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Kast RE. The OSR9 Regimen: A New Augmentation Strategy for Osteosarcoma Treatment Using Nine Older Drugs from General Medicine to Inhibit Growth Drive. Int J Mol Sci 2023; 24:15474. [PMID: 37895152 PMCID: PMC10607234 DOI: 10.3390/ijms242015474] [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] [Received: 09/23/2023] [Revised: 10/13/2023] [Accepted: 10/19/2023] [Indexed: 10/29/2023] Open
Abstract
As things stand in 2023, metastatic osteosarcoma commonly results in death. There has been little treatment progress in recent decades. To redress the poor prognosis of metastatic osteosarcoma, the present regimen, OSR9, uses nine already marketed drugs as adjuncts to current treatments. The nine drugs in OSR9 are: (1) the antinausea drug aprepitant, (2) the analgesic drug celecoxib, (3) the anti-malaria drug chloroquine, (4) the antibiotic dapsone, (5) the alcoholism treatment drug disulfiram, (6) the antifungal drug itraconazole, (7) the diabetes treatment drug linagliptin, (8) the hypertension drug propranolol, and (9) the psychiatric drug quetiapine. Although none are traditionally used to treat cancer, all nine have attributes that have been shown to inhibit growth-promoting physiological systems active in osteosarcoma. In their general medicinal uses, all nine drugs in OSR9 have low side-effect risks. The current paper reviews the collected data supporting the role of OSR9.
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Xu H, Li P, Ma H, Tan Y, Wang X, Cai F, Xu J, Sun H, Zhuang H, Hua Z. ADT-OH synergistically enhanced the antitumor activity of celecoxib in human colorectal cancer cells. Cancer Med 2023; 12:17193-17211. [PMID: 37492969 PMCID: PMC10501245 DOI: 10.1002/cam4.6342] [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] [Received: 04/07/2023] [Revised: 06/29/2023] [Accepted: 07/02/2023] [Indexed: 07/27/2023] Open
Abstract
BACKGROUND Colorectal cancer is one of the most prevalent cancers in the world, but the research on its prevention, early diagnosis and treatment is still a major challenge in clinical oncology. Thus, there is a pressing requirement to find effective strategies to improve the survival of colon cancer patients. METHODS Celecoxib has been accounted to be an effective antitumor drug, but may exhibit significant side effects. In recent studies, 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH), one of the most commonly used reagents for the synthesis of sustained-release H2 S donors, has also been reported to inhibit cancer progression by affecting processes such as cell cycle, angiogenesis, and apoptosis. Therefore, we evaluated the therapeutic effect of the combination of ADT-OH and celecoxib on colorectal cancer through in vitro and in vivo, hoping to achieve better therapeutic effect and reduce the effect of celecoxib on gastric injury through exogenous administration of H2 S. RESULTS Our results demonstrated that ADT-OH combined with celecoxib synergistically inhibited the proliferation and migration ability of human colorectal cancer HCT116 cells, altered cell cycle and cytoskeleton, increased intracellular reactive oxygen species (ROS), and promoted cell apoptosis. Noteworthy, in vivo studies also indicated the excellent antitumor therapeutic effect of the combination therapy without apparent toxicity. CONCLUSIONS In general, our results provide a reasonable combination strategy of low-dose ADT-OH and celecoxib in the preclinical application of colorectal cancer.
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Affiliation(s)
- Huangru Xu
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life SciencesNanjing UniversityNanjingP.R. China
| | - Ping Li
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life SciencesNanjing UniversityNanjingP.R. China
| | - Hailin Ma
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life SciencesNanjing UniversityNanjingP.R. China
| | - Yuanhao Tan
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life SciencesNanjing UniversityNanjingP.R. China
| | - Xiaoyang Wang
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life SciencesNanjing UniversityNanjingP.R. China
| | - Fangfang Cai
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life SciencesNanjing UniversityNanjingP.R. China
- School of BiopharmacyChina Pharmaceutical UniversityNanjingChina
| | - Jiaqi Xu
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life SciencesNanjing UniversityNanjingP.R. China
| | - Huisong Sun
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life SciencesNanjing UniversityNanjingP.R. China
| | - Hongqin Zhuang
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life SciencesNanjing UniversityNanjingP.R. China
| | - Zi‐Chun Hua
- The State Key Laboratory of Pharmaceutical Biotechnology, College of Life SciencesNanjing UniversityNanjingP.R. China
- School of BiopharmacyChina Pharmaceutical UniversityNanjingChina
- Changzhou High‐Tech Research Institute of Nanjing University and Jiangsu TargetPharma Laboratories Inc.ChangzhouP.R. China
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Wu SR, Liu J, Zhang LF, Wang N, Zhang LY, Wu Q, Liu JY, Shi YQ. Lamb’s tripe extract and vitamin B 12 capsule plus celecoxib reverses intestinal metaplasia and atrophy: A retrospective cohort study. World J Clin Cases 2021; 9:10472-10483. [PMID: 35004979 PMCID: PMC8686147 DOI: 10.12998/wjcc.v9.i34.10472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 08/31/2021] [Accepted: 10/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Chronic atrophic gastritis (AG) with intestinal metaplasia (IM) significantly increases the risk of gastric cancer. Some medicines have showed definite therapeutic effects in AG and IM regression.
