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Svein Ivar Bekkelund - One of the best experts on this subject based on the ideXlab platform.
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hemicrania continua changed to chronic paroxysmal hemicrania after treatment with Cyclooxygenase 2 Inhibitor
Headache, 2011Co-Authors: Kai Ivar Muller, Svein Ivar BekkelundAbstract:(Headache 2011;51:300-305) Remission of hemicrania continua (HC) and transformation from HC to chronic paroxysmal hemicrania (CPH) are unusual. We report a patient with left-sided HC who, after a period of remission, presented as CPH. The continuous HC headache disappeared completely after initiating treatment with Cyclooxygenase (COX)-2 Inhibitor, but reappeared on the same side after 14 months remission with paroxysmal, frequent, intense and short-lasting headache attacks accompanied by ipsilateral cranial autonomic symptoms. This happened shortly after the treatment was discontinued because of withdrawal of the COX-2 Inhibitor from the market. The response to indomethacin was prompt, and the patient became completely free from her paroxysmal headache with a dose of 50 mg 2 times daily. This case questions a possible modification effect on the course of HC by use of COX-2 Inhibitor, as well as further supporting that some aspects of the pathophysiology of HC may resemble those of CPH, and may argue for common biological mechanisms in HC and CPH.
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hemicrania continua changed to chronic paroxysmal hemicrania after treatment with Cyclooxygenase 2 Inhibitor
Headache, 2011Co-Authors: Kai Ivar Muller, Svein Ivar BekkelundAbstract:Remission of hemicrania continua (HC) and transformation from HC to chronic paroxysmal hemicrania (CPH) are unusual. We report a patient with left-sided HC who, after a period of remission, presented as CPH. The continuous HC headache disappeared completely after initiating treatment with Cyclooxygenase (COX)-2 Inhibitor, but reappeared on the same side after 14 months remission with paroxysmal, frequent, intense and short-lasting headache attacks accompanied by ipsilateral cranial autonomic symptoms. This happened shortly after the treatment was discontinued because of withdrawal of the COX-2 Inhibitor from the market. The response to indomethacin was prompt, and the patient became completely free from her paroxysmal headache with a dose of 50 mg 2 times daily. This case questions a possible modification effect on the course of HC by use of COX-2 Inhibitor, as well as further supporting that some aspects of the pathophysiology of HC may resemble those of CPH, and may argue for common biological mechanisms in HC and CPH.
Kai Ivar Muller - One of the best experts on this subject based on the ideXlab platform.
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hemicrania continua changed to chronic paroxysmal hemicrania after treatment with Cyclooxygenase 2 Inhibitor
Headache, 2011Co-Authors: Kai Ivar Muller, Svein Ivar BekkelundAbstract:(Headache 2011;51:300-305) Remission of hemicrania continua (HC) and transformation from HC to chronic paroxysmal hemicrania (CPH) are unusual. We report a patient with left-sided HC who, after a period of remission, presented as CPH. The continuous HC headache disappeared completely after initiating treatment with Cyclooxygenase (COX)-2 Inhibitor, but reappeared on the same side after 14 months remission with paroxysmal, frequent, intense and short-lasting headache attacks accompanied by ipsilateral cranial autonomic symptoms. This happened shortly after the treatment was discontinued because of withdrawal of the COX-2 Inhibitor from the market. The response to indomethacin was prompt, and the patient became completely free from her paroxysmal headache with a dose of 50 mg 2 times daily. This case questions a possible modification effect on the course of HC by use of COX-2 Inhibitor, as well as further supporting that some aspects of the pathophysiology of HC may resemble those of CPH, and may argue for common biological mechanisms in HC and CPH.
