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Yang HL, Kuo YT, Vudhya Gowrisankar Y, Lin KY, Hsu LS, Huang PJ, Lin HC, Hseu YC. The Leaf Extracts of Toona sinensis and Fermented Culture Broths of Antrodia camphorata Synergistically Cause Apoptotic Cell Death in Promyelocytic Leukemia Cells. Integr Cancer Ther 2020; 19:1534735420923734. [PMID: 32618215 PMCID: PMC7336824 DOI: 10.1177/1534735420923734] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Toona sinensis is a common edible vegetable that is used in
certain Chinese dishes and has importance in folk medicine. The leaf extracts of
T sinensis possess and exhibit anticancer efficacy against
various cancer cell types. In Taiwanese folklore, Antrodia
camphorata, also known as “Niu-Cheng-Zi,” is used in traditional
medicine to treat various illnesses. Its fruit and mycelium possess various
potent antiproliferative properties. Two studies from our group have reported
that T sinensis or A camphorata has the
ability to cause apoptosis in various cancer cells. Conversely, underlying
molecular mechanisms and any beneficial effects remain unknown. This study shows
anticancer efficacy for both T sinensis and A
camphorata co-treatments that target HL-60 cells. The combination
index values indicate that 40 µg/mL of T sinensis and 25 µg/mL
of A camphorata as a combined treatment shows a synergetic
effect, which reduces HL-60 cell proliferation. Alternately, this treatment
exhibited no cytotoxic effects for human umbilical vein endothelial cells.
Western blot data showed that T sinensis and A
camphorata as a combined treatment result in augmented expression
of apoptosis, cytochrome c release, Bcl-2 inhibition, expression of Bax, Fas,
and FasL, as well as the cleavage of Bid in HL-60 cells. Moreover, this combined
treatment overshadowed monotherapy in its ability to inhibit uPAR, MMP-9, MMP-2,
COX-2 expression, and PGE2 secretions. Our study strongly implies
that this combined treatment offers more beneficial effects to suppress and
treat leukemia due to apoptosis-mediated cell inhibition. Further in
vivo studies related to the combined treatment could establish its
future potential.
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Affiliation(s)
- Hsin-Ling Yang
- Department of Nutrition, China Medical University, Taichung, Taiwan
| | - Ya-Ting Kuo
- Department of Nutrition, China Medical University, Taichung, Taiwan
| | | | - Kai-Yuan Lin
- Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan
| | - Li-Sung Hsu
- Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
| | - Pei-Jane Huang
- Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan
| | - Hui-Chang Lin
- School of Pharmacy, China Medical University, Taichung, Taiwan
| | - You-Cheng Hseu
- Department of Cosmeceutics, School of Pharmacy, China Medical University, Taichung, Taiwan.,Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan.,Chinese Medicine Research Center, China Medical University, Taichung, Taiwan.,Research Center of Chinese Herbal Medicine, China Medical University, Taichung, Taiwan
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The role of bile acids in cellular invasiveness of gastric cancer. Cancer Cell Int 2018; 18:75. [PMID: 29942193 PMCID: PMC5963058 DOI: 10.1186/s12935-018-0569-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 05/08/2018] [Indexed: 12/23/2022] Open
Abstract
Background Bile acids have been implicated in the development of digestive tract malignancy by epidemiological, clinical and animal studies. The growth and transformation signaling by most of the bile acids is thought to be related to the induced cyclooxygenase-2 (COX-2) expression and increased production of prostaglandin E2 (PGE2). The highly hydrophobic bile acids such as chenodeoxycholic acid (CD) and deoxycholic acid can promote carcinogenesis and stimulate the invasion of colon cancer cells. On the contrary, ursodeoxycholic acid (UDCA), a less hydrophobic stereoisomer of CD, inhibits proliferation and induces apoptosis in colon cancer cells. We examined the effects of bile acid on human gastric cancer cells MKN-74. Methods Early-passage human gastric cancer MKN-74 cells were used for drug treatment, preparation of whole cell lysates, subcellular extracts and Western blot analysis. The levels of PGE2 released by the cells were measured by enzyme inummoassay to indicate COX-2 enzymatic activity. Cellular invasion assay was performed in Boyden chamber. Results Exposure of CD led to activation of protein kinase C (PKC) alpha, increased COX-2 expression and increased PGE2 synthesis. The induced COX-2 protein expression could be detected within 4 h exposure of 200 μM CD, and it was dose- and time-dependent. PGE2 is the product of COX-2, and has been reported to cause tumor invasion and angiogenesis in animal study. Safingol (SAF), a PKC inhibitor, suppressed the COX-2 protein expression and PGE2 production by CD in MKN-74. Furthermore, UDCA suppressed PGE2 production by CD but did not affect COX-2 protein expression induced by CD. Using a Boyden chamber invasion assay, both SAF and UDCA impeded CD induced tumor invasiveness of MKN-74 by 30–50%. Conclusions Our results indicate that signaling of hydrophobic bile acid such as CD in gastric cancer cells is through PKC activation and COX-2 induction, which leads to increased cellular invasion. By perturbing the bile acid pool, UDCA attenuates CD-induced PGE2 synthesis and tumor invasiveness.
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Eser F, Mutlu Altundag E, Gedik G, Demirtas I, Onal A, Selvi B. Anti-inflammatory effect of D-pinitol isolated from the leaves of Colutea cilicica Boiss et Bal. on K562 cells. ACTA ACUST UNITED AC 2017. [DOI: 10.1515/tjb-2016-0120] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
AbstractAim:D-pinitol, a natural compound has shown various biological and pharmacological effects. Last studies are focused on the determination of its further pharmacological activities including mainly biological activity. Therefore, isolation of D-pinitol from the leaves ofMaterials and methods:Isolation of D-pinitol was performed by column chromatography. Chemical structure of the compound was confirmed by spectroscopic methods includingResults:Stimulation of cells with D-pinitol (0–80 μM) was observed for 24, 48 and 72 h. It is determined that D-pinitol inhibited protein expression of Cox-2 in K562 cells. We observed that Poly (ADP-ribose) polymerase (PARP) protein expression did not change, but Cox-2 protein expression reduced with non-cytotoxic concentrations of D-pinitol.Conclusion:It is concluded that D-pinitol did not affect cell proliferation and apoptosis in K562 cells however reduced the inflammation, significantly. These results show that D-pinitol may be anti-inflammatory agent for the treatment of K562 cells.
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Chang CT, Hseu YC, Thiyagarajan V, Huang HC, Hsu LS, Huang PJ, Liu JY, Liao JW, Yang HL. Antrodia salmonea induces G 2 cell-cycle arrest in human triple-negative breast cancer (MDA-MB-231) cells and suppresses tumor growth in athymic nude mice. JOURNAL OF ETHNOPHARMACOLOGY 2017; 196:9-19. [PMID: 27986611 DOI: 10.1016/j.jep.2016.12.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 10/19/2016] [Accepted: 12/10/2016] [Indexed: 06/06/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Antrodia salmonea (AS), is a well-known folk medicinal mushroom in Taiwan, has been reported to exhibit anti-oxidant, anti-angiogenic, and anti-inflammatory effects. MATERIALS AND METHODS In the present study, we examined the effects of AS on cell-cycle arrest in vitro in MDA-MB-231 cells and on tumor regression in vivo using an athymic nude mice model. RESULTS AS (0-200μg/mL) treatment significantly induced G2 cell-cycle arrest in MDA-MB-231 cells by reducing the levels of cyclin B1, cyclin A, cyclin E, and CDC2 proteins. In addition, N-acetylcysteine (NAC) pretreatment prevented AS induced G2 cell-cycle arrest, indicating that ROS accumulation and subsequent cell cycle arrest might be a major mechanism of AS-induced cytotoxicity. Further, AS treatment decreased COX-2 expression and induced PARP cleavage was significantly reversed by NAC pretreatment in MDA-MB-231 cells. The in vivo study results revealed that AS treatment was effective in terms of delaying the tumor incidence and reducing the tumor growth in MDA-MB-231-xenografted nude mice. TUNEL assay, immunohistochemical staining and Western blotting confirmed that AS significantly modulated the xenografted tumor progression as demonstrated by induction of apoptosis, autophagy, and cell-cycle arrest. CONCLUSION Our data strongly suggest that Antrodia salmonea could be an anti-cancer agent for human breast cancer.
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Affiliation(s)
- Chia-Ting Chang
- Institute of Nutrition, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 40402, Taiwan
| | - You-Cheng Hseu
- Department of Cosmeceutics,Cosmeceutics, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 40402, Taiwan; Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan
| | - Varadharajan Thiyagarajan
- Department of Cosmeceutics,Cosmeceutics, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 40402, Taiwan
| | - Hui-Chi Huang
- School of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 40402, Taiwan
| | - Li-Sung Hsu
- Institute of Biochemistry and Biotechnology, Chung Shan Medical University, 40402 Taichung, Taiwan
| | - Pei-Jane Huang
- Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan
| | - Jer-Yuh Liu
- Graduate Institute of Cancer Biology, China Medical University, Taichung 40402, Taiwan
| | - Jiunn-Wang Liao
- Graduate Institute of Veterinary Pathology, National Chung Hsing University, Taichung 402, Taiwan
| | - Hsin-Ling Yang
- Institute of Nutrition, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 40402, Taiwan.
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Ali AM, El-Sayed MI. Metronomic chemotherapy and radiotherapy as salvage treatment in refractory or relapsed pediatric solid tumours. ACTA ACUST UNITED AC 2016; 23:e253-9. [PMID: 27330362 DOI: 10.3747/co.23.2873] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Metronomic chemotherapy (mctx) combined with radiation therapy (rt) is an emerging anticancer strategy. The aim of the present study was to assess the efficacy of mctx combined with rt as salvage treatment in children with refractory or relapsed solid malignancies. METHODS This prospective study enrolled patients with refractory or relapsed pediatric solid tumours from January 2013 to January 2015. Treatment consisted of 3-12 courses of mctx in all patients, followed by rt in patients who experienced local recurrence, distant metastases, or both. Each course of mctx consisted of oral celecoxib 100-400 mg twice daily (days 1-42), intravenous vinblastine 3 mg/m(2) weekly (weeks 1-6), oral cyclophosphamide 2.5 mg/m(2) daily (days 1-21), and oral methotrexate 15 mg/m(2) twice weekly (days 21-42). Statistical methods used were the log-rank test and binary logistic regression. RESULTS A favourable disease response (partial response or stable disease) was seen in 49 of 64 patients (76.6%), with mild acute toxicity occurring in 41 (64%). After a median follow-up of 14 months, 1-year overall survival was 62%. Pattern of disease relapse (p < 0.0001), time from initial treatment to relapse (p = 0.0002), and response to treatment (p < 0.0001) significantly affected survival. Age was the only factor that significantly correlated with treatment toxicity (p = 0.002; hazard ratio: 3.37; 95% confidence interval: 1.53 to 7.35). CONCLUSIONS Combining mctx with rt resulted in a favourable response rate, minimal toxicity, and 62% 1-year overall survival in patients with heavily pretreated recurrent disease. Patients with localized late recurrence or disease progression are the most likely to benefit from this regimen.