AIM To validate the efficacy of Lamb’s tripe extract and vitamin B12 capsule (LTEVB12) initial therapy and celecoxib rescue therapy for IM and AG.
METHODS A total of 255 patients were included to receive LTEVB12 initial therapy (2 capsules each time, three times daily for 6 mo) in hospital in this study. The patients with failure of IM regression continued to receive celecoxib rescue therapy (200 mg, once daily for 6 mo). After each therapy finished, the patients underwent endoscopy and biopsy examination. The regression efficiency was assessed by the operative link on gastritis assessment (OLGA) and the operative link on the gastric intestinal metaplasia assessment (OLGIM) staging system. Logistic regression analysis was applied to identify factors associated with the curative effect.
RESULTS For LTEVB12 initial therapy, the reversal rates of IM and AG were 52.95% and 48.24%, respectively. Analogously, for celecoxib rescue therapy, the effective rates for IM and AG were 56.25% and 51.56%, respectively. The IM regression rate of complete therapy was up to 85.03%. In different OLGA and OLGIM stages of IM patients, therapeutic efficiency showed a significant difference in each group (P < 0.05). For both therapies, patients with high stages (III or IV) of both the OLGA and OLGIM evaluation systems showed a higher IM or AG regression rate than those with low stages (I or II). Among patients with high stages (OLGIM III and IV), the IM regression rate was above 70% for each therapy. Eating habits, fresh vegetable intake, and high-salt diet were identified as independent factors for the IM reversal effect of LTEVB12 therapy, especially high-salt diet (odds ratio = 1.852, P < 0.05).
CONCLUSION Monotherapy could reverse IM and AG. LTEVB12 initial therapy and celecoxib rescue therapy significantly increase the regression effect. IM may not be the point of no return among gastric precancerous lesions.
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Affiliation(s)
- Si-Ran Wu
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Jie Liu
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Li-Feng Zhang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Na Wang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Lu-Yao Zhang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Qiong Wu
- Department of Clinical Nutrition, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Jun-Ye Liu
- Department of Radiation Protective Medicine, Air Force Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Yong-Quan Shi
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi'an 710032, Shaanxi Province, China
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Celecoxib induces apoptosis through Akt inhibition in 5-fluorouracil-resistant gastric cancer cells. Toxicol Res 2021; 37:25-33. [PMID: 33489855 DOI: 10.1007/s43188-020-00044-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 02/10/2020] [Accepted: 03/04/2020] [Indexed: 10/24/2022] Open
Abstract
Gastric cancer is the fifth leading cause of cancer and a global public health problem. 5-Fluorouracil (5-FU) is the primary drug chosen for the treatment of advanced gastric cancer, but acquired cancer drug resistance limits its effectiveness and clinical use. Proliferation assays showed that a gastric carcinoma cell line, AGS and 5-FU-resistant AGS cells (AGS FR) treated with 3-100 μM 5-FU for 48 h or 72 h showed different sensitivities to 5-FU. Immunoblot assay demonstrated that AGS FR cells expressed more COX-2 and PGE2-cognated receptor EP2 than AGS cells. AGS FR cells considerably produced PGE2 than AGS upon stimulation with 5-FU. These results suggest that COX-2 expression is associated with 5-FU resistance. Unlike AGS FR cells, AGS cells showed increased levels of both cleaved caspase-3 and Bax following 5-FU treatment. Treatment of cells with the COX-2 selective inhibitor celecoxib induced cell death of AGS FR cells in a time- and concentration-dependent manner. FACS analysis showed that celecoxib at high doses caused apoptotic cell death, demonstrating a concentration-dependent increase in the cell populations undergoing early apoptosis and late apoptosis. This apoptotic induction was strongly supported by the expression profiles of apoptosis- and survival-associated proteins in response to celecoxib; pro-apoptotic cellular proteins increased while expressions of COX-2 and p-Akt were downregulated in a concentration-dependent manner. An increase in PTEN expression was accompanied with downregulation of p-Akt. Based on the data that downregulation of COX-2 was correlated with the concentrations of celecoxib, COX-2 may play a key role in celecoxib-induced cell death of AGS FR cells. Butaprost, the EP2 agonist, promoted proliferative activity of AGS FR cells in a concentration-dependent manner compared with AGS cells. In cells exposed to butaprost, expressions of COX-2 and p-Akt were increased in a concentration-dependent manner with concomitantly reduced PTEN levels. Taken together, 5-FU-resistance in gastric cancer is correlated with COX-2 expression, and therefore the selective inhibition of COX-2 leads to suppression of cell proliferation of AGS FR cells. Modulation of COX-2 expression and its catalytic activity may be a potential therapeutic strategy to overcome 5-FU-resistant gastric cancer.