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hemicrania continua changed to chronic paroxysmal hemicrania after treatment with Cyclooxygenase 2 Inhibitor
Headache, 2011Co-Authors: Kai Ivar Muller, Svein Ivar BekkelundAbstract:Remission of hemicrania continua (HC) and transformation from HC to chronic paroxysmal hemicrania (CPH) are unusual. We report a patient with left-sided HC who, after a period of remission, presented as CPH. The continuous HC headache disappeared completely after initiating treatment with Cyclooxygenase (COX)-2 Inhibitor, but reappeared on the same side after 14 months remission with paroxysmal, frequent, intense and short-lasting headache attacks accompanied by ipsilateral cranial autonomic symptoms. This happened shortly after the treatment was discontinued because of withdrawal of the COX-2 Inhibitor from the market. The response to indomethacin was prompt, and the patient became completely free from her paroxysmal headache with a dose of 50 mg 2 times daily. This case questions a possible modification effect on the course of HC by use of COX-2 Inhibitor, as well as further supporting that some aspects of the pathophysiology of HC may resemble those of CPH, and may argue for common biological mechanisms in HC and CPH.
Takashi Fujimura - One of the best experts on this subject based on the ideXlab platform.
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a selective Cyclooxygenase 2 Inhibitor prevents inflammation related squamous cell carcinogenesis of the forestomach via duodenogastric reflux in rats
Cancer, 2009Co-Authors: Koichi Miwa, Takashi Fujimura, Shinichi Harada, Shozo Sasaki, Katsunobu Oyama, Tetsuo Ohta, Takanori HattoriAbstract:BACKGROUND: Duodenal reflux causes inflammation-related squamous cell carcinogenesis in the forestomach of rats without any carcinogens. The aim of this study was to investigate the efficacy of a selective Cyclooxygenase (COX)-2 Inhibitor, meloxicam, in preventing this carcinogenesis. METHODS: A series of 188 rats underwent a surgical duodenogastric reflux procedure and were divided into 2 groups. One group was given commercial chow (control group), and the other was given experimental chow containing meloxicam (0.3 mg/kg body weight/day) (meloxicam group). The animals were sequentially sacrificed at Weeks 20, 30, 40, 50, and 60 after surgery. The forestomach was examined for the presence of carcinoma, the incidence of reflux-related morphological changes, COX-2 expression, and its activity. RESULTS: At Week 60, squamous cell carcinoma developed in 8 of 21 animals (38%) in the control group, but none of 20 (0%) in the meloxicam group (P < .05). In addition, basal cell dysplasia developed in 19 of 21 (90%) animals in the control group, but only 4 of 20 (20%) in the meloxicam group (P < .01). COX-2 immunoreactivity was predominantly detected in macrophages in the epithelial stroma. Compared with nonsurgical rats, RNA expression of COX-2 in the epithelium was up-regulated, reaching peak at an early stage of Week 20 in both groups (P < .005). The expression of microsomal prostaglandin E synthase-1 was lower in the meloxicam group than in the control group. PGE2 production was significantly suppressed throughout the experiment in the meloxicam group compared with the control group (P < .005). CONCLUSIONS: Meloxicam was effective in preventing reflux-induced squamous cell carcinogenesis via an inflamed squamous epithelium. Cancer 2009. © 2009 American Cancer Society.
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a selective Cyclooxygenase 2 Inhibitor prevents inflammation related squamous cell carcinogenesis of the forestomach via duodenogastric reflux in rats
Cancer, 2009Co-Authors: Masaru Oba, Koichi Miwa, Takashi Fujimura, Shinichi Harada, Shozo Sasaki, Katsunobu Oyama, Tetsuo Ohta, Takanori HattoriAbstract:BACKGROUND: Duodenal reflux causes inflammation-related squamous cell carcinogenesis in the forestomach of rats without any carcinogens. The aim of this study was to investigate the efficacy of a selective Cyclooxygenase (COX)-2 Inhibitor, meloxicam, in preventing this carcinogenesis. METHODS: A series of 188 rats underwent a surgical duodenogastric reflux procedure and were divided into 2 groups. One group was given commercial chow (control group), and the other was given experimental chow containing meloxicam (0.3 mg/kg body weight/day) (meloxicam group). The animals were sequentially sacrificed at Weeks 20, 30, 40, 50, and 60 after surgery. The forestomach was examined for the presence of carcinoma, the incidence of reflux-related morphological changes, COX-2 expression, and its activity. RESULTS: At Week 60, squamous cell carcinoma developed in 8 of 21 animals (38%) in the control group, but none of 20 (0%) in the meloxicam group (P < .05). In addition, basal cell dysplasia developed in 19 of 21 (90%) animals in the control group, but only 4 of 20 (20%) in the meloxicam group (P < .01). COX-2 immunoreactivity was predominantly detected in macrophages in the epithelial stroma. Compared with nonsurgical rats, RNA expression of COX-2 in the epithelium was up-regulated, reaching peak at an early stage of Week 20 in both groups (P < .005). The expression of microsomal prostaglandin E synthase-1 was lower in the meloxicam group than in the control group. PGE2 production was significantly suppressed throughout the experiment in the meloxicam group compared with the control group (P < .005). CONCLUSIONS: Meloxicam was effective in preventing reflux-induced squamous cell carcinogenesis via an inflamed squamous epithelium. Cancer 2009. © 2009 American Cancer Society.