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Affiliation(s)
- A M Ali
- Department of Pediatric Oncology, South Egypt Cancer Institute, Assiut University, Egypt
| | - M I El-Sayed
- Department of Radiotherapy, South Egypt Cancer Institute, Assiut University, Egypt
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Norouzi S, Norouzi M, Amini M, Amanzadeh A, Nabiuni M, Irian S, Salimi M. Two COX-2 inhibitors induce apoptosis in human erythroleukemia K562cells by modulating NF-κB and FHC pathways. ACTA ACUST UNITED AC 2016; 24:1. [PMID: 26739353 PMCID: PMC4704250 DOI: 10.1186/s40199-015-0139-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 12/18/2015] [Indexed: 11/20/2022]
Abstract
Background Leukemia is distinguished by abnormal proliferation of leukocytes. Although there has been some progress in developing novel cancer therapies, no significant improvement was observed in the overall survival rate over the last decade. Selective cyclooxygenase-2 (COX-2) inhibitors are known to inhibit tumor growth by exerting antimetastatic and antiangiogenic effects through inhibition of COX –dependent and independent pathways. The ability of two new triaryl-oxadiazole derivatives, compounds A (3-(4-chlorophenyl) -5-(4-flurophenyl)-4-Phenyl-4,5-dihydro-1,2,4-oxadiazole) and B (3,5-bis(4-chlorophenyl)-4-Phenyl-4,5-dihydro-1,2,4-oxadiazole), to induce apoptosis in human erythroleukemia K562 cells was evaluated and the upstream mechanism was investigated. Methods K562 cells were treated with compounds A and B at their IC50 concentrations and analyzed by DAPI staining and Annexin-V-FLUOS labelling solution. Nuclear factor kappa-B (NF-κB) activation was evaluated by TransAM kit. Cyclooxygenase-2 (COX-2), Caspase-3, Bax, Bcl-2, ferritin heavy chain (FHC), extra cellular signal-regulated kinase (ERK), p-ERK and early growth response protein-1 (Egr1) levels were determined using Western blotting, while c-Myc mRNA level was investigated by RT-PCR. Results Changes in nuclear morphology and the increased annexin-V/PI staining revealed the apoptotic cell death in compounds A- and B-treated K562 cells. A significant reduction in NF-κB activity as well as FHC and p-ERK levels were detected in these cells. No change was observed in the levels of Bax, Bcl-2, Caspase-3, COX-2, c-Myc and Egr1, following treatment with the two compounds. Collectively, compounds A and B potentiate apoptosis as shown by DAPI staining, flowcytometry, FHC and p-ERK downregulation and NF-κB inactivation. Conclusion Two compounds induce apoptosis in a COX-2-independent manner which also appears to be independent from mitochondria, caspase and c-Myc/Egr1 pathways.
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Affiliation(s)
- Shaghayegh Norouzi
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, P.O. Box 1481765544, Tehran, Iran
| | - Mahnaz Norouzi
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, P.O. Box 1481765544, Tehran, Iran
| | - Mohsen Amini
- Department of Medicinal Chemistry, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Amanzadeh
- National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran
| | - Mohamad Nabiuni
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, P.O. Box 1481765544, Tehran, Iran
| | - Saeed Irian
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, P.O. Box 1481765544, Tehran, Iran.
| | - Mona Salimi
- Department of Physiology and Pharmacology, Pasteur Institute of Iran, P.O. Box 13164, Tehran, Iran.
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Kuo CC, Chen JJ, Tsai JY, Hsueh CT. Effects of Chinese herbal medicine in combination with mitomycin C on gastric cancer cells. Biomark Res 2014; 2:26. [PMID: 25553241 PMCID: PMC4280692 DOI: 10.1186/s40364-014-0026-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Accepted: 12/11/2014] [Indexed: 11/20/2022] Open
Abstract
Chinese herbal medicine (CHM) is frequently used by cancer patients in Chinese community. It remains largely unknown about the interaction between CHM and chemotherapeutic agents. Herein, we evaluated 3 commonly used CHM formulas for cancer patients: Bu-Zhong-Yi-Qi-Tang (BZYQT), Bao-Yuan-Tang (BYT), and Ju-Yuan-Jian (JYJ). We examined the effects of these 3 formulas in human gastric cancer cells MKN-74, in terms of cytotoxicity and apoptosis induction when used alone or in combination with mitomycin C (MMC). Cytotoxicity was determined by tetrazolium dye colorimetric assay. The 10% inhibitory concentration of CHM was used in this study. Cells were first exposed to CHM or phosphate buffered saline (as control) for 48 h. Then MMC at final concentration of 0.25 μg/ml was added to media for another 24-h. Among these 3 CHM formulas, BZYQT showed the most pronounced effect in augmenting MMC-induced cytotoxicity. The viability of MKN-74 cells was decreased to 43.1% when treated with BZYQT and MMC, compared to 94.9% with MMC alone. We subsequently examined apoptosis induction by quantitative florescent microscopy and single-strand DNA enzyme-linked immunosorbent assay, and found BZYQT did not enhance MMC-induced apoptosis. Our findings indicate BZYQT in combination with MMC induces cell death in gastric cancer cells via non-apoptotic mechanism. Our results provide a rationale for further investigation in the interaction of CHM and anti-cancer treatment.
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Affiliation(s)
- Che-Chang Kuo
- Department of Chinese Medicine, St. Joseph Hospital, Kaohsiung, Taiwan. School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung, Taiwan
| | - Jian-Jung Chen
- Department of Chinese Medicine, Taichung Tzu Chi General Hospital, Taichung, Taiwan
| | - James Y Tsai
- Division of Medical Oncology and Hematology, Loma Linda University, Loma Linda, California USA
| | - Chung-Tsen Hsueh
- Division of Medical Oncology and Hematology, Loma Linda University, Loma Linda, California USA
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Metronomic chemotherapy in progressive pediatric malignancies: old drugs in new package. Indian J Pediatr 2012; 79:1617-22. [PMID: 22544675 DOI: 10.1007/s12098-012-0759-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2012] [Accepted: 04/04/2012] [Indexed: 02/04/2023]
Abstract
Despite intensive research in the field of cancer, many pediatric cancers are still incurable with current treatment protocols. Repetitive administration of conventional chemotherapy at maximal tolerated dose imposes many side effects that further limits the dosing and therefore decreases the anticancer effects. Usually limited options remain when a malignancy progresses after one or two lines of standard chemotherapy protocol. The goal of an oncologist at this point of time remains mainly palliative with an effort to halt the progression of cancer and improve quality of life. Metronomic chemotherapy is defined as the chronic administration of chemotherapeutic agents at relatively low, minimally toxic doses, and with no prolonged drug-free breaks. It is thought this type of chemotherapy inhibits tumor growth primarily through anti-angiogenic mechanisms, promoting apoptosis and immune- surveillance.
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Liu B, Wen JK, Li BH, Fang XM, Wang JJ, Zhang YP, Shi CJ, Zhang DQ, Han M. Celecoxib and acetylbritannilactone interact synergistically to suppress breast cancer cell growth via COX-2-dependent and -independent mechanisms. Cell Death Dis 2011; 2:e185. [PMID: 21796157 PMCID: PMC3199716 DOI: 10.1038/cddis.2011.64] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The use of celecoxib is associated with a significant decrease in breast cancer risk. However, the long-term use of high-dose celecoxib might be limited owing to cardiovascular side effects. In this study, we found that acetylbritannilactone (ABL), extract from a Chinese medicinal herb, could reduce celecoxib dose and potentiate the growth-inhibitory effect in breast cancer cells. ABL enhanced the apoptotic effect of celecoxib in COX-2-expressing cells, but had little effect in COX-2-negative cells. The apoptosis induced by the combination treatment disappeared when COX-2 was knocked down, whereas the lack of apoptotic effects in COX-2-negative cells was reversed after COX-2 transfection. However, the combination treatment induced a G(0)/G(1) phase arrest independent of whether or not the cells expressed COX-2. The G(0)/G(1) arrest was attributed to a decreased expression of cyclinD1, cyclinE, CDK2 and CDK6, especially the upregulation of p21. In addition, inhibition of Akt and p38 signaling pathways was required by the synergism, as the constitutively active Akt and p38 protected cells against apoptosis and cell cycle arrest induced by the combination treatment. In vivo, administration of celecoxib and ABL were more effective than the individual agents against xenograft tumor growth. Thus, our data suggested that the combinatorial approach of celecoxib and ABL might be helpful for breast cancer treatment.
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Affiliation(s)
- B Liu
- Department of Biochemistry and Molecular Biology, Institute of Basic Medicine, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, PR China
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Zhu FS, Chen XM, Huang ZG, Wang ZR, Zhang DW, Zhang X. Rofecoxib augments anticancer effects by reversing intrinsic multidrug resistance gene expression in BGC-823 gastric cancer cells. J Dig Dis 2010; 11:34-42. [PMID: 20132429 DOI: 10.1111/j.1751-2980.2009.00411.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To investigate combined chemotherapeutic effects of rofecoxib in combination with 5-fluorouracil (5-FU), cisplatin (DDP) and etoposide (VP-16) in vitro, and to explore the potential mechanisms in modulating multidrug resistance (MDR) expression. METHODS The BGC-823 gastric cancer cell line was incubated for 48 h with 0.1 micromol/L rofecoxib, 5-FU, DDP and VP-16 (1 microg/mL, 10 microg/mL and 100 microg/mL) alone, and combined with rofecoxib, respectively. Methyl-thiazolyl-tetrazolium and the terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-yriphosphate nick-end labeling assays were performed to calculate inhibitory rates and apoptotic index. Middle effects principles (CI values) were used to determine the interaction between rofecoxib and chemotherapeutic agents. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis were employed to determine expression of MDR1, multidrug resistance-associated protein 1 (MRP1), glutathione S-tranferase-pi (GST-pi) mRNA and protein in gastric cancer cells administered by rofecoxib, respectively. RESULTS Both anticancer drugs such as 5-FU, DDP and VP-16 and rofecoxib inhibited the cells' proliferation and induced apoptosis in a dose-dependent manner, and a more significant inhibition was achieved when the cells were co-treated with anticancer drugs and rofecoxib. There was a synergetic role when different concentrations of chemotherapeutic agents were combined with rofecoxib (all CI < 1, P < 0.01 or 0.05). RT-PCR analyses of MDR gene families in BGC-823 gastric cancer cells revealed a strong expression in MRP1 and GST-pi mRNA, but MDR1 mRNA was undetectable. After administration with different concentrations of rofecoxib (0.1, 1.0, 10 micromol/L), significant downregulation of MRP1 and GST-pi mRNA was observed (MRP1: from 0.984 +/- 0.093-0.513 +/- 0.098; GST-pi: from 1.078 +/- 0.201-0.472 +/- 0.084, P < 0.01 or 0.05). In addition, MRP1 and GST-pi protein expression induced by rofecoxib were also reduced (P < 0.01 or 0.05). CONCLUSION Rofecoxib, a specific cyclooxygenase-2 inhibitor, plays a chemotherapeutic sensitizer role in various anticancer agents on the BGC-823 gastric cancer cell line, which could be partly explained by its ability to reverse the intrinsic MRP1 and GST-piin vitro.