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Tołoczko-Iwaniuk N, Dziemiańczyk-Pakieła D, Nowaszewska BK, Celińska-Janowicz K, Miltyk W. Celecoxib in Cancer Therapy and Prevention - Review. Curr Drug Targets 2020; 20:302-315. [PMID: 30073924 DOI: 10.2174/1389450119666180803121737] [Citation(s) in RCA: 107] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 06/04/2018] [Accepted: 08/02/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND OBJECTIVES It is generally accepted that inflammatory cells found in the tumor microenvironment are involved in the neoplastic process, promoting cell proliferation, survival, and migration. Therefore, administering anti-inflammatory medication in cancer therapy seems to be justified. A potential pathway associated with the aforementioned issue is cyclooxygenase-2 inhibition, particularly as the overexpression of this enzyme has been proven to occur in cancer tissues and is also associated with a poor prognosis in several types of human malignancies. Celecoxib, a COX-2 selective inhibitor, has been utilized for over 20 years, particularly as an anti-inflammatory, analgesic and antipyretic medication. However, to date, its antineoplastic properties have not been sufficiently investigated. In recent years, the number of research studies on the antineoplastic effects of celecoxib has increased considerably. The vast majority of publications refers to preclinical studies attempting to elucidate its mechanisms of action. Clinical trials concerning celecoxib have focused primarily on the treatment of cancers of the colon, breast, lung, prostate, stomach, head and neck, as well as premalignant lesions such as familial adenoma polyposis. In this review article authors attempt to summarise the latest research which has elucidated celecoxib use in the treatment and prevention of cancer. CONCLUSION Both preclinical and clinical studies have demonstrated promising results of the role of celecoxib in the treatment and prevention of cancer - the best outcome was observed in colon, breast, prostate and head and neck cancers. However, more clinical trials providing real evidence-based clinical advances of celecoxib use are needed.
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Affiliation(s)
- Natalia Tołoczko-Iwaniuk
- Department of Pharmaceutical Analysis, Medical University of Bialystok, Mickiewicza 2D Street, 15-222 Bialystok, Poland
| | - Dorota Dziemiańczyk-Pakieła
- Department of Maxillofacial and Plastic Surgery, Medical University of Bialystok, Skłodowskiej-Curie 24A, 15-404 Bialystok, Poland
| | - Beata Klaudia Nowaszewska
- Department of Maxillofacial and Plastic Surgery, Medical University of Bialystok, Skłodowskiej-Curie 24A, 15-404 Bialystok, Poland
| | - Katarzyna Celińska-Janowicz
- Department of Pharmaceutical Analysis, Medical University of Bialystok, Mickiewicza 2D Street, 15-222 Bialystok, Poland
| | - Wojciech Miltyk
- Department of Pharmaceutical Analysis, Medical University of Bialystok, Mickiewicza 2D Street, 15-222 Bialystok, Poland
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Ma M, Yang X, Zhao L, Wang X, Liu L, Jiao W, Wei Y, Shan B. Celecoxib enhances sensitivity to chemotherapy drugs of T-cell lymphoma. Oncol Lett 2018. [PMID: 29541237 DOI: 10.3892/ol.2018.7897] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Celecoxib is a newly-identified nonsteroidal anti-inflammatory drug, which has been used to treat fever in clinical practice. Celecoxib has been demonstrated to suppress the viability of various human tumor cells. However, the effect of celecoxib on response of T-cell lymphoma to chemotherapy agents remains unclear. The aim of the present study was to investigate the effect of celecoxib on chemosensitivity of human T-cell lymphoma, and to address the underlying mechanism of action. The cytotoxicity of CDDP, epirubicin and VCR on Jurkat and Hut-78 cells treated with celecoxib was assessed by MTT assay, and the half-maximal inhibitory concentration (IC50) value was calculated by Origin 75 software. The effect of celecoxib on apoptosis and intracellular concentration of Rhodamine-123 in Jurkat and Hut-78 cells was analyzed by flow cytometry. The expression of transcription factor p65 (p65), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), multidrug resistance 1 (MDR1) and multidrug resistance-associated protein 1 (MRP1) at mRNA and protein levels were detected by reverse transcription quantitative polymerase chain reaction and western blotting, respectively. Proliferation suppression rates and apoptosis levels were significantly increased in Jurkat and Hut-78 cells combined with celecoxib compared with those without celecoxib, when treated with CDDP, epirubicin and VCR. The IC50 values of the chemotherapy agents were lower in Jurkat and Hut-78 cells treated with celecoxib compared with those that were not. The apoptosis level, expression of Bax and the intracellular concentration of Rhodamine-123 were increased, whereas the expression of p65, Bcl-2, MDR1 and MRP1 were decreased, in celecoxib-treated Jurkat and Hut-78 cells compared with those without celecoxib treatment. These results indicated that celecoxib may enhance the sensitivity of T-cell lymphoma to chemotherapy drugs by inhibiting the expression of multidrug resistance (MDR)-associated proteins via downregulating the activity of the nuclear factor-κB signaling pathway, suggesting that celecoxib may improve the curative effect of chemotherapy drugs in T-cell lymphoma.