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chemoprevention for gastric carcinoma in rat duodenogastric reflux model by a selective Cyclooxygenase 2 Inhibitor meloxicam
Cancer Research, 2006Co-Authors: Takashi Fujimura, Katsunobu Oyama, Tetsuo Ohta, Tomoharu Miyashita, Shinichi Kinami, Itasu Ninomiya, Sachio Fushida, Genichi Nishimura, Koichi MiwaAbstract:2355 Background & Aims: Reflux of duodenal contents to stomach is related with development of gastric carcinoma. Cyclooxygenase-2 (COX-2) expression, which involves tumor proliferation, suppressed apoptosis, and tumor invasion, is reported in human gastric carcinoma. The aims of this study are to investigate the relationship between COX-2 and gastric cancer, and to disclose the chemopreventive effect of a selective COX-2 Inhibitor. Methods: Meloxicam (MLX, Boehringer Ingelheim) was used as a COX-2 Inhibitor. The F344 male rats surgically induced duodenogastic reflux were allocated to two groups, given commercial chow (control) and experimental chow containing MLX (2.0 mg/Kg body weight/day). The animals were sacrificed postoperatively at every ten weeks between 20 and 60 weeks. Pathological findings, COX-2 expression, prostaglandin (PG) E2 production, and proliferative activity (BrdU labeling index) were assessed. Results: In the control group, gastritis cystica profunda (GCP) developed at the 20th week and its incidence reached to 100% at the 60th week, and incidences of adenomatous lesion (ADM) and carcinoma were 52% and 29% at the 60th week, respectively. In the MLX group, neither ADM nor carcinoma was observed though this study. The incidences of GCP, ADM, and carcinoma in the MLX group were significantly lower than the control group (p
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the effect of celecoxib a Cyclooxygenase 2 Inhibitor in familial adenomatous polyposis
The New England Journal of Medicine, 2000Co-Authors: Gideon Steinbach, Patrick M Lynch, R K S Phillips, Marina Wallace, Ernest T Hawk, Gary Gordon, Naoki Wakabayashi, Brian D Saunders, Yu Shen, Takashi FujimuraAbstract:Background Patients with familial adenomatous polyposis have a nearly 100 percent risk of colorectal cancer. In this disease, the chemopreventive effects of nonsteroidal antiinflammatory drugs may be related to their inhibition of Cyclooxygenase-2. Methods We studied the effect of celecoxib, a selective Cyclooxygenase-2 Inhibitor, on colorectal polyps in patients with familial adenomatous polyposis. In a double-blind, placebo-controlled study, we randomly assigned 77 patients to treatment with celecoxib (100 or 400 mg twice daily) or placebo for six months. Patients underwent endoscopy at the beginning and end of the study. We determined the number and size of polyps from photographs and videotapes; the response to treatment was expressed as the mean percent change from base line. Results At base line, the mean (±SD) number of polyps in focal areas where polyps were counted was 15.5±13.4 in the 15 patients assigned to placebo, 11.5±8.5 in the 32 patients assigned to 100 mg of celecoxib twice a day, and 12...