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Affiliation(s)
- Feng Shang Zhu
- Department of Gastroenterology, Tongji Hospital, Digestive Disease Institute of Tongji University, Shanghai, China
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Antiangiogenic and anticolorectal cancer effects of metronomic irinotecan chemotherapy alone and in combination with semaxinib. Br J Cancer 2008; 98:1619-29. [PMID: 18443598 PMCID: PMC2391121 DOI: 10.1038/sj.bjc.6604352] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Metronomic chemotherapy refers to the administration of chemotherapy at low, nontoxic doses on a frequent schedule with no prolonged breaks. The aim of the study is to rationally develop a CPT-11 metronomic regimen in preclinical settings of colon cancer. In vitro cell proliferation, apoptosis and thrombospondin-1/vascular endothelial growth factor (TSP-1/VEGF) expression analyses were performed on endothelial (HUVEC, HMVEC-d) and colorectal cancer (HT-29, SW620) cells exposed for 144 h to metronomic concentrations of SN-38, the active metabolite of CPT-11. HT-29 human colorectal cancer xenograft model was used, and tumour growth, microvessel density and VEGF/TSP-1 quantification was performed in tumours. In vitro and in vivo combination studies with the tyrosine inhibitor semaxinib were also performed. SN-38 preferentially inhibited endothelial cell proliferation alone and interacted synergistically with semaxinib; it induced apoptosis and increased the expression and secretion of TSP-1. Metronomic CPT-11 alone and combined with semaxinib significantly inhibits tumour growth in the absence of toxicity, which was accompanied by decreases in microvessel density and increases in TSP-1 gene expression in tumour tissues. In vitro results show the antiangiogenic properties of low-concentration SN-38, suggesting a key role of TSP-1 in this effect. In vivo, the CPT-11 metronomic schedule is effective against tumour and microvessel growth without toxic effect on mice.
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Bocci G, Culler MD, Fioravanti A, Orlandi P, Fasciani A, Colucci R, Taylor JE, Sadat D, Danesi R, Del Tacca M. In vitro antiangiogenic activity of selective somatostatin subtype-1 receptor agonists. Eur J Clin Invest 2007; 37:700-8. [PMID: 17696959 DOI: 10.1111/j.1365-2362.2007.01848.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND Endothelial cells of human blood vessels (arteries and veins) show high levels of somatostatin subtype-1 receptor (sst(1)). The aim of the present study is to investigate the inhibitory effects of novel somatostatin analogs, highly selective for human sst(1), on in vitro angiogenesis and their modulation of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2) expression. MATERIALS AND METHODS Somatostatin analogs BIM-23745 and BIM-23926 were tested for their ability to prevent proliferation and migration of human endothelial HMEC-1 cells, to modulate VEGF and VEGFR-2 expression and to inhibit sprouting of microvessels from cultured human placental vessel explants in fibrin matrix for 28 days. RESULTS The somatostatin sst(1 )receptor-selective agonists, BIM-23745 and BIM-23926 showed a suppression of endothelial proliferation (e.g. 10(-6) M BIM-23475, 40.0 +/- 2.1% vs. 100% of controls; 10(-7) M BIM-23926, 55.3 +/- 3.3% vs. 100% of controls), migration (e.g. 10(-7) M BIM-23475, 35.0 +/- 1.56% vs. 100% of controls; 10(-7) M BIM-23926, 53.7 +/- 1.77% vs. 100% of controls) and microvessel sprouting (e.g. 10(-8) M BIM-23475, 42.8 +/- 5.6% vs. 100% of controls; 10(-7) M BIM-23926, 17.2 +/- 11.8% vs. 100% of controls). A small but significant percentage of cells exposed to BIM-23745 and BIM-23926 for 24 h and for 72 h presented typical apoptotic morphology. Moreover, both the analogs significantly inhibit VEGF and VEGFR-2 gene expression in endothelial cells grown for 144 h in a fibrin matrix and the VEGF secretion in conditioned media. CONCLUSIONS The inhibition of endothelial activities suggests potential therapeutic utility for administration of somatostatin sst(1 )receptor-selective agonists in the proliferative diseases involving angiogenesis.
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Affiliation(s)
- G Bocci
- University of Pisa, Pisa, Italy.
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Jeong HG, Pokharel YR, Han EH, Kang KW. Induction of cyclooxygenase-2 by ginsenoside Rd via activation of CCAAT-enhancer binding proteins and cyclic AMP response binding protein. Biochem Biophys Res Commun 2007; 359:51-6. [PMID: 17524357 DOI: 10.1016/j.bbrc.2007.05.034] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2007] [Accepted: 05/05/2007] [Indexed: 12/27/2022]
Abstract
Panax ginseng is a widely used herbal medicine in East Asia and is reported to have a variety of pharmacological effects against cardiovascular diseases and cancers. Here we show a unique effect of ginsenoside Rd (Rd) on cyclooxygenase-2 (COX-2) expression in RAW264.7 macrophages. Rd (100 microg/ml), but not other ginsenosides induced COX-2 and increased prostaglandin E(2) production. Gel shift and Western blot analyses using nuclear fractions revealed that Rd increased both the DNA binding of and the nuclear levels of CCAAT/enhancer binding protein (C/EBP)alpha/beta and cyclic AMP response element binding protein (CREB), but not of p65, in RAW264.7 cells. Moreover, Rd increased the luciferase reporter gene activity in cells transfected with a 574-bp mouse COX-2 promoter construct. Site-specific mutation analyses confirmed that Rd-mediated transcriptional activation of COX-2 gene was regulated by C/EBP and CREB. These results provide evidence that Rd activated C/EBP and CREB, and that the activation of C/EBP and CREB appears to be essential for induction of COX-2 in RAW264.7 cells.
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Affiliation(s)
- Hye Gwang Jeong
- BK21 Project Team, College of Pharmacy, Chosun University, Seosuk-dong, Dong-gu, Gwangju 501-759, South Korea
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14
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15
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Hseu YC, Chen SC, Tsai PC, Chen CS, Lu FJ, Chang NW, Yang HL. Inhibition of cyclooxygenase-2 and induction of apoptosis in estrogen-nonresponsive breast cancer cells by Antrodia camphorata. Food Chem Toxicol 2006; 45:1107-15. [PMID: 17391824 DOI: 10.1016/j.fct.2006.12.012] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2006] [Revised: 12/06/2006] [Accepted: 12/12/2006] [Indexed: 01/16/2023]
Abstract
The objective of this study was to investigate the fermented culture broth of Antrodia camphorata (A. camphorata) to induce apoptosis and inhibit cyclooxygenase-2 (COX-2) in estrogen-nonresponsive (MDA-MB-231) human breast cancer cells. Treatment of the highly invasive MDA-MB-231 cells with A. camphorata (40-240 microg/ml) resulted in dose and time-dependent sequences of events marked by apoptosis, as evidenced by loss of cell viability, chromatin condensation, and internucleosomal DNA fragmentation. Apoptosis in the MDA-MB-231 cells was accompanied by release of cytochrome c, activation of caspase-3, -8, and -9, and specific proteolytic cleavage of poly (ADP-ribose) polymerase (PARP). Although the A. camphorata-induced apoptosis was associated with a reduction in Bcl-2 protein levels, negligible Bax increase was observed. Furthermore, A. camphorata treatment inhibited COX-2 protein expression and prostaglandin E2 (PGE2) production in MDA-MB-231 cells. Analysis of the study data suggests that A. camphorata exerts growth inhibition on (highly invasive) estrogen-nonresponsive human breast cancer cells through apoptosis induction associated with COX-2 inhibition, and that it may possess anticancer properties potentially valuable for application in drug products.
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Affiliation(s)
- You-Cheng Hseu
- Department of Cosmeceutics, China Medical University, Taichung, Taiwan
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16
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Martin S, Phillips DC, Szekely-Szucs K, Elghazi L, Desmots F, Houghton JA. Cyclooxygenase-2 inhibition sensitizes human colon carcinoma cells to TRAIL-induced apoptosis through clustering of DR5 and concentrating death-inducing signaling complex components into ceramide-enriched caveolae. Cancer Res 2006; 65:11447-58. [PMID: 16357153 DOI: 10.1158/0008-5472.can-05-1494] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Cyclooxygenase-2 (COX-2) is up-regulated in human colon carcinomas, and its inhibition is associated with a reduction in tumorigenesis and a promotion of apoptosis. However, the mechanisms responsible for the antitumor effects of COX-2 inhibitors and how COX-2 modulates apoptotic signaling have not been clearly defined. We have shown that COX-2 inhibition sensitizes human colon carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by inducing clustering of the TRAIL receptor DR5 at the cell surface and the redistribution of the death-inducing signaling complex components (DR5, FADD, and procaspase-8) into cholesterol-rich and ceramide-rich domains known as caveolae. This process requires the accumulation of arachidonic acid and sequential activation of acid sphingomyelinase for the generation of ceramide within the plasma membrane outer leaflet. The current study highlights a novel mechanism to circumvent colorectal carcinoma cell resistance to TRAIL-mediated apoptosis using COX-2 inhibitors to manipulate the lipid metabolism within the plasma membrane.