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Affiliation(s)
- Ming Ma
- Clinical Laboratory, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Xingxiao Yang
- Department of Infection Management, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Lianmei Zhao
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Xuexiao Wang
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Lihua Liu
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Wenjing Jiao
- Clinical Laboratory, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Yuanyuan Wei
- Clinical Laboratory, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Baoen Shan
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
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Li Y, Tan BB, Fan LQ, Zhao Q, Liu Y, Wang D. Heterogeneity of COX-2 and Multidrug Resistance between Primary Tumors and Regional Lymph Node Metastases of Gastric Cancer. TUMORI JOURNAL 2018; 98:516-22. [DOI: 10.1177/030089161209800418] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Aims and background Cyclooxygenase-2 (COX-2) is involved in the progression of gastric cancer; however, the role of COX-2 in multidrug resistance (MDR) is still unclear. This study aimed to elucidate the relationship between COX-2 and MDR so as to show the heterogeneity of gastric primary tumors and regional lymph node metastases. Methods Between 2008 and 2009, 56 primary tumor samples and paired metastatic lymph node tissues from gastric cancer patients confirmed by surgery and pathological examination in our hospital were collected. The expression levels of COX-2 and MDR-associated factors such as P-glycoprotein (P-gp), glutathione S-transferase pi (GST-π) and topoisomerase II alpha (Topo-II-α) were determined by immunohistochemical staining. Tumor cells from these tissues were cultured and the cell chemosensitivities for 11 chemotherapeutic agents were measured by sulforhodamine B assay. Results The expression levels of COX-2, P-gp and GST-π were significantly higher in metastatic lymph node tissues than in primary tumors, while the expression level of Topo-II-α was lower in metastatic lymph node tissues than in primary tumors (all P <0.05). In primary tumors, COX-2 and GST-π were positively correlated and COX-2 and Topo-II-α were negatively correlated; in metastatic lymph node tissues, a positive correlation was found between COX-2 and P-gp (all P <0.05). The inhibition rates of eADM, VP-16, THP and MMC on cells from primary tumors were significantly lower than those on cells from metastatic lymph nodes, while the inhibition rates of HCPT, L-OHP and VCR on cells from metastatic lymph nodes were lower than those on cells from primary tumors. Conclusion The expression of COX-2 and MDR-associated factors as well as cell chemosensitivities are different in primary tumors and regional lymph node metastases of gastric cancer, and this may be an indication of their heterogeneity.
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Affiliation(s)
- Yong Li
- Department of General Surgery, the Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang, China
| | - Bi-bo Tan
- Department of General Surgery, the Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang, China
| | - Li-qiao Fan
- Department of General Surgery, the Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang, China
| | - Qun Zhao
- Department of General Surgery, the Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang, China
| | - Yü Liu
- Department of General Surgery, the Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang, China
| | - Dong Wang
- Department of General Surgery, the Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang, China
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Wang Z, Chen JQ, Liu JL. COX-2 Inhibitors and Gastric Cancer. Gastroenterol Res Pract 2014; 2014:132320. [PMID: 25371669 PMCID: PMC4209764 DOI: 10.1155/2014/132320] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Accepted: 09/03/2014] [Indexed: 12/12/2022] Open
Abstract
The evidence that cyclooxygenase-2 (COX-2) is upregulated and plays an important role in carcinogenesis of gastric cancer has triggered the topic of COX-2 inhibitors as chemopreventive agents for gastric cancer. Studies find that COX-2 inhibitors are associated not only with chemoprophylactic effects, but also with chemotherapeutic potentials in gastric cancer. Both COX-dependent and COX-independent pathways have a role in the anticancer efficiency of COX-2 inhibitors. However, enthusiasm is thwarted by the potential toxicity, that is, gastrointestinal toxicity of nonselective COX-2 inhibitors and cardiovascular risk of selective COX-2 inhibitors. Therefore, more studies are needed to develop new targeted antitumor agents (such as prostaglandin E receptor antagonist) and to define fundamental questions such as optimal treatment regimens, integration of cotherapy, and careful selection of candidates.