Karen Seibert - One of the best experts on this subject based on the ideXlab platform.
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chemoprevention of breast cancer in rats by celecoxib a Cyclooxygenase 2 Inhibitor
Cancer Research, 2000Co-Authors: Randall E Harris, Galal A Alshafie, Hussein Abouissa, Karen SeibertAbstract:Nonsteroidal anti-inflammatory drugs (NSAIDs) have been observed to reduce the relative risk of breast cancer. This prompted our investigation of the chemopreventive potential of celecoxib, a specific Cyclooxygenase 2 blocker, against mammary carcinogenesis induced by 7,12-dimethyl-benz(a)anthracene in female Sprague Dawley rats. Treatment with celecoxib was examined and compared to treatment with the general NSAID, ibuprofen, and to a control group receiving only dimethylbenz(a)anthracene. Dietary administration of celecoxib (1500 ppm) produced striking reductions in the incidence, multiplicity, and volume of breast tumors relative to the control group (68%, 86%, and 81%, respectively; P < 0.001). Ibuprofen also produced significant effects, but of lesser magnitude (40%, 52%, and 57%, respectively; P < 0.001). These results help confirm the chemopreventive activity of NSAIDs against breast cancer and provide the first evidence that a Cyclooxygenase 2 blocking agent, celecoxib, possesses strong chemopreventive activity against mammary carcinogenesis.
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chemoprevention of colon cancer by specific Cyclooxygenase 2 Inhibitor celecoxib administered during different stages of carcinogenesis
Cancer Research, 2000Co-Authors: Bandaru S Reddy, Yoshinobu Hirose, Ronald A Lubet, Vernon E Steele, Gary J Kelloff, Susan Paulson, Karen Seibert, Chinthalapally V RaoAbstract:Epidemiological observations and laboratory research have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colon cancer and that the inhibition of colon carcinogenesis by NSAIDs is mediated through the modulation of prostaglandin production by rate-limiting enzymes known as Cyclooxygenases (COXs). Because traditional NSAIDs inhibit both COX-1 and COX-2, these drugs induce side effects, such as gastrointestinal ulceration and renal toxicity, through the inhibition of the constitutive COX-1. Overexpression of COX-2 has been observed in colon tumors; therefore, specific Inhibitors of COX-2 could serve as chemopreventive agents. Our previous study has shown that celecoxib, an Inhibitor of COX-2, while sparing COX-1, inhibited azoxymethane (AOM)-induced colon tumorigenesis when administered during both initiation and postinitiation stages, i.e. , celecoxib administered continuously before, during, and after carcinogen treatment. This study examined the dose-response effect of celecoxib when administered during the initiation and postinitiation stages. In addition, the chemopreventive effects of high-dose celecoxib administered during the promotion/progression stage of colon carcinogenesis, i.e. , continuous celecoxib administration beginning 14 weeks after the carcinogen treatment, was determined in male F344 rats. We also measured the steady-state levels of celecoxib in the plasma of animals given this Inhibitor. Groups of 5-week-old male F344 rats were fed either a control diet or experimental diets containing 500, 1000, or 1500 ppm celecoxib. At 7 and 8 weeks of age, rats scheduled for carcinogen treatment were injected s.c. with AOM at a dose rate of 15 mg/kg body weight/week. Groups of animals destined for the promotion/progression study and initially receiving the control diet were switched to a diet containing 1500 ppm celecoxib beginning 14 weeks after the second AOM treatment. All rats remained on their respective dietary regimens until the termination of the study, i.e. , 52 weeks, and were then sacrificed. Colon tumors were evaluated histopathologically. Administration of 500, 1000, or 1500 ppm celecoxib during the initiation and postinitiation stages significantly inhibited the incidence ( P < 0.01 to P < 0.0001) as well as the multiplicity ( P < 0.01 to P < 0.0001) of adenocarcinomas of the colon in a dose-dependent manner. Importantly, administration of 1500 ppm celecoxib during the promotion/progression stage also significantly suppressed the incidence and multiplicity of adenocarcinomas of the colon ( P < 0.01). Also, administration of celecoxib to the rats during the initiation and postinitiation periods and throughout the promotion/progression stage strongly suppressed colon tumor volume ( P < 0.0002 to P < 0.001). The steady-state plasma concentration of celecoxib increases somewhat with the dose. Thus, in this model system, the chemopreventive efficacy of celecoxib is dose-dependent when this COX-2 Inhibitor is administered during the initiation and postinitiation periods. This study provides the first evidence that celecoxib is also very effective when it is given during the promotion/progression stage of colon carcinogenesis, indicating that the chemopreventive efficacy is achieved during the later stages of colon tumor development. This suggests that celecoxib may potentially be an effective chemopreventive agent for the secondary prevention of colon cancer in patients with familial adenomatous polyposis and sporadic polyps.