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Affiliation(s)
- Sophie Martin
- Division of Molecular Therapeutics, Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
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17
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Uchida K, Schneider S, Yochim JM, Kuramochi H, Hayashi K, Takasaki K, Yang D, Danenberg KD, Danenberg PV. Intratumoral COX-2 gene expression is a predictive factor for colorectal cancer response to fluoropyrimidine-based chemotherapy. Clin Cancer Res 2005; 11:3363-8. [PMID: 15867236 DOI: 10.1158/1078-0432.ccr-04-1650] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Cyclooxygenase-2 (COX-2) is generally elevated in tumors compared with normal tissue and apparently has an important role in tumor development. A number of studies have found high expression of COX-2 to be an unfavorable prognostic factor for overall survival in several cancers. However, the influence of COX-2 expression levels on tumor response to chemotherapy has been relatively little studied. The purpose of this study was to ascertain if COX-2 gene expression is associated with tumor response in the clinical treatment of colorectal cancer with the fluoropyrimidine-based therapy S-1. EXPERIMENTAL DESIGN Patients with advanced (stage IV) colorectal cancer were treated with S-1 twice daily based on the patient's body surface area (BSA; BSA < 1.25 m2, 80 mg/d; 1.25 m2 < or = BSA < 1.5 m2, 100 mg/d; BSA > or = 1.5 m2, 120 mg/d) for 28 days followed by a 2-week period rest. mRNA was isolated from paraffin-embedded pretreatment primary tumor specimens and expression levels of COX-2 relative to beta-actin as the internal reference gene were measured using a quantitative reverse transcription-PCR (Taqman) system. RESULTS The overall response rate in a group of 44 patients treated with S-1 was 40.9%. Sufficient tumor tissue was available from 40 of these patients for COX-2 mRNA quantitation. COX-2 gene expression was significantly lower in the responding tumors compared with the nonresponders (P = 0.012, Wilcoxon test). Patients with COX-2 values above the cutoff value of 3.28 x 10(-3) had a significantly shorter survival than those with COX-2 gene expressions below the cutoff value (adjusted P = 0.031). CONCLUSIONS Intratumoral COX-2 gene expression is associated with likelihood of response to chemotherapy with S-1 and is a prognostic factor for survival of patients after the start of S-1 chemotherapy.
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Affiliation(s)
- Kazumi Uchida
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
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18
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Ma L, Xie YL, Yu Y, Zhang QN. Apoptosis of human gastric cancer SGC-7901 cells induced by mitomycin combined with sulindac. World J Gastroenterol 2005; 11:1829-32. [PMID: 15793875 PMCID: PMC4305885 DOI: 10.3748/wjg.v11.i12.1829] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of mitomycin (MMC) combined with sulindac on cell viability, apoptotic induction and expression of apoptosis-related gene Bcl-2 and cyclooxygenase-2 (COX-2) in gastric cancer SGC-7901 cells.
METHODS: Human gastric cancer SGC-7901 cells were divided into three treatment groups,namely sulindac treatment group, MMC treatment group and combined sulindac with MMC treatment group. After being treated with drugs, cell viability was examined by MTT assay. Flow cytometry was used to evaluate the cell cycle distribution and apoptotic rates. Morphology of the cells was observed under light microscope and interactive laser microscope. Expression of COX-2 and Bcl-2 was determined by immunocytochemical method.
RESULTS: After exposure for 12 h to three kinds of drugs, gastric cancer SGC-7901 cells presented some morphological features of apoptosis, including cell shrinkage, nuclear condensation, DNA fragmentation and formation of apoptotic bodies. Growth inhibition was more obvious in combined sulindac with MMC treatment group and sulindac treatment group than in MMC treatment group. The apoptotic rates in co-treated cells and MMC-treated cells 24 h after treatment were 12.0% and 7.2%, respectively. After exposure for 24 h to MMC, the expression of COX-2 and Bcl-2 protein was up-regulated, COX-2 levels were down-regulated but Bcl-2 gene expression was not changed significantly in combined treatment group.
CONCLUSION: MMC-induced apoptosis is reduced by up-regulating the expression of COX-2 and Bcl-2 genes. MMC combined with sulindac can suppress the growth of gastric cancer cells through induction of apoptosis mediated by down-regulation of apoptosis-related Bcl-2 and COX-2 gene.
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Affiliation(s)
- Li Ma
- Department of Gastroenterology, Second Affiliated Hospital, Lanzhou Medical University, Lanzhou 730000, Gansu Province, China.
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19
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Yim HW, Jong HS, Kim TY, Choi HH, Kim SG, Song SH, Kim J, Ko SG, Lee JW, Kim TY, Bang YJ. Cyclooxygenase-2 inhibits novel ginseng metabolite-mediated apoptosis. Cancer Res 2005; 65:1952-1960. [PMID: 15753395 DOI: 10.1158/0008-5472.can-04-1740] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Recently, a novel intestinal bacterial metabolite of ginseng protopanaxadiol saponins, i.e., 20-O-(beta-D-glucopyranosyl)-20(S)-protopanaxadiol (IH-901), has been reported to induce apoptosis in a variety of cancer cells. Here we show a differential effect of IH-901 on several cell types. Exposure to IH-901 for 48 hours at a supposedly subapoptotic concentration of 40 mumol/L led to both apoptotic cell death and G1 arrest in Hep3B cells, but only resulted in G1 arrest in MDA-MB-231, Hs578T, and MKN28 cells. Additionally, the treatment of MDA-MB-231, but not of Hep3B, with IH-901 up-regulated cyclooxygenase-2 (COX-2) mRNA (2 hours) and protein (6 hours), and enhanced the production of prostaglandin E2. In MDA-MB-231 cells, IH-901 induced the sustained activation of extracellular signal-regulated kinase (ERK), whereas inhibition of mitogen-activated protein/ERK kinase blocked IH-901-mediated COX-2 induction and resulted in apoptosis, suggesting the involvement of an ERK-COX-2 pathway. Combined treatment with IH-901 and nonsteroidal anti-inflammatory drugs inhibited COX-2 enzyme and induced apoptosis in MDA-MB-231 and Hs578T cells. Adenovirus-mediated COX-2 small interfering RNAs also effectively inhibited COX-2 protein expression and enhanced IH-901-mediated apoptosis without inhibiting ERK 1/2 phosphorylation, thus providing direct evidence that COX-2 is an antiapoptotic molecule. Moreover, IH-901-mediated G1 arrest resulted from an increase in p27Kip1 mRNA and protein expression followed by a decrease in CDK2 kinase activity that was concurrent with the hypophosphorylation of Rb and p130. In conclusion, IH-901 induced both G1 arrest and apoptosis, and this apoptosis could be inhibited by COX-2 induction.
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Affiliation(s)
- Hyung Woo Yim
- National Research Laboratory for Cancer Epigenetics, Cancer Research Institute and Department of Internal Medicine, Seoul National University College of Medicine, Chongno, Seoul, Republic of Korea
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20
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Xiong B, Sun TJ, Hu WD, Cheng FL, Mao M, Zhou YF. Expression of cyclooxygenase-2 in colorectal cancer and its clinical significance. World J Gastroenterol 2005; 11:1105-8. [PMID: 15754389 PMCID: PMC4250698 DOI: 10.3748/wjg.v11.i8.1105] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To clarify the clinicopathologic significance of COX-2 expression in human colorectal cancer.
METHODS: A total of 128 surgically resected colorectal cancer specimens were immunohistochemically analyzed with the use of anti-COX-2, anti-VEGF and anti-MMP-2 antibodies. The relationship between the cyclooxygenase-2 expression in primary lesions of colorectal cancer and clinicopathologic parameters was evaluated by chi-square test.
RESULTS: Among 128 cases of colorectal cancer, 87 (67.9%) were positive for cyclooxygenase-2. The expression of cyclooxygenase-2 was significantly correlated with the depth of invasion, stage of disease, and metastasis (lymph node and liver). Patients in T3-T4, stages III-IV and with metastasis had much higher expression of cyclooxygenase-2 than ones in T1-T2, stages I-II and without metastasis (P<0.05). Among 45 cases of colorectal cancer with lymph node metastasis, the COX-2- positive rate was 86.7% (39/45) for primary lesions and diffuse cytoplasmic staining for COX-2 protein was detected in cancer cells in 100% of metastatic lesions of the lymph nodes. VEGF expression was detected in 49 tumors (38.3%), and VEGF expression was closely correlated with COX-2 expression. The positive expression rate of VEGF (81.6%) in the cyclooxygenase-2-positive group was higher than that in the cyclooxygenase-2- negative group (18.4%, P<0.05). MMP-2 expression was detected in 88 tumors (68.8%), and MMP-2 expression was closely correlated with COX-2 expression. The positive expression rate of MMP-2 (79.6%) in the positive COX-2 group was higher than that in the negative COX-2 group (20.4%, P<0.05).
CONCLUSION: Cyclooxygenase-2 may be associated with tumor progression by modulating the angiogenesis and cancer cell motility and invasive potential in colorectal cancer and it can be used as a possible biomarker.
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Affiliation(s)
- Bin Xiong
- Affiliated Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China.
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Riedl K, Krysan K, Põld M, Dalwadi H, Heuze-Vourc'h N, Dohadwala M, Liu M, Cui X, Figlin R, Mao JT, Strieter R, Sharma S, Dubinett SM. Multifaceted roles of cyclooxygenase-2 in lung cancer. Drug Resist Updat 2004; 7:169-84. [PMID: 15296859 DOI: 10.1016/j.drup.2004.04.003] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2004] [Revised: 04/13/2004] [Accepted: 04/14/2004] [Indexed: 01/02/2023]
Abstract
Lung cancer is the leading cause of cancer death in the United States. Although the low 5-year survival rate (under 15%) has changed minimally in the last 25 years, new agents and combinations of agents that target tumor proliferation, invasion, and survival may lead to improvement in patient outcomes. There is evidence that cyclooxygenase-2 (COX-2) is overexpressed in lung cancer and promotes tumor proliferation, invasion, angiogenesis, and resistance to apoptosis. COX-2 inhibitors have been found to inhibit tumor growth in animal models and have demonstrated responses when combined with conventional therapy in phase II clinical trials. Further understanding of the mechanisms involved in COX-2-mediated tumorigenesis and its interaction with other molecules in lung cancer may lead to improved therapeutic strategies for this disease. In addition, delineation of how COX-2-dependent genes modulate the malignant phenotype will provide novel insights in lung cancer pathogenesis.
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Affiliation(s)
- Karen Riedl
- UCLA Lung Cancer Research Program, Department of Medicine, 37-131 CHS, David Geffen School of Medicine at UCLA, 10833 LeConte Avenue, Los Angeles, CA 90095-1690, USA
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22
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Affiliation(s)
- Charles Blanke
- Oregon Health Science University, 3181 Southwest Sam Jackson Park Rd., Portland, OR 97201, USA.