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Affiliation(s)
- Zhen Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region 530021, China
| | - Jun-qiang Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region 530021, China
| | - Jin-lu Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region 530021, China
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Chung MH, Kim DH, Na HK, Kim JH, Kim HN, Haegeman G, Surh YJ. Genistein inhibits phorbol ester-induced NF-κB transcriptional activity and COX-2 expression by blocking the phosphorylation of p65/RelA in human mammary epithelial cells. Mutat Res 2014; 768:74-83. [PMID: 24742714 DOI: 10.1016/j.mrfmmm.2014.04.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Revised: 03/30/2014] [Accepted: 04/03/2014] [Indexed: 06/03/2023]
Abstract
Genistein, an isoflavone present in soy products, has chemopreventive effects on mammary carcinogenesis. In the present study, we have investigated the effects of genistein on phorbol ester-induced expression of cyclooxygenase-2 (COX-2) that plays an important role in the pathophysiology of inflammation-associated carcinogenesis. Pretreatment of cultured human breast epithelial (MCF10A) cells with genistein reduced COX-2 expression induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). There are multiple lines of evidence supporting that the induction of COX-2 is regulated by the eukaryotic transcription factor NF-κB. Genistein failed to inhibit TPA-induced nuclear translocation and DNA binding of NF-κB as well as degradation of IκB. However, genistein abrogated the TPA-induced transcriptional activity of NF-κB as determined by the luciferase reporter gene assay. Genistein inhibited phosphorylation of the p65 subunit of NF-κB and its interaction with cAMP regulatory element-binding protein-binding protein (CBP)/p300 and TATA-binding protein (TBP). TPA-induced NF-κB phosphorylation was abolished by pharmacological inhibition of extracellular signal-regulated kinase (ERK). Likewise, pharmacologic inhibition or dominant negative mutation of ERK suppressed phosphorylation of p65. The above findings, taken together, suggest that genistein inhibits TPA-induced COX-2 expression in MCF10A cells by blocking ERK-mediated phosphorylation of p65 and its subsequent interaction with CBP and TBP.
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Affiliation(s)
- Myung-Hoon Chung
- Research Institute for Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Do-Hee Kim
- Research Institute for Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Hye-Kyung Na
- Department of Food and Nutrition, Sungshin Women's University, Seoul, South Korea
| | - Jung-Hwan Kim
- Research Institute for Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Ha-Na Kim
- Research Institute for Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | | | - Young-Joon Surh
- Research Institute for Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul, South Korea; Cancer Research Institute, Seoul National University, Seoul, South Korea.
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Biological evaluation of bismuth non-steroidal anti-inflammatory drugs (BiNSAIDs): Stability, toxicity and uptake in HCT-8 colon cancer cells. J Inorg Biochem 2014; 135:28-39. [DOI: 10.1016/j.jinorgbio.2014.02.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Revised: 02/05/2014] [Accepted: 02/18/2014] [Indexed: 11/22/2022]
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Liu M, Li CM, Chen ZF, Ji R, Guo QH, Li Q, Zhang HL, Zhou YN. Celecoxib regulates apoptosis and autophagy via the PI3K/Akt signaling pathway in SGC-7901 gastric cancer cells. Int J Mol Med 2014; 33:1451-8. [PMID: 24676394 PMCID: PMC4055439 DOI: 10.3892/ijmm.2014.1713] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2013] [Accepted: 03/20/2014] [Indexed: 01/16/2023] Open
Abstract
Gastric cancer, one of the most common malignancies worldwide, typically has a poor prognosis and poor survival rate. Previous studies have investigated the chemopreventive effect of celecoxib. In the present study, the SGC-7901 human gastric cancer cell line was utilized to examine the chemopreventive mechanisms of celecoxib. The inhibition of cell proliferation was determined using MTT assay, cell apoptosis was monitored by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) and flow cytometry, and cell ultrastructural changes were assessed via transmission electron microscopy. The mRNA expression of Akt, caspase-8 and -9 was examined using quantitative reverse-transcription-polymerase chain reaction (qRT-PCR) and p-Akt, procaspase-8 and -9 were analyzed via western blotting. The results showed that celecoxib inhibited the proliferation of SGC-7901 cells in a time- and dose-dependent manner. Additionally, celecoxib induced apoptosis as substantiated by typical apoptotic bodies, autophagosomes and an increased apoptotic rate. It was found that following celecoxib treatment, Akt mRNA expression was not significantly altered, and that p-Akt protein levels decreased in a time- and dose-dependent manner. Additionally, caspase-8 and -9 mRNA expression was significantly increased, while procaspase-8 and -9 protein expression decreased relative to the time- and dose-dependent effects. These results demonstrated that celecoxib induced apoptosis and autophagy of gastric cancer cells in vitro through the PI3K/Akt signaling pathway. Moreover, our findings suggested that celecoxib induces apoptosis in gastric cancer cells through the mitochondrial and death receptor pathways, providing additional understanding regarding the chemopreventive behaviors of celecoxib and its uses in cancer therapy.