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chemopreventive activity of celecoxib a specific Cyclooxygenase 2 Inhibitor and indomethacin against ultraviolet light induced skin carcinogenesis
Molecular Carcinogenesis, 1999Co-Authors: Susan M Fischer, Ronald A Lubet, Gary J Kelloff, Karen Seibert, Gary B Gordon, Claudio J ContiAbstract:Epidemiological and dietary studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colon cancer, possibly through a mechanism involving inhibition of Cyclooxygenase (COX)-2, which is overexpressed in premalignant adenomatous polyps and colon cancer. Because ultraviolet light (UV) can induce COX-2 and nonspecific NSAIDs can decrease UV-induced skin cancer, we evaluated the ability of two compounds, celecoxib (a specific COX-2 Inhibitor) and indomethacin (a nonspecific NSAID), to block UV-induced skin tumor development in SKH:HR-1-hrBr hairless mice. Mice fed 150 or 500 ppm celecoxib showed a dose-dependent reduction (60% and 89%, respectively) in tumor yield. Indomethacin (4 ppm) reduced tumor yield by 78%. Although both acute and chronic UV exposure increased cell proliferation and edema, neither compound reduced these parameters. In contrast, UV-induced prostaglandin synthesis in the epidermis was effectively blocked by both compounds. UV-induced increases in COX-2 expression in skin were also not altered in any of the treatment groups. Similarly, tumors that constitutively express high levels of COX-2 displayed no reduction by treatment with celecoxib or indomethacin. The dramatic protective effects of celecoxib suggests that specific COX-2 Inhibitors may offer a way to safely reduce the risk of skin cancer in humans. Mol. Carcinog. 25:231–240, 1999. © 1999 Wiley-Liss, Inc.
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chemopreventive activity of celecoxib a specific Cyclooxygenase 2 Inhibitor against colon carcinogenesis
Cancer Research, 1998Co-Authors: Toshihiko Kawamori, Karen Seibert, Chinthalapally V Rao, Bandaru S ReddyAbstract:Epidemiological and laboratory studies suggest that nonsteroidal anti-inflammatory drugs reduce the risk of colon cancer and that the inhibition of colon carcinogenesis is mediated through modulation of prostaglandin production by Cyclooxygenase (COX) isozymes (COX-1 and -2). Overexpression of COX-2 has been observed in colon tumors; therefore, specific Inhibitors of COX-2 activity could potentially serve as chemopreventive agents. Our recent study indicated that celecoxib (SC-58635), a specific COX-2 Inhibitor, suppressed colonic aberrant crypt foci formation induced by azoxymethane in rats and led us to investigate more specifically the chemopreventive potential of this compound using colon tumors as end points. Five-week-old male F344 rats were fed the control diet (modified AIN-76A) or an experimental diet containing 1500 ppm celecoxib. Two weeks later, all animals except those in the saline-treated groups received s.c. injections of azoxymethane (15 mg/kg of body weight) once weekly for 2 weeks. All groups were kept on their regimen until the experiment was terminated, 50 weeks after carcinogen treatment. Colon tumors were evaluated histopathologically. Remarkably, dietary administration of celecoxib inhibited both incidence and multiplicity of colon tumors by about 93 and 97%, respectively. It also suppressed the overall colon tumor burden by more than 87%. The degree of tumor inhibition was more pronounced with celecoxib than it was with previously evaluated nonsteroidal anti-inflammatory drugs. The results of this study provide evidence, for the first time, that a specific COX-2 Inhibitor, celecoxib, possesses strong chemopreventive activity against colon carcinogenesis.