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23
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Giovannetti E, Mey V, Danesi R, Mosca I, Del Tacca M. Synergistic cytotoxicity and pharmacogenetics of gemcitabine and pemetrexed combination in pancreatic cancer cell lines. Clin Cancer Res 2004; 10:2936-2943. [PMID: 15131028 DOI: 10.1158/1078-0432.ccr-03-0520] [Citation(s) in RCA: 79] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Gemcitabine is an inhibitor of ribonucleotide reductase (RR) and DNA synthesis and is an effective agent in the treatment of pancreas cancer. The present study investigates whether the multitargeted antifolate pemetrexed would be synergistic with gemcitabine against MIA PaCa-2, PANC-1, and Capan-1 pancreatic cancer cell lines. EXPERIMENTAL DESIGN Cells were treated with gemcitabine and pemetrexed, and the type of drug interaction was assessed using the combination index. Cytotoxicity of gemcitabine was examined with inhibitors of (a) deoxycytidine kinase (dCK), which activates gemcitabine by phosphorylation, and (b) 5'-nucleotidase (drug dephosphorylation) and cytidine deaminase (drug deamination), the main inactivating enzymes. The effects of gemcitabine and pemetrexed on cell cycle were analyzed by flow cytometry, and apoptosis was examined by fluorescence microscopy. Finally, quantitative, real-time PCR was used to study the pharmacogenetics of the drug combination. RESULTS Synergistic cytotoxicity and enhancement of apoptosis was demonstrated, mostly with the sequence pemetrexed-->gemcitabine. Pemetrexed increased cells in S phase, the most sensitive to gemcitabine, and a positive correlation was found between the expression ratio of dCK:RR and gemcitabine sensitivity. Indeed, pemetrexed significantly enhanced dCK gene expression (+227.9, +86.0, and +135.5% in MIA PaCa-2, PANC-1, and Capan-1 cells, respectively), and the crucial role of this enzyme was confirmed by impairment of gemcitabine cytotoxicity after dCK saturation with 2'-deoxycytidine. CONCLUSIONS These data demonstrate that the gemcitabine and pemetrexed combination displays schedule-dependent synergistic cytotoxic activity, favorably modulates cell cycle, induces apoptosis, and enhances dCK expression in pancreatic cancer cells.
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Affiliation(s)
- Elisa Giovannetti
- Division of Pharmacology and Chemotherapy, Department of Oncology, Transplants and Advanced Technologies in Medicine, Pisa, Italy
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24
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Johnson CR, Chun J, Bittman R, Jarvis WD. Intrinsic cytotoxicity and chemomodulatory actions of novel phenethylisothiocyanate sphingoid base derivatives in HL-60 human promyelocytic leukemia cells. J Pharmacol Exp Ther 2004; 309:452-61. [PMID: 14724218 DOI: 10.1124/jpet.103.060665] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The protein kinase C (PKC) isoenzyme superfamily represents a popular target in pharmacological interventions designed to elicit apoptosis directly in tumor cells or to potentiate the lethal effects of antineoplastic agents. Numerous observations support the clinical utility of PKC inhibition by experimental sphingolipid derivatives such as safingol. The present studies document the cytotoxicity and chemomodulatory capacity of phenethylisothiocyanate derivatives of sphinganine and sphingosine (PEITC-Sa and PEITC-So) in the human myeloid leukemia cell line HL-60. The biological actions of these novel derivatives were compared directly with those of the parent compounds sphinganine and sphingosine. Exposure to natural and modified sphingoid bases promoted extensive apoptotic cell death. The PEITC-sphingoid base derivatives exhibited higher cytotoxicity than their natural counterparts and were also distinctly superior to the clinically relevant sphingoid base analog safingol. In each instance, lethality was shown to correlate with inhibition of conventional and novel PKC isoforms and downstream loss of extracellular signal-regulated kinase (ERK)1/ERK2. The involvement of these signaling systems in potentiating the lethal actions of 1-(beta-D-arabinofuranosyl)cytosine (araC) was also examined with regard to the differential actions of PEITC-Sa and PEITC-So to that of the parent compounds as well as safingol. Exposure to araC alone rapidly increased PKC activity. In the presence of PEITC-Sa or PEITC-So, the therapeutic efficacy of araC increased markedly; moreover, potentiation was directly related to the loss of araC-stimulated PKC activity. These findings demonstrate that PEITC-substituted sphingoid base analogs exert potent antineoplastic effects in human leukemia cells. We suggest that these synthetic lipids represent potentially useful agents in the development of conventional PKC/novel PKC-directed chemotherapeutic strategies.
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Affiliation(s)
- Charlene R Johnson
- Department of Integrative Biology and Pharmacology, University of Texas Health Sciences Center, Houston, USA
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25
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Xie YL, Ma L. Apoptosis induced by mitomycin with sulindac on human gastric cancer cell SGC7901. Shijie Huaren Xiaohua Zazhi 2004; 12:542-545. [DOI: 10.11569/wcjd.v12.i3.542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of mitomycin (MMC) with sulindac on the cell viability, apoptotic induction and expression of apoptosis-related gene Bcl-2 and cyclooxygenase-2 (COX-2) in gastric adenocarcinoma cell SGC7901.
METHODS: Human gastric cancer SGC7901 cells were divided into three groups, sulindac, MMC and sulindac with MMC. After treatment with drugs, cell viability was examined by MTT assay. Flow cytometry was used for the cell cycle distribution and apoptotic rates. The morphology of the cells was observed under light microscope and interactive laser cytometer. The expression of COX-2, Bcl-2 was determined by the immunocytochemical method.
RESULTS: After exposure for 12 h to three kinds of drugs, gastric cancer cells SGC7901 presented some morphologic features of apoptosis, including cell shrinkage, nuclear condensation, DNA fragmentation, formation of apoptotic bodies. The effects of growth inhibition were more obvious in cotreatment group with MMC and sulindac than MMC group. The apoptotic rates in cotreated cells and MMC-treated cells at 24 h after treatment were 12.0% and 7.2%, respectively. After exposure for 24 h to MMC, upregulation of COX-2 and Bcl-2 protein expression was noted, meanwhile, in cotreatment group, the levels of COX-2 were downregulated but the expression of Bcl-2 gene was not changed significantly.
CONCLUSION: MMC-induced apoptosis is reduced by upregulating the expression of COX-2 and Bcl-2 genes. MMC combined with sulindac can suppress growth of gastric cancer cells through induction of apoptosis which may be mediated by downregulation of apoptosis-related Bcl-2 gene and COX-2 gene.
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26
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Nakata E, Mason KA, Hunter N, Husain A, Raju U, Liao Z, Ang KK, Milas L. Potentiation of tumor response to radiation or chemoradiation by selective cyclooxygenase-2 enzyme inhibitors. Int J Radiat Oncol Biol Phys 2004; 58:369-75. [PMID: 14751505 DOI: 10.1016/j.ijrobp.2003.09.061] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Cyclooxygenase-2 (COX-2) is an enzyme expressed primarily in pathologic states, such as inflammatory disorders and cancer, where it mediates prostaglandin production. Its overexpression is associated with more aggressive biologic tumor behavior and adverse patient outcome. Increasing evidence shows that agents that selectively inhibit COX-2 enhance tumor response to radiation or chemotherapeutic agents. This article gives an overview of some of this evidence. In addition, we describe new results showing that celecoxib, a selective COX-2 inhibitor, enhanced response of A431 human tumor xenografts in nude mice to radiation by an enhancement factor (EF) of 1.43 and to the chemotherapeutic agent docetaxel by an EF of 2.07. Celecoxib also enhanced tumor response when added to the combined docetaxel plus radiation treatment (EF = 2.13). Further experiments showed that selective COX-2 inhibitors enhanced tumor cell sensitivity to ionizing radiation, involving inhibition of cellular repair from radiation damage and cell cycle redistribution as mechanisms for some cell types. The results show that selective COX-2 inhibitors have the potential to improve tumor radiotherapy or radiochemotherapy, and this therapeutic strategy is currently under clinical testing.
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Affiliation(s)
- Eiko Nakata
- Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA
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27
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Lahn M, Paterson BM, Sundell K, Ma D. The role of protein kinase C-alpha (PKC-alpha) in malignancies of the gastrointestinal tract. Eur J Cancer 2004; 40:10-20. [PMID: 14687784 DOI: 10.1016/j.ejca.2003.08.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Drugs specifically designed to block cellular signalling proteins are currently evaluated as a new way to treat gastrointestinal tumours. One such "new targeted agent" is aprinocarsen, an antisense oligonucleotide that specifically blocks the mRNA of protein kinase C-alpha (PKC-alpha). Blocking PKC-alpha, an important cellular signalling molecule associated with tumour growth, is anticipated to result in tumour cell arrest and achieve clinical benefits. However, it is not known which patients may benefit most from a specific inhibition of PKC-alpha. Past experience with other novel targeted agents suggests that expression of the target molecule is an important factor for the success of such a specific therapy. Therefore, reviewing the specific role of PKC-alpha in various gastrointestinal tumours may contribute to focus the clinical development of selective or specific PKC-alpha inhibitors, such as aprinocarsen, on those patients with a distinctive PKC-alpha expression pattern.
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Affiliation(s)
- M Lahn
- Divison of Oncology Product Development, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
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28
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Gasparini G, Longo R, Sarmiento R, Morabito A. Inhibitors of cyclo-oxygenase 2: a new class of anticancer agents? Lancet Oncol 2003; 4:605-15. [PMID: 14554238 DOI: 10.1016/s1470-2045(03)01220-8] [Citation(s) in RCA: 275] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Experimental studies have shown that cyclo-oxygenase 2 (COX2) is involved in tumour development and progression. Selective inhibitors of COX2 (coxibs) block tumour growth through many mechanisms, especially by antiangiogenic and proapoptotic effects. In experimental models, coxibs potentiate the activity of cytotoxic agents, hormones, and radiotherapy. Large clinical studies have shown chemopreventive activity of coxibs in colorectal cancer. The findings of preclinical studies coupled with the overexpression of COX2 observed in advanced human tumours are the basis for new therapeutic anticancer strategies based on combinations of coxibs with other anticancer treatment modalities. Early clinical studies have documented the feasibility, good tolerability, and promising activity of coxibs combined with chemotherapy in patients with advanced colorectal and non-small-cell lung cancers. Here, we describe the recent findings on the antitumour effects of coxibs with particular focus on the opportunities that have emerged for treatment of cancer.
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Liao Z, Milas L, Komaki R, Stevens C, Cox JD. Combination of a COX-2 inhibitor with radiotherapy or radiochemotherapy in the treatment of thoracic cancer. Am J Clin Oncol 2003; 26:S85-91. [PMID: 12902863 DOI: 10.1097/01.coc.0000074307.55019.29] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Cyclooxygenase-2 (COX-2) is an enzyme involved in prostaglandin production in pathologic states such as inflammatory processes and cancer. The enzyme is often overexpressed in premalignant lesions and cancer, including cancers of the lung and esophagus. Inhibition of this enzyme with selective COX-2 inhibitors was found to enhance tumor response to radiation in preclinical studies, suggesting that these agents can improve the response of various cancers to radiotherapy. On the basis of these preclinical findings, clinical trials of the combination of celecoxib, a selective COX-2 inhibitor, with radiotherapy were initiated in patients with lung carcinoma and with chemoradiotherapy in patients with esophageal carcinoma. The rationale for using selective COX-2 inhibitors is discussed, and the current clinical protocols and the initial findings are described.