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Affiliation(s)
- Min Liu
- Division of Gastroenterology and Hepatology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Chun-Mei Li
- Division of Oncology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Zhao-Feng Chen
- Division of Gastroenterology and Hepatology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Ri Ji
- Division of Gastroenterology and Hepatology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Qing-Hong Guo
- Division of Gastroenterology and Hepatology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Qiang Li
- Division of Gastroenterology and Hepatology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Hong-Ling Zhang
- Division of Gastroenterology and Hepatology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Yong-Ning Zhou
- Division of Gastroenterology and Hepatology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
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Kim J, Kim N, Park JH, Chang H, Kim JY, Lee DH, Kim JM, Kim JS, Jung HC. The Effect of Helicobacter pylori on Epidermal Growth Factor Receptor-Induced Signal Transduction and the Preventive Effect of Celecoxib in Gastric Cancer Cells. Gut Liver 2013; 7:552-9. [PMID: 24073313 PMCID: PMC3782670 DOI: 10.5009/gnl.2013.7.5.552] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2012] [Revised: 12/31/2012] [Accepted: 01/17/2013] [Indexed: 12/14/2022] Open
Abstract
Background/Aims Helicobacter pylori infection induces cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) overexpression, and these factors may engage in cross-talk. The aim of the present study was to evaluate the effect of H. pylori on EGFR signaling pathways and to determine whether celecoxib has an inhibitory effect on this pathway. Methods The AGS cell line was cocultured with H. pylori G27 and the isogenic cagE- mutant. The expression of COX-2, EGFR, heparin binding-epidermal growth factor (HB-EGF), and transforming growth factor-β (TGF-β) was measured by real time-polymerase chain reaction (RT-PCR). Next, Western blot analyses of COX-2, EGFR, total Akt, phosphorylated Akt (pAkt), and phosphorylated glycogen synthase kinase-3β (pGSK3β) were performed after incubating H. pylori-treated AGS cells for 24 hours with various concentrations of celecoxib (0, 10, 20, and 30 µmol/L). Results H. pylori infection upregulated the mRNA levels of COX-2, EGFR, HB-EGF, and TGF-β, as detected by RT-PCR. However, AGS cells treated with cagE- mutants, which have a defective type IV secretion system, did not exhibit EGFR upregulation. Celecoxib had inhibitory effects on the H. pylori-induced overexpression of COX-2 (p=0.015), EGFR (p=0.025), pAkt (p=0.025), and pGSK3β (p=0.029) by Western blot analysis. Conclusions H. pylori with an intact type IV secretion system activated the COX-2 and EGFR-Akt pathways in the AGS cell line. As celecoxib exhibited inhibitory effects on the EGFR signaling pathway, the cross-talk of COX-2 and EGFR likely mediates H. pylori-induced gastric cancer.
