeletal degradation. This result was also observed in cells resistant to apoptosis in terms of TNF-alpha initiation. Such directed apoptosis could eventually serve as a treatment for an entire class of Cox-2-overexpressing carcinomas.
Collapse
Affiliation(s)
- W T Godbey
- Laboratory for Cellular Therapeutics and Tissue Engineering, Harvard Medical School, The Children's Hospital, Boston, MA 02115, USA
| | | |
Collapse
|
|
25
|
Borzacchiello G, Ambrosio V, Galati P, Perillo A, Roperto F. Cyclooxygenase-1 and -2 expression in urothelial carcinomas of the urinary bladder in cows. Vet Pathol 2003; 40:455-9. [PMID: 12824517 DOI: 10.1354/vp.40-4-455] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Bovine urinary bladder tumors occur frequently in animals suffering from chronic enzootic hematuria because of prolonged ingestion of bracken fern (Pteridium spp.). Cyclooxygenase (COX) genes (COX-1 and COX-2) are known to be involved in the carcinogenesis of human and some animal urothelial tumors. The aim of the present study was to investigate COX-1 and COX-2 expression by immunohistochemical methods in 20 bovine urothelial carcinomas collected at public slaughterhouses from cows that had been suffering from chronic enzootic hematuria. COX-1 immunostaining was identified intracytoplasmically in normal urothelium and in 15 of 20 neoplastic specimens. COX-1 immunosignal in the tumor cells was either absent or weak. COX-2 was also expressed intracytoplasmically in 17 of 20 urothelial carcinomas. Moderate to intense COX-2 labeling was detected in both noninvasive and invasive urothelial carcinomas. Coexpression of both enzyme isoforms was also revealed by confocal laser scanning microscopic investigations. This study indicates that COX-2 is overexpressed in naturally occurring urothelial carcinomas of cows.
Collapse
Affiliation(s)
- G Borzacchiello
- Department of Pathology and Animal Health, General Pathology Division, Faculty of Veterinary Medicine, Federico II University of Naples, Via Veterinaria 1, 80137 Naples, Italy
| | | | | | | | | |
Collapse
|
|
26
|
Wu GS, Zou SQ, Liu ZR, Tang ZH, Wang JH. Celecoxib inhibits proliferation and induces apoptosis via prostaglandin E 2 pathway in human cholangiocarcinoma cell lines. World J Gastroenterol 2003; 9:1302-6. [PMID: 12800245 PMCID: PMC4611805 DOI: 10.3748/wjg.v9.i6.1302] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the roles and mechanisms of celecoxib in inducing proliferation inhibition and apoptosis of human cholangiocarcinoma cell lines.
METHODS: Cyclooxygenase-2-overexpressing human cholangiocarcinoma cell line QBC939 and cyclooxygenase-2-deficient human cholangiocarcinoma cell line SK-CHA-1 were used in the present study. The anti-proliferative effect was measured by methabenzthiazuron (MTT) assay; apoptosis was determined by transferase-mediated dUTP nick end labeling (TUNEL) detection and transmission electron microscopy (TEM). Cell cycle was analyzed by flow cytometry (FCM). The PGE2 levels in the supernatant of cultured cholangiocarcinoma cells were quantitated by enzyme-linked immunoabsordent assay (ELISA).