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Affiliation(s)
- Zhongxing Liao
- Division of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
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Affiliation(s)
- Daniel G Haller
- University of Pennsylvania Cancer Center, Philadelphia, PA 19104, USA
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Abstract
On the strength of in vitro, in vivo, observational, and clinical data, nonsteroidal antiinflammatory drugs (NSAIDs)-also referred to as COX inhibitors-have emerged as lead compounds for cancer prevention, and possible adjuncts to cancer therapy. Thus far, the routine use of NSAIDs for these indications is limited, largely owing to toxicity concerns, the paucity of efficacy data for any specific target organ, and uncertainties with regard to the most appropriate regimen (i.e., the best agent, formulation, dose, route of administration, and duration). Strategies to address these concerns primarily aim to improve the therapeutic index (i.e., benefit:risk ratio) of COX inhibitors by 1) minimizing systemic exposures whenever feasible, 2) achieving greater mechanistic specificity, 3) coadministering agents that provide prophylaxis against common toxicities, and 4) coadministering other effective anticancer agents. Clinical trials testing most of these strategies have been completed or are under way. The National Cancer Institute has a substantial research portfolio dedicated to the identification, testing, and development of NSAIDs as preventive and therapeutic anticancer agents. Discovering how to apply NSAIDs in persons with-or at risk for-cancer, although challenging, has the potential for considerable clinical and public health benefits.
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Affiliation(s)
- Asad Umar
- Gastrointestinal & Other Cancers Research Group, National Cancer Institute, Division of Cancer Prevention, Bethesda, Maryland 20892-7317, USA
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Altorki NK, Keresztes RS, Port JL, Libby DM, Korst RJ, Flieder DB, Ferrara CA, Yankelevitz DF, Subbaramaiah K, Pasmantier MW, Dannenberg AJ. Celecoxib, a selective cyclo-oxygenase-2 inhibitor, enhances the response to preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer. J Clin Oncol 2003; 21:2645-50. [PMID: 12860939 DOI: 10.1200/jco.2003.07.127] [Citation(s) in RCA: 211] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
PURPOSE Preclinical studies suggest that treatment with a selective cyclo-oxygenase-2 (COX-2) inhibitor may augment the antitumor effects of chemotherapy. In this study, patients with non-small-cell lung cancer (NSCLC) were preoperatively treated with celecoxib in combination with chemotherapy. End points were toxicity, response rates, and measurement of intratumoral levels of prostaglandin E2 (PGE2). METHODS In this phase II trial, 29 patients with stages IB to IIIA NSCLC were treated with two preoperative cycles of paclitaxel and carboplatin, as well as daily celecoxib, followed by surgical resection. Levels of PGE2 in the primary tumors and adjacent normal lung tissue were compared in 17 study patients versus 13 controls, who received preoperative paclitaxel/carboplatin without celecoxib. RESULTS All patients completed preoperative chemotherapy, and 26 completed preoperative celecoxib. The overall clinical response rate was 65% (48% with partial response; 17% with complete response). Grade 3 or 4 neutropenia was observed in 18 patients (62%). Twenty-eight patients were explored and underwent complete resection of their tumors. There were no complete pathologic responses, but seven patients (24%) had minimal residual microscopic disease. The addition of celecoxib to a regimen of paclitaxel and carboplatin abrogated the marked increase in levels of PGE2 detected in primary tumors after treatment with paclitaxel and carboplatin alone. CONCLUSION In comparison with historically reported response rates, these data suggest that the addition of a selective COX-2 inhibitor may enhance the response to preoperative paclitaxel and carboplatin in patients with NSCLC. Moreover, treatment with celecoxib 400 mg twice daily was sufficient to normalize the increase in PGE2 levels found in NSCLC patients after treatment with paclitaxel and carboplatin. Confirmatory trials are planned.
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Affiliation(s)
- N K Altorki
- Department of Cardiothoracic Surgery, Strang Cancer Prevention Center and Weill Medical College of Cornell University, New York, NY 10021, USA.
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Xiong B, Sun TJ, Yuan HY, Hu MB, Hu WD, Cheng FL. Cyclooxygenase-2 expression and angiogenesis in colorectal cancer. World J Gastroenterol 2003; 9:1237-40. [PMID: 12800231 PMCID: PMC4611791 DOI: 10.3748/wjg.v9.i6.1237] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [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: Cyclooxygenase-2 is involved in a variety of important cellular functions, including cell growth and differentiation, cancer cell motility and invasion, angiogenesis and immune function. However, the role of cyclooxygenase-2 as an angiogenic factor in colorectal cancer tissue is still unclear. We investigated the relationship between cyclooxygenase-2 and angiogenesis by analyzing the expression of cyclooxygenase-2 in colorectal cancer tissue, as well as its association with vascular endothelial growth factor (VEGF) and microvascular density (MVD).
METHODS: The expression of cyclooxygenase-2, VEGF, as well as MVD was detected in 128 cases of colorectal cancer by immunohistochemical staining. The relationship between the cyclooxygenase-2 and VEGF expression and MVD was evaluated. Our objective was to determine the effect of cyclooxygenase-2 on the angiogenesis of colorectal cancer tissue.
RESULTS: Among 128 cases of colorectal cancer, 87 were positive for cyclooxygenase-2 (67.9%), and 49 for VEGF (38.3%), respectively. The microvessel counts ranged from 23 to 142, with a mean of 51.7 (standard deviation, 19.8). The expression of cyclooxygenase-2 was correlated significantly with the depth of invasion, stage of disease, metastasis (lymph node and liver), VEGF expression and MVD. Patients in T3-T4, stage III-IV and with metastasis had much higher expression of cyclooxygenase-2 than patients in T1-T2, stage I-II and without metastasis (P < 0.05). The positive expression rate of VEGF (81.6%) in the cyclooxygenase-2 positive group was higher than that in the cyclooxygenase-2 negative group (18.4%, P < 0.05). Also, the microvessel count (56 ± 16) in cyclooxygenase-2 positive group was significantly higher than that in cyclooxygenase-2 negative group (43 ± 12, P < 0.05). The microvessel count in tumors with positive cyclooxygenase-2 and VEGF was the highest (60 ± 18, 41-142, P < 0.05), whereas that in tumors with negative cyclooxygenase-2 and VEGF was the lowest (39 ± 16, 23-68, P < 0.05).
CONCLUSION: Cyclooxygenase-2 may be associated with tumor progression by madulating the angiogenesis in colorectal cancer tissue and used as a possible biomarker.
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Affiliation(s)
- Bin Xiong
- Department of Oncology, Affiliated Zhongnan Hospital of Wuhan University,Wuhan 430071, Hubei Province, China.
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Horrobin DF. A low toxicity maintenance regime, using eicosapentaenoic acid and readily available drugs, for mantle cell lymphoma and other malignancies with excess cyclin D1 levels. Med Hypotheses 2003; 60:615-23. [PMID: 12710892 DOI: 10.1016/s0306-9877(03)00075-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Mantle cell lymphoma is a difficult to treat non-Hodgkin's lymphoma (NHL) whose biochemistry is unusually well characterised. Almost all and perhaps all patients overexpress the cyclin D1 protein which is crucial in driving cells from the G1 to the S phase. This overexpression may be responsible for the refractoriness. Despite this understanding, treatments for mantle cell lymphoma are based on standard NHL regimes of cyclophosphamide, doxorubicin, vincristine and prednisone, perhaps supplemented with the monoclonal antibody rituximab. There has never been any attempt to direct treatment to the cyclin D1 mechanism or to angiogenesis which is now known to be important in all lymphomas. Both these targets lend themselves to long-term maintenance regimes of relatively low toxicity which can be used as adjuvants to standard therapy. Agents which have recently been shown to block cyclin D1 translation by regulating calcium levels are the unsaturated essential fatty acid, eicosapentaenoic acid (EPA), the antidiabetic thiazolidinediones, and the antifungal agent, clotrimazole. Two types of agent which have been shown to inhibit angiogenesis are the teratogen, thalidomide, and the selective inhibitors of cyclo-oxygenase 2 (COX-2). Retinoids exert synergistic effects with EPA and have been shown to inhibit both tumour growth and angiogenesis. The mechanisms of action of these various agents are discussed, and specific suggestions are made for low toxicity maintenance therapy of mantle cell lymphoma and of other tumours which overexpress cyclin D1.
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Xue YW, Zhang QF, Zhu ZB, Wang Q, Fu SB. Expression of cyclooxygenase-2 and clinicopathologic features in human gastric adenocarcinoma. World J Gastroenterol 2003; 9:250-3. [PMID: 12532441 PMCID: PMC4611321 DOI: 10.3748/wjg.v9.i2.250] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [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 study the expression of cyclooxygenase-2 (COX-2) gene in gastric cancer and the relationship between COX-2 expression and clinicopathologic features of gastric cancer.
METHODS: With reference to the expression of β-actin gene, COX-2 mRNA level was examined in cancerous tissues and adjacent noncancerous mucosa from 33 patients by semiquantitative reverse transcription- polymerase chain reaction (RT-PCR). Quantitation of relative band Adj volume counts was performed using molecular Analyst for windows software. The COX-2 index was determined from the band Adj volume counts ratio of COX-2 to constitutively expressed actin.
RESULTS: The COX-2 index in gastric carcinoma was significantly higher than that in normal mucosa (0.5966 ± 0.2659 vs 0.2979 ± 0.171, u = 5.4309, P < 0.01). Significantly higher expression of COX-2 mRNA was also observed in patients with lymph node involvement than that in those without (0.6775 ± 0.2486 vs 0.4105 ± 0.2182, t = 2.9341, P < 0.01). Furthermore, the staging in the UICC TNM classification significantly correlated with COX-2 overexpression (F = 3.656, P < 0.05), the COX-2 index in stage III and IV was significantly higher than those in stage I and II (q = 3.2728 and q = 3.4906, P < 0.05). The COX-2 index showed no correlation with patient抯 age, sex, blood group, tumor location, gross typing, depth of invasion, differentiation, and the greatest tumor dimension (P > 0.05).
CONCLUSION: Expression of COX-2 mRNA in gastric carcinoma was significantly higher, which may enhance lymphatic metastasis in patients with gastric carcinoma. The staging in the UICC TNM classification was significantly correlated with COX-2 over-expression. COX-2 may contribute to progression of tumor in human gastric adenocarcinoma.
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Affiliation(s)
- Ying-Wei Xue
- Department of General Surgery, The Third Clinical Hospital, Harbin Medical University, Harbin 150040, Heilongjiang Province, China.