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evaluation of Cyclooxygenase 2 Inhibitor for potential chemopreventive properties in colon carcinogenesis
Cancer Research, 1996Co-Authors: Bandaru S Reddy, Karen SeibertAbstract:Epidemiological and laboratory studies indicate an inverse relationship between the risk of colon cancer development and intake of nonsteroidal antiinflammatory agents, including aspirin. One of the mechanisms by which nonsteroidal antiinflammatory agents inhibit colon carcinogenesis is through the inhibition of prostaglandin production by Cyclooxygenase isozymes (COX-1 and COX-2). Overexpression of COX-2 has been observed in colon tumors. Thus, selective Inhibitors of COX-2 could potentially serve as chemopreventive agents. We have assessed the chemopreventive properties of SC-58635, a COX-2 Inhibitor, and of sulindac, as a positive control, in a double-blind study, using azoxymethane-induced colonic aberrant crypt foci (ACF) as a measure of efficacy. Five-week-old male F344 rats were fed the control diet (modified AIN-76A) or experimental diets containing 150 or 1500 ppm SC-58635, 320 ppm sulindac, or 1500 ppm placebo. Two weeks later, all animals except those in vehicle (normal saline)-treated groups were s.c. injected with azoxymethane (15 mg/kg of body weight, once weekly for 2 weeks). At 16 weeks of age, all rats were sacrificed and colons were evaluated for ACF. As expected, dietary administration of sulindac suppressed ACF development as such and reduced crypt multiplicity in terms of number of aberrant crypts/focus. Administration of 1500 ppm SC-58635 inhibited total ACF induction and crypt multiplicity by about 40–49%. Our finding that SC-58635 significantly suppressed colonic ACF formation and crypt multiplicity strengthens the hypothesis that a selective COX-2 Inhibitor possesses chemopreventive activity against colon carcinogenesis.
Chingshih Chen - One of the best experts on this subject based on the ideXlab platform.
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pharmacological exploitation of an off target antibacterial effect of the Cyclooxygenase 2 Inhibitor celecoxib against francisella tularensis
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Haochieh Chiu, John S Gunn, Shilpa Soni, Jian Yang, Samuel K Kulp, Larry S Schlesinger, Chingshih ChenAbstract:Francisella tularensis, a bacterium which causes tularemia in humans, is classified as a CDC category A bioterrorism agent. In this study, we demonstrate that celecoxib, an anti-inflammatory Cyclooxygenase-2 Inhibitor in clinical use, exhibits activity against a type A strain of F. tularensis (Schu S4), the live vaccine strain of F. tularensis (a type B strain), and F. novicida (“F. tularensis subsp. novicida”) directly in growth medium. This bacterial killing, however, was not noted with rofecoxib, despite its higher potency than that of celecoxib in inhibiting Cyclooxygenase-2. The unique ability of celecoxib to inhibit the proliferation of F. tularensis could be pharmacologically exploited to develop novel anti-Francisella therapeutic agents, of which the proof of principle is demonstrated by compound 20, a celecoxib derivative identified through the screening of a celecoxib-based focused compound library. Compound 20 inhibited the intracellular proliferation of Francisella in macrophages without causing appreciable toxicity to these host cells. Together, these data support the translational potential of compound 20 for the further development of novel, potent anti-Francisella agents.