RESULTS: Celecoxib suppressed the production of PGE2 and inhibited the growth of QBC939 cells. Celecoxib at 10, 20, and 40 μmol/L inhibited PGE2 production by 26%, 58%, and 74% in QBC939 cells. The PGE2 level was much lower constitutively in SK-CHA-1 cells (18.6 ± 3.2) compared with that in QBC939 (121.9 ± 5.6) cells (P < 0.01) and celecoxib had no significant influence on PGE2 level in the SK-CHA-1 cells. The PGE2 concentration in SK-CHA-1 cells also reduced but not significantly after treatment with celecoxib. The PGE2 concentration in SK-CHA-1 cells was (16.5 ± 2.9) ng/well, (14.8 ± 3.4) ng/well, (13.2 ± 2.0) ng/well and (12.6 ± 3.1) ng/well respectively, when pre-treated with 1 μmol/L, 10 μmol/L, 20 μmol/L and 40 μmol/L of celecoxib for 48 h (P > 0.05, vs control). The anti-proliferation effect of celecoxib (20 μmol/L) on QBC939 cells was time-dependent, it was noticeable on day 2 (OD490 = 0.23 ± 0.04) and became obvious on day 3 (OD490 = 0.31 ± 0.07) to day 4 (OD490 = 0.25 ± 0.06), and the OD490 in the control group (day 1) was 0.12 ± 0.03 (P < 0.01, vs control). The anti-proliferation effect of celecoxib could be abolished by the addition of 200 pg/mL PGE2. The proliferation of SK-CHA-1 cells was inhibited slightly by celecoxib, the cell density OD490 in the presence of celecoxib and in control group was 0.31 ± 0.04 and 0.42 ± 0.03 respectively on day 2 (P > 0.05), 0.58 ± 0.07 and 0.67 ± 0.09 respectively on day 3 (P > 0.05), and 0.71 ± 0.08 and 0.78 ± 0.06 respectively on day 4 (P > 0.05). Celecoxib induced proliferation inhibition and apoptosis by G1-S cell cycle arrest: the percentage of QBC939 cells in G0-G1phase after treatment with 40 μmol/L (74.6 ± 66.21) and 20 μmol/L (68.63 ± 4.36) celecoxib increased significantly compared with control cells (54.41 ± 5.12, P < 0.01). The percentage of SK-CHA-1 cells in G0-G1 phase after treatment with various concentrations of celecoxib didn't change significantly compared with control cells. The TUNEL index was much higher in QBC939 cells treated with 20 μmol/L celecoxib for 2 d (0.063 ± 0.018) and for 4 d (0.102 ± 0.037) compared with control cells (0.017 ± 0.004, P < 0.01).
CONCLUSION: The current in vitro study indicates that inhibition of proliferation and induction of apoptosis in human cholangiocarcinoma cells by cyclooxygenase-2 specific inhibitor celecoxib may involve in COX-dependent mechanisms and PGE2pathway. Celecoxib as a chemopreventive and chemotherapeutic agent might be effective primarily on COX-2-expressing cholangiocarcinoma.
Collapse
Affiliation(s)
- Gao-Song Wu
- Department of General Surgery, Tongji Hospital, 1095 Jiefang Road, Wuhan, 430030, Hubei Province, China.
| | | | | | | | | |
Collapse
|
|
27
|
Pruthi RS, Derksen E, Gaston K. Cyclooxygenase-2 as a potential target in the prevention and treatment of genitourinary tumors: a review. J Urol 2003; 169:2352-9. [PMID: 12771797 DOI: 10.1097/01.ju.0000047364.56051.74] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
PURPOSE Recent years have seen a dramatic expansion in our discovery and knowledge of the molecular mechanisms of cancer development and progression. The discovery and elucidation of prostaglandin pathways, in particular the molecular and clinical role of cyclooxygenase (COX)-2 function, has had important application to neoplasms. Current understanding of the role of COX-2 activity and, thereby, the potential clinical usefulness of COX-2 specific inhibitors as they apply to urological oncology are discussed. MATERIALS AND METHODS The discovery of prostaglandin pathways, the molecular and clinical role of COX-2 function, and the corresponding application to neoplasms were reviewed in the scientific literature (MEDLINE from 1960 to the present). In particular, a thorough review of the current literature and recent abstract presentations at scientific meetings was done regarding the potential role of COX-2 in urological cancers (MEDLINE from 1960 to the present, and American Urological Association and American Society of Clinical Oncology annual meeting abstracts from1998 to the present). RESULTS Decreased apoptosis, increased angiogenesis and immunosuppression are just some of the known sequelae of COX-2 over expression and each effect may have an important role in tumor formation and progression. Preclinical research and pilot clinical studies in urological oncology, in particular prostate, bladder and kidney cancer, have proved to be quite promising to date. CONCLUSIONS Currently we are just beginning to understand the molecular mechanisms and clinical effects of COX-2 function and inhibition, and the potential for COX-2 specific inhibitors to affect potentially tumor biology and growth and, thereby, serve as antitumor drugs with therapeutic and chemopreventive roles for urological cancers. The absence of complete scientific understanding in these areas provides a generous opportunity for innovative and important scientific study.
Collapse
Affiliation(s)
- Raj S Pruthi
- Division of Urologic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | | | | |
Collapse
|