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Brockhausen I. Glycodynamics of Mucin Biosynthesis in Gastrointestinal Tumor Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2003; 535:163-88. [PMID: 14714895 DOI: 10.1007/978-1-4615-0065-0_11] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Glycoproteins found in the secretions and on the surfaces of cancer cells include mucins and mucin-like glycoproteins. These molecules have been shown to carry antigens that are characteristically expressed on cancer cells, including Tn and T antigens and Lewis epitopes. The structures of O-glycans are often abnormal in gastrointestinal tumors, or else are present in abnormal amounts, and these structures greatly contribute to the phenotype and biology of cancer cells. It has been shown that glycans of cancer cells have functional importance in cell adhesion, invasion and metastasis. The possible mechanisms leading to these cancer-specific changes in carbohydrate structures (termed glycodynamics) involve altered mRNA expression and catalytic activities of glycosyltransferases and sulfotransferases found in tissues and cells of gastrointestinal tumors. In a number of cases it has been possible to correlate enzyme changes with oligosaccharide structures. Different mechanisms have been suggested leading to the synthesis of cancer-specific Lewis, T and Tn antigens, but the regulation of cancer mucin antigens generally appears to be very complex and is poorly understood. The expression levels of specific mucin antigens and enzymes in gastro-intestinal tumors have diagnostic as well as prognostic value. These antigens also have potential for cancer immunotherapy. However, we first need to unravel the complexity of the control of glycosylation in cancer cells. Most importantly, studies of the functional implications of the glycodynamics in cancer cells, as related to cell adhesion and impact on the immune system will provide promising directions for future research.
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Affiliation(s)
- Inka Brockhausen
- Department of Medicine, and Human Mobility Research Centre, Queen's University, Kingston, Ontario, K7L 3N6 Canada
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Giles FJ, Kantarjian HM, Bekele BN, Cortes JE, Faderl S, Thomas DA, Manshouri T, Rogers A, Keating MJ, Talpaz M, O'Brien S, Albitar M. Bone marrow cyclooxygenase-2 levels are elevated in chronic-phase chronic myeloid leukaemia and are associated with reduced survival. Br J Haematol 2002; 119:38-45. [PMID: 12358901 DOI: 10.1046/j.1365-2141.2002.03784.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Increased angiogenesis is important in the pathophysiology of haematological malignancies. Cyclooxygenase-2 (Cox-2) converts arachidonic acid to prostaglandins, which induce expression of angiogenic factors, including vascular endothelial growth factor (VEGF), basic-fibroblast growth factor, transforming growth factor-beta and interleukin 6. Cox-2 may also reduce apoptosis and reduce cellular attachment to the extracellular matrix (ECM). Increased bone marrow (BM) vascularity, increased BM cellular and plasma VEGF levels, and decreased progenitor adherence to BM ECM have all been observed in chronic myeloid leukaemia (CML). We investigated the prognostic significance of levels of Cox-2 in BM cells from patients with CML. Western blot and solid-phase radioimmunoassay (RIA) were used to measure Cox-2 BM levels in 149 patients with chronic phase CML (CP CML). Results were compared with those of normal controls. Expression of Cox-2 was significantly higher in CML than in normal controls (P < 0.0001). Increasing levels of Cox-2 were significantly associated with shorter survival (P = 0.0002, Cox proportional hazard model). A multivariate model based on Cox-2 and degree of splenomegaly was developed for survival in patients with early CP CML. Agents that inhibit Cox-2 activity merit investigation in patients with CP CML.
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Affiliation(s)
- Francis J Giles
- Department of Leukaemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
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Strauss KI, Marini AM. Cyclooxygenase-2 inhibition protects cultured cerebellar granule neurons from glutamate-mediated cell death. J Neurotrauma 2002; 19:627-38. [PMID: 12042097 PMCID: PMC1456322 DOI: 10.1089/089771502753754091] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Primary insults to the brain can initiate glutamate release that may result in excitotoxicity followed by neuronal cell death. This secondary process is mediated by both N-methyl-D-aspartate (NMDA) and non-NMDA receptors in vivo and requires new gene expression. Neuronal cyclooxygenase-2 (COX2) expression is upregulated following brain insults, via glutamatergic and inflammatory mechanisms. The products of COX2 are bioactive prostanoids and reactive oxygen species that may play a role in neuronal survival. This study explores the role of neuronal COX2 in glutamate excitotoxicity using cultured cerebellar granule neurons (day 8 in vitro). Treatment with excitotoxic concentrations of glutamate or kainate transiently induced COX2 mRNA (two- and threefold at 6 h, respectively, p < 0.05, Dunnett) and prostaglandin production (five- and sixfold at 30 min, respectively, p < 0.05, Dunnett). COX2 induction peaked at toxic concentrations of these excitatory amino acids. Surprisingly, NMDA, L-quisqualate, and trans-ACPD did not induce COX2 mRNA at any concentration tested. The glutamate receptor antagonist NBQX (5 microM, AMPA/kainate receptor) completely inhibited kainate-induced COX2 mRNA and partially inhibited glutamate-induced COX2 (p < 0.05, Dunnett). Other glutamate receptor antagonists, such as MK-801 (1 microM, NMDA receptor) or MCPG (500 microM, class 1 metabotropic receptors), partially attenuated glutamate-induced COX2 mRNA. These antagonists all reduced steady-state COX2 mRNA (p < 0.05, Dunnett). To determine whether COX2 might be an effector of excitotoxic cell death, cerebellar granule cells were pretreated (24 h) with the COX2-specific enzyme inhibitor, DFU (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2((5)H)-furanone) prior to glutamate challenge. DFU (1 to 1000 nM) completely protected cultured neurons from glutamate-mediated neurotoxicity. Approximately 50% protection from NMDA-mediated neurotoxicity, and no protection from kainate-mediated neurotoxicity was observed. Therefore, glutamate-mediated COX2 induction contributes to excitotoxic neuronal death. These results suggest that glutamate, NMDA, and kainate neurotoxicity involve distinct excitotoxic pathways, and that the glutamate and NMDA pathways may intersect at the level of COX2.
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Affiliation(s)
- Kenneth I Strauss
- Department of Neurosurgery, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
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Prinsloo SE, van Aswegen CH. Effect of fatty acids on estradiol and testosterone binding to whole DU-145 prostate cells. Prostaglandins Leukot Essent Fatty Acids 2002; 66:419-25. [PMID: 12054912 DOI: 10.1054/plef.2002.0368] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Cancer of the prostate is one of the leading causes of cancer related deaths in men. An important role in the development of prostate cancer is played by androgens and androgen ablation is therefore currently used in cancer treatment. In the past, estrogens were widely used in treatment of prostate cancer, but there are indications that estrogens could also be involved in carcinogenesis. Lately, much research has been done on the modulation of the binding of steroid hormones to their receptors by polyunsaturated fatty acids (PUFAs), which could interfere with the steroid hormone's message. Therefore, the aim of this study was to determine in whole DU-145 human prostate cells the effect of EFAs and their metabolites on the binding and affinity of the estrogen receptor (ER) and androgen receptor (AR) to estradiol (E(2)) and testosterone (T), respectively. Fatty acids were dissolved in ethanol and added to the cell culture in a final ethanol concentration of 0.2% on the fourth day of incubation. The results showed that the PUFAs under investigation inhibited the AR's capacity, in contrast to the ER's capacity which was stimulated. However, the dissociation constants (K(d)) of the AR and ER complexes in the presence of the PUFAs, were as follows. Except for eicosapentaenoic acid (EPA) which decreased the AR dissociation constant and EPA and alpha-linolenic acid (ALA) which increased the ER dissociation constant, the remaining FAs had no significant effect on the K(d) values of both the AR and ER complexes. According to these priliminary results it is postulated that men should benefit with a diet rich in certain essential polyunsaturated fatty acids although its function remains to be clarified.
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Affiliation(s)
- S E Prinsloo
- Wolmarans Research Laboratory, Department of Urology, University of Pretoria, Pretoria, South Africa.
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Wu YL, Sun B, Zhang XJ, Wang SN, He HY, Qiao MM, Zhong J, Xu JY. Growth inhibition and apoptosis induction of Sulindac on Human gastric cancer cells. World J Gastroenterol 2001; 7:796-800. [PMID: 11854904 PMCID: PMC4695597 DOI: 10.3748/wjg.v7.i6.796] [Citation(s) in RCA: 56] [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: 02/06/2023] Open
Abstract
AIM: To evaluate the effects of sulindac in inducing growth inhibition and apoptosis of human gastric cancer cells in comparison with human hepatocellular carcinoma (HCC) cells.
METHODS: The human gastric cancer cell lines MKN45 and MKN28 and human hepatocellular carcinoma cell lines HepG2 and SMMC7721 were used for the study. Anti-proliferative effect was measured by MTT assay, and apoptosis was determined by Hoechst-33258 staining, electronography and DNA fragmentation. The protein of cyclooxygenase-2 (COX-2) and Bcl-2 were detected by Western dot blotting.
RESULTS: Sulindac could initiate growth inhibition and apoptosis of MKN45, MKN28, HepG2 and SMMC7721 cells in a dose-and time-dependent manner. Growth inhibitory activity and apoptosis were more sensitive in HepG2 cells than in SMMC7721 cells, MKN45 and MKN28 cells. After 24 h incubation with sulindac at 2 mmol•L¯¹ and 4 mmol•L¯¹, the level of COX-2 and Bcl-2 protein were lowered in MKN45, SMMC7721 and HepG2 cells but not in MKN28 cells.
CONCLUSION: Sulindac could inhibit the growth of gastric cancer cells and HCC cells effectively in vitro by apoptosis induction, which was associated with regression of COX- 2 and Bcl-2 expression. The growth inhibition and apoptosis of HCC cells were greater than that of human gastric cancer cells. The different effects of apoptosis in gastric cancer cells may be related to the differentiation of the cells.
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Affiliation(s)
- Y L Wu
- Department of Gastroenterology, Ruijin Hospital, Shanghai Second Medical University, Shanghai 200025, China.