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Affiliation(s)
- Jaeyeon Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea. ; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Li F, Liu S, Ouyang Y, Fan C, Wang T, Zhang C, Zeng B, Chai Y, Wang X. Effect of celecoxib on proliferation, collagen expression, ERK1/2 and SMAD2/3 phosphorylation in NIH/3T3 fibroblasts. Eur J Pharmacol 2011; 678:1-5. [PMID: 22209876 DOI: 10.1016/j.ejphar.2011.12.018] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2011] [Revised: 12/07/2011] [Accepted: 12/09/2011] [Indexed: 11/18/2022]
Abstract
In the present study, the effects of celecoxib on proliferation, collagen expression, ERK1/2 and SMAD2/3 phosphorylation in NIH/3T3 fibroblasts were investigated. NIH/3T3 fibroblasts stimulated with fibroblast growth factor-2 (FGF-2) or transforming growth factor-β1 (TGF-β1) were examined in the presence of celecoxib. Proliferation was assessed by MTT assays; ERK1/2 expression and SMAD2/3 expression were assessed by quantitative RT-PCR and western blotting; ERK1/2 phosphorylation and SMAD2/3 phosphorylation were assessed by western blot analysis. The results indicated that celecoxib could suppress cell proliferation stimulated by FGF-2 (IC(50) FGF+group, 75±1.9μmol/l) and TGF-β1 (IC(50) TGF+group, 48±1.4μmol/l), by inhibiting ERK1/2 phosphorylation but not ERK1/2 expression. Celecoxib also suppressed collagen expression (0.35-fold COL3 and 0.43-fold COL1 at 320μmol/l celecoxib relative to the untreated control after stimulation with TGF-β1 for 3h, P<0.01), by inhibiting SMAD2/3 phosphorylation but not SMAD2/3 expression. The suppression of NIH/3T3 fibroblast proliferation and collagen expression upon stimulation by FGF-2 and TGF-β1 is likely a result of the inhibition of ERK1/2 and SMAD2/3 phosphorylation by celecoxib.
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Affiliation(s)
- Fengfeng Li
- Department of Orthopaedics, The Sixth Affiliated People's Hospital, Shanghai Jiaotong University School of Medicine, 600 Yishan Road, Shanghai 200233, China
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Synthesis and evaluation of indole, pyrazole, chromone and pyrimidine based conjugates for tumor growth inhibitory activities--development of highly efficacious cytotoxic agents. Eur J Med Chem 2010; 45:4968-82. [PMID: 20810192 DOI: 10.1016/j.ejmech.2010.08.004] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2010] [Revised: 07/28/2010] [Accepted: 08/05/2010] [Indexed: 12/16/2022]
Abstract
Based upon the lead compounds 10 and 11, a number of conjugates were synthesized by the combination of chromone-pyrimidine, chromone-indolinone, chromone-pyrazole, indole-pyrimidine, indole-indolinone and indole-pyrazole moieties. Evaluation of these compounds for tumor growth inhibitory activities over 60 human tumor cell lines provided highly efficacious compounds 15, 41, 43, 66, 69, and 72 with an average GI(50) over all the 60 human tumor cell lines as 3.2 μM, 3.1 μM, 1.7 μM, 2.6 μM, 50.1 μM and 2.0 μM, respectively.
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Rostom A, Moayyedi P, Hunt R. Canadian consensus guidelines on long-term nonsteroidal anti-inflammatory drug therapy and the need for gastroprotection: benefits versus risks. Aliment Pharmacol Ther 2009; 29:481-96. [PMID: 19053986 DOI: 10.1111/j.1365-2036.2008.03905.x] [Citation(s) in RCA: 105] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used, but are not without risks. AIM To provide evidence-based management recommendations to help clinicians determine optimal long-term NSAID therapy and the need for gastroprotective strategies based on an assessment of both gastrointestinal (GI) and cardiovascular (CV) risks. METHODS A multidisciplinary group of 21 voting participants revised and voted on the statements and the strength of evidence (assessed according to GRADE) at a consensus meeting. RESULTS An algorithmic approach was developed to help manage patients who require long-term NSAID therapy. The use of low-dose acetylsalicylic acid in patients with high CV risk was assumed. For patients at low GI and CV risk, a traditional NSAID alone may be acceptable. For patients with low GI risk and high CV risk, full-dose naproxen may have a lower potential for CV risk than other NSAIDs. In patients with high GI and low CV risk, a COX-2 inhibitor plus a proton pump inhibitor (PPI) may offer the best GI safety profile. When both GI and CV risks are high and NSAID therapy is absolutely necessary, risk should be prioritized. If the primary concern is GI risk, a COX-2 inhibitor plus a PPI is recommended; if CV risk, naproxen 500 mg b.d. plus a PPI would be preferred. NSAIDs should be used at the lowest effective dose for the shortest possible duration. CONCLUSION More large, long-term trials that examine clinical outcomes of complicated and symptomatic upper and lower GI ulcers are needed.
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Affiliation(s)
- A Rostom
- Division of Gastroenterology, University of Calgary Medical Clinic, AB, Canada.