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from the Cyclooxygenase 2 Inhibitor celecoxib to a novel class of 3 phosphoinositide dependent protein kinase 1 Inhibitors
Cancer Research, 2004Co-Authors: Jiuxiang Zhu, Samuel K Kulp, Pinghui Tseng, Yating Yang, Juiwen Huang, Joseph W Fowble, Chungwai Shiau, Yengjeng Shaw, Chingshih ChenAbstract:The blockade of Akt activation through the inhibition of 3-phosphoinositide-dependent kinase-1 (PDK-1) represents a major signaling mechanism whereby celecoxib mediates apoptosis. Celecoxib, however, is a weak PDK-1 Inhibitor (IC(50), 48 microM), requiring at least 30 microM to exhibit discernable effects on the growth of tumor cells in vitro. Here, we report the structure-based optimization of celecoxib to develop PDK-1 Inhibitors with greater potency in enzyme inhibition and growth inhibition. Kinetics of PDK-1 inhibition by celecoxib with respect to ATP suggest that celecoxib derivatives inhibit PDK-1 by competing with ATP for binding, a mechanism reminiscent to that of many kinase Inhibitors. Structure-activity analysis together with molecular modeling was used to generate compounds that were tested for their potency in inhibiting PDK-1 kinase activity and in inducing apoptosis in PC-3 prostate cancer cells. Docking of potent compounds into the ATP-binding site of PDK-1 was performed for lead optimization, leading to two compounds, OSU-03012 and OSU-03013, with IC(50) values in PDK-1 inhibition and apoptosis induction in the low microM range. Exposure of PC-3 cells to these agents led to Akt dephosphorylation and inhibition of p70 S6 kinase activity. Moreover, overexpression of constitutively active forms of PDK-1 and Akt partially protected OSU-03012-induced apoptosis. Screening in a panel of 60 cell lines and more extensive testing in PC-3 cells indicated that the mean concentration for total growth inhibition was approximately 3 microM for both agents. Considering the conserved role of PDK-1/Akt signaling in promoting tumorigenesis, these celecoxib analogs are of translational relevance for cancer prevention and therapy.
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Cyclooxygenase 2 player or spectator in Cyclooxygenase 2 Inhibitor induced apoptosis in prostate cancer cells
Journal of the National Cancer Institute, 2002Co-Authors: Xueqin Song, Samuel K Kulp, Hopi Lin, Amy J Johnson, Pinghui Tseng, Yating Yang, Chingshih ChenAbstract:Background: The antitumor activity of Cyclooxygenase-2 (COX-2) Inhibitors is thought to involve COX-2 enzyme inhibition and apoptosis induction, but it is unclear whether COX-2 inhibition is required for apoptosis. Different COX-2 Inhibitors have similar IC 50 values (concentration for 50% inhibition) for COX-2 inhibition but differ considerably in their abilities to induce apoptosis, suggesting the involvement of a COX-2-independent pathway in apoptosis. To test this hypothesis, we investigated the effect of COX-2 depletion on apoptosis and performed a structure-activity analysis of the COX-2 Inhibitor celecoxib in the androgenindependent prostate cancer cell line PC-3. Methods: Tetracycline-inducible (Tet-On) COX-2 antisense clones were isolated to assess the effect of COX-2 expression on cell viability and sensitivity to apoptosis induced by COX-2 Inhibitors. Untreated Tet-On clones differentially expressed COX-2, and doxycycline-treated clones were depleted of COX-2. We synthesized and characterized various celecoxib derivatives with various COX-2 Inhibitory activities and determined their apoptotic activity in PC-3 cells. Apoptosis was assessed with four tests. Results: In contrast to the effect of COX-2 Inhibitors, which induced apoptosis, COX-2 depletion did not induce cell death. Susceptibility to COX-2 Inhibitor-induced apoptosis was independent of the level of COX-2 expression. Structure-activity analysis found no correlation between apoptosis induction and COX-2 inhibition. Some celecoxib derivatives that lacked COX-2 Inhibitory activity facilitated apoptosis and vice versa. Moreover, celecoxib and apoptosis-active celecoxib derivatives mediated cell death by inhibiting the same pathway. Conclusion: We have dissociated the apoptosis-inducing activity from the COX-2 Inhibitory activity by structural modifications of the COX-2 Inhibitor celecoxib. This separation of activities may provide a molecular basis for the development of new classes of apoptosis-inducing agents.