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DISTRIBUTION OF DT-DIAPHORASE AND REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE:. J Urol 2001. [DOI: 10.1097/00005392-200112000-00130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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LI DONG, GAN YUEBO, WIENTJES M, BADALAMENT ROBERTA, AU JESSIELS. DISTRIBUTION OF DT-DIAPHORASE AND REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE: CYTOCHROME P450 OXIDOREDUCTASE IN BLADDER TISSUES AND TUMORS. J Urol 2001. [DOI: 10.1016/s0022-5347(05)65624-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- DONG LI
- From the College of Pharmacy, Ohio State University, Columbus, Ohio
| | - YUEBO GAN
- From the College of Pharmacy, Ohio State University, Columbus, Ohio
| | - M.GUILL WIENTJES
- From the College of Pharmacy, Ohio State University, Columbus, Ohio
| | | | - JESSIE L.-S. AU
- From the College of Pharmacy, Ohio State University, Columbus, Ohio
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Abstract
Tumour endothelium is a new target for anticancer treatments. Proliferating endothelial cells from the tumour, even if qualitatively different from those of blood vessels in the normal tissue of origin, remain putatively normal and genetically stable cells. The results of recent experimental studies have suggested that frequent administration of certain cytotoxic agents at low doses (a tenth to a third of the maximum tolerated dose), known as 'metronomic' chemotherapy, increases the antiangiogenic activity of the drugs. The effects of these metronomic schedules of cytotoxic agents may be further enhanced by concurrent administration of novel, selective, treatments that inhibit, at a molecular level, the processes of tumour formation and growth eg angiogenesis, growth factor pathways, and other signal transduction cascades. The need to treat patients for long periods also supports the use of metronomic scheduling for chemotherapy, to minimise toxicity and to target both proliferating tumour cells and endothelial cells. This review describes the experimental studies involving metronomic schedules of chemotherapy, alone and in combination with angiogenesis inhibitors, and suggests a new therapeutic anticancer paradigm for controlling cancer by long-term therapy, based on the development of combinations of metronomic cytotoxic agents with individually tailored compounds designed to target specific molecules.
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Affiliation(s)
- G Gasparini
- Division of Medical Oncology, Azienda Complesso Ospedaliero San Filippo Neri, Rome, Italy.
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44
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Kalkeri G, Khalap N, Akhter S, Garry RF, Fermin CD, Dash S. Hepatitis C viral proteins affect cell viability and membrane permeability. Exp Mol Pathol 2001; 71:194-208. [PMID: 11733945 DOI: 10.1006/exmp.2001.2392] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
To determine the effect of hepatitis C virus (HCV) proteins on cell growth, Huh-7 cells were transfected with a full-length HCV cDNA (pMO9.6-T7 Rz) clone and HCV proteins were expressed using a replication-defective adenovirus that encodes the gene for the T7 RNA polymerase. Expression of HCV proteins from this full-length clone resulted in reduction in viability of transfected cells as measured by trypan blue viability assay. For identification and separation of cells expressing hepatitis C virus proteins by fluorescence microscopy and flow cytometry, GFP was cloned in the HCV full-length clone. Cells transfected with the HCV-GFP chimera clone produced high levels of accurately processed structural and nonstructural proteins similar to those of the HCV full-length clone, which could be detected by Western blot analysis. Cells expressing all HCV proteins lost membrane permeability and underwent apoptotic cell death, indicated by the appearance of a sub-G0 peak in cell cycle analysis, DNA fragmentation in a TUNEL assay, and microscopic detection of nuclear condensation. Using double-channel flow analysis we confirmed that high-level expression of HCV proteins affected membrane permeability and cell survival. These results suggest that expression of all structural and nonstructural proteins from HCV cDNA in hepatic cells induces apoptotic cell death, which might be an important event in chronic hepatitis infection in humans.
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Affiliation(s)
- G Kalkeri
- Department of Pathology and Laboratory Medicine, Tulane University Health Science Center, New Orleans, Louisiana 70112, USA
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45
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Atten MJ, Attar BM, Milson T, Holian O. Resveratrol-induced inactivation of human gastric adenocarcinoma cells through a protein kinase C-mediated mechanism. Biochem Pharmacol 2001; 62:1423-32. [PMID: 11709203 DOI: 10.1016/s0006-2952(01)00788-2] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Resveratrol, a polyphenolic phytochemical present in berries, grapes, and wine, has emerged as a promising chemopreventive candidate. Because there is scant information regarding natural agents that prevent, suppress, or reverse gastric carcinogenesis, the aim of the present study was to determine the chemopreventive potential of resveratrol against gastric cancer by investigating cellular and molecular events associated with resveratrol treatment of human gastric adenocarcinoma cells. We determined the action of resveratrol on cellular function and cellular integrity by measuring DNA synthesis, cellular proliferation, cell cycle distribution, cytolysis, apoptosis, and phosphotransferase activities of two key signaling enzymes, protein kinase C (PKC) and mitogen-activated protein kinases (ERK1/ERK2), in human gastric adenocarcinoma KATO-III and RF-1 cells. Resveratrol inhibited [3H]thymidine incorporation into cellular DNA of normally proliferating KATO-III cells and of RF-1 cells whose proliferation was stimulated with carcinogenic nitrosamines. Treatment with resveratrol arrested KATO-III cells in the G(0)/G(1) phase of the cell cycle and eventually induced apoptotic cell death, but had a minimal effect on cell lysis. Resveratrol treatment had no effect on ERK1/ERK2 activity but significantly inhibited PKC activity of KATO-III cells and of human recombinant PKCalpha. Results indicate that resveratrol has potential as a chemopreventive agent against gastric cancer because it exerts an overall deactivating effect on human gastric adenocarcinoma cells. Resveratrol-induced inhibition of PKC activity and of PKCalpha, without any change in ERK1/ERK2 activity, suggests that resveratrol utilizes a PKC-mediated mechanism to deactivate gastric adenocarcinoma cells.
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Affiliation(s)
- M J Atten
- Department of Medicine, Division of Gastroenterology, Cook County Hospital and Hektoen Institute for Medical Research, 627 S. Wood St., Room 765, Chicago, IL 60612, USA
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Macchia M, Barontini S, Bertini S, Di Bussolo V, Fogli S, Giovannetti E, Grossi E, Minutolo F, Danesi R. Design, synthesis, and characterization of the antitumor activity of novel ceramide analogues. J Med Chem 2001; 44:3994-4000. [PMID: 11689086 DOI: 10.1021/jm010947r] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
A deficiency in apoptosis is one of the key events in the proliferation and resistance of malignant cells to antitumor agents; for these reasons, the search for apoptosis-inducing drugs represents a valuable approach for the development of novel anticancer therapies. In this study we report the first example of conformationally restrained analogues of ceramide (compounds 1-4), where the polar portion of the molecule has been replaced by a thiouracil (1, 3) or uracil (2, 4) ring. The evaluation of their biologic activity on CCRF-CEM human leukemia cells demonstrated that the most active was compound 1 followed by compound 2 (mean 50% inhibition of cell proliferation [IC(50)] 1.7 and 7.9 microM, respectively), while compounds 3 and 4 were inactive, as were uracil, thiouracil, and 5,6-dimethyluracil, the pyrimidine moieties of compounds 1-4. For comparison, the IC(50) of the reference substance, the cell-permeable C2-ceramide, was 31.6 microM. Compounds 1 and 2 and C2-ceramide were able to trigger apoptosis, as shown by the occurrence of DNA and nuclear fragmentation, and to release cytochrome c from treated cells. The treatment of female CD-1 nu/nu athymic mice bearing a WiDr human colon xenograft with the most active compound 1 at 2, 10, 50, and 200 mg/kg ip daily for 10 days resulted in an antitumor effect that was equivalent at 50 mg/kg or superior (200 mg/kg) to that of cyclophosphamide, 20 mg/kg ip daily, delivered on the same schedule, with markedly lower systemic toxicity. In conclusion, the present study demonstrates that the new ceramide analogues 1 and 2 are characterized by in vitro and in vivo antitumor activity and low toxicity.
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Affiliation(s)
- M Macchia
- Department of Pharmaceutical Sciences, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
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Di Paolo A, Danesi R, Caputo S, Macchia M, Lastella M, Boggi U, Mosca F, Marchetti A, Del Tacca M. Inhibition of protein farnesylation enhances the chemotherapeutic efficacy of the novel geranylgeranyltransferase inhibitor BAL9611 in human colon cancer cells. Br J Cancer 2001; 84:1535-43. [PMID: 11384105 PMCID: PMC2363657 DOI: 10.1054/bjoc.2001.1820] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Proteins belonging to the ras superfamily are involved in cell proliferation of normal and neoplastic tissues. To be biologically active, they require post-translational isoprenylation by farnesyl-transferase and geranylgeranyl-transferase. Enzyme inhibition by drugs may thus represent a promising approach to the treatment of cancer. Therefore, the combined effect of BAL9611, a novel inhibitor of geranylgeranylation, and manumycin, a farnesyl-transferase inhibitor, was evaluated on the SW620 human colon cancer cell line which harbours a mutated K-ras gene. BAL9611 and manumycin dose-dependently inhibited SW620 cell growth with 50% inhibitory concentration (IC(50)) of 0.47 +/- 0.03 and 5.24 +/- 1.41 microM (mean +/- SE), respectively. The isobologram analysis performed at the IC(50)level revealed that the combined treatment was highly synergistic with respect to cell growth inhibition. BAL9611 and manumycin were able to inhibit the geranylgeranylation of p21rhoA and farnesylation of p21ras; both drugs inhibited p42ERK2/MAPK phosphorylation, but their combination was more effective than either drug alone. Moreover, the enhanced inhibition of cell growth in vitro by the BAL9611-manumycin combination was also observed in vivo in CD nu/nu female mice xenografted with SW620 tumours. Finally, both drugs were able to induce cell death by apoptosis in vitro and in vivo, as demonstrated by perinuclear chromatin condensation, cytoplasm budding and nuclear fragmentation, and interoligonucleosomal DNA digestion. In conclusion, the inhibition of protein farnesylation enhances the chemotherapeutic effect of BAL9611 in vitro and in vivo in a synergistic fashion, as a result of the impairment of post-translational isoprenylation of proteins and phosphorylation of p42ERK2/MAPK, whose activation is associated with post-translational geranylgeranylation and farnesylation of p21rhoA and p21ras.
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Affiliation(s)
- A Di Paolo
- Division of Pharmacology and Chemotherapy, University of Pisa, Italy
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Abstract
Mitomycin C was reviewed in this journal 25 years ago and an update of its clinical usefulness is appropriate. The current review is based on representative publications covering clinical trials performed throughout the world. Single agent activity in each of the major neoplastic diseases has been reassessed when possible and the most important combinations evaluated. It is concluded that mitomycin C has a definite place in the treatment of localized bladder cancer, is active, but needs to be redefined, in the context of newer regimens for breast, head and neck, and non-small cell lung cancers, is active in, but is being displaced by, other drugs in cervical, gastric and pancreatic cancers, and is probably no longer of therapeutic value in colon cancer. It is also recognized that as many newer treatments have clinical success, the therapeutic role of mitomycin C will require continuing re-investigation.
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Affiliation(s)
- W T Bradner
- Research Advisors, 4903 Briarwood Circle, Manlius, New York 13104, USA
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