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Forones NM, Kawamura KY, Segreto HRC, Artigiani Neto R, Focchi GRDA, Oshima CTF. Expression of COX-2 in stomach carcinogenesis. J Gastrointest Cancer 2008; 39:4-10. [PMID: 19107602 DOI: 10.1007/s12029-008-9039-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2008] [Accepted: 11/26/2008] [Indexed: 12/15/2022]
Abstract
BACKGROUND Gastric cancer is a frequent cause of cancer in Brazil. The understanding of gastric carcinogenesis is not completely known but the progress of the molecular biology has provided that the initiation and progression of gastric cancer process is a consequence of a cumulative series of multiple gene alterations. AIM The aim of the study is to investigate the relationship among cytoplasmatic COX-1 and COX-2, Bcl-2 and nuclear P53 in chronic gastritis, metaplasia, and intestinal and gastric cancer. PATIENTS AND METHODS COX-1, COX-2, P53, and Bcl-2 were evaluated by immunohistochemistry in 34 gastric adenocarcinoma (GA) tissues obtained from gastric resection, 21 tissues of patients with chronic gastritis (CG), and 34 with intestinal metaplasia (IM) obtained from endoscopic biopsies. RESULTS COX-1 and COX-2 were expressed in more than 85% of the tissues. A correlation between COX-1 and COX-2 were observed (r = 0.66). P53 was positive in 29% CG, 20% of IM and in 59 % of GA. Bcl-2 was negative in all the CG, in 88% of IM, and in 85% of GA. P53 staining was expressed more frequently in gastric cancer when compared to CG (p = 0.05) or IM (p = 0.003). The expression of Bcl-2 was also higher in gastric cancer (p = 0.002) and in intestinal metaplasia (p = 0.04) when compared to CG. There were no difference between metaplasia and chronic gastritis for P53 or Bcl-2. The immunoreactivity of COX-2 in gastric cancer was higher in the intestinal type (58%) than in diffuse type. A higher expression of COX-2 was found in advanced gastric cancer (p = 0.019). P53 was also more frequent in node positive cancer (p = 0.04). CONCLUSION COX-2 is probably involved in gastric carcinogenesis, being an early alteration in cancer. Although we observed in this study a correlation between COX-2 and depth of cancer, this association as a prognostic marker is not well defined. P53 and Bcl-2 was expressed mainly in gastric cancer, being probably a latest alteration in gastric development.
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Affiliation(s)
- Nora Manoukian Forones
- Oncology Group/Gastroenterology Division, Pathology Department, Universidade Federal de Sao Paulo (UNIFESP/EPM), Sao Paulo, Sao Paulo, Brazil.
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Liu Z, Wang X, Lu Y, Han S, Zhang F, Zhai H, Lei T, Liang J, Wang J, Wu K, Fan D. Expression of 15-PGDH is downregulated by COX-2 in gastric cancer. Carcinogenesis 2008; 29:1219-27. [PMID: 18174234 DOI: 10.1093/carcin/bgm297] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
To explore the proteins regulated by cyclooxygenase-2 (COX-2) in gastric cancer, the expression plasmid of COX-2siRNA was constructed and transfected into gastric cancer cell line SGC7901. Then, two-dimensional electrophoresis and the PDQuest software analysis were applied to discover the differentially expressed proteins. The differential protein spots were analyzed by matrix-assisted laser desorption/ionization time of flight mass spectrometry. Fourteen differentially expressed proteins between the two cell lines were identified. 15-Hydroxyprostaglandin dehydrogenase [NAD(+)] (15-PGDH), a key enzyme in prostaglandin degradation, was identified as an upregulated protein in SGC7901 cells transfected with the COX-2siRNA plasmid. To further explore whether the 15-PGDH is regulated by COX-2, western blotting and immunocytochemical assay were performed to detect the expression of 15-PGDH in different cell lines with different expression level of COX-2. The results showed that the expression of 15-PGDH was upregulated (128.57%) as COX-2 was suppressed by small interfering RNA and downregulated (51.72%) as COX-2 was enhanced by COX-2 cDNA transfection in gastric cancer cells. In tissue specimens with gastric cancer, there was a decreased expression of 15-PGDH and an increased expression of COX-2 simultaneously. A significantly negative correlation of 15-PGDH expression was found to COX-2 level, tumor differentiation, tumor, lymph node, metastasis (TNM) staging and lymph node metastasis of gastric cancer. All the results suggest that 15-PGDH is downregulated by COX-2 in human gastric cancer and may contribute to the carcinogenesis and development of human gastric cancer in combination with COX-2.
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Affiliation(s)
- Zhenxiong Liu
- State key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, 15 Changle West Road, Shaanxi Province, Xi'an 710032, China
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