BACKGROUNDChemopreventive effect of a selective cyclooxygenase-2 (COX-2) inhibitor JTE-522 on diethylnitrosamine (DEN)-induced hepatocarcinogenesis was evaluated in Wistar rats.METHODSAnimals in the control group (G1) were injected with phosphate buffered saline (PBS), those in hepatocellular carcinoma (HCC) group (G2) were injected with DEN with regular foods for 14 weeks, and those in the treatment groups were injected with DEN for 14 weeks fed with JTE-522 for 7 (G3) and 14 weeks (G4), respectively. Proliferation and precancerous lesions were evaluated by expression levels of proliferating cell nuclear antigen (PCNA) and glutathione S-transferase-P (GST-P), respectively by immunohistochemistry and Western blot analysis. Apoptosis and oxidative stress were evaluated by TdT-mediated dUTP-biotin nick-end labeling (TUNEL) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) staining, respectively.RESULTSAfter 14 weeks of the treatment, HCC was developed in G2, G3, and G4 showing no significant differences in gross appearance and histology of the liver among the three groups. There were no significant differences in the expression levels of PCNA and numbers of TUNEL and 8-OHdG positive cells in the liver among the three groups. However, GST-P positive area was significantly suppressed in G3 and G4 compared to G2.CONCLUSIONOur data revealed that JTE-522 had a modest inhibitory effect on hepatocarcinogenesis in rats in a manner independent of induction of apoptosis and inhibition of oxidative stress.

01 Jan 2010·Urologia InternationalisQ4 · MEDICINE

Enhancement of the Sensitivity of Renal Cell Carcinoma Cells to Fas-Mediated Cytotoxicity and Apoptosis by the Selective Cyclooxygenase-2 Inhibitor JTE-522

Q4 · MEDICINE

Article

Author: Fujiwara, Jun ; Ishida, Hirokazu ; Mizutani, Yoichi ; Abe, Koichi ; Sato, Nodoka ; Nakanishi, Hiroyuki ; Kawauchi, Akihiro ; Toiyama, Daisuke ; Hayashi, Issei ; Li, Yong Nan ; Miki, Tsuneharu

Background: Cyclooxygenase-2 (COX-2) is a key enzyme involved in the production of prostaglandins and its inhibitors have been shown to induce apoptosis in a variety of cancer cells. We reasoned that combination treatment of renal cell carcinoma (RCC) cells with COX-2 inhibitors and anticancer agents may result in synergistic apoptosis. We examined whether the selective COX-2 inhibitor JTE-522 synergizes with anticancer agents in cytotoxicity and apoptosis against RCC cells. Methods: The cytotoxicity of the selective COX-2 inhibitor JTE-522 and other anticancer agents against the RCC cell lines and the normal renal cell line was determined by the microculture tetrazolium dye assay. Results: JTE-522 was cytotoxic against the Caki-1 RCC cell line. JTE-522 and anti-Fas monoclonal antibody (CH-11) exhibited a synergistic cytotoxic effect against Caki-1 cells. In contrast, JTE-522 in combination with 5-fluorouracil, adriamycin, cis-diamminedichloroplatinum, or interferon-α, all commonly used clinically, resulted in an additive cytotoxic effect. Synergy achieved in cytotoxicity with JTE-522 and CH-11 was shown to be due to apoptosis. Conclusions: The present study demonstrated that the selective COX-2 inhibitor JTE-522 had a cytotoxic effect on RCC and that synergistic cytotoxicity against RCC was obtained with JTE-522 in combination with anti-Fas monoclonal antibody. These results suggest that selective COX-2 inhibitors in combination with immunotherapy may be useful in treating patients with RCC.

01 May 2006·Journal of Surgical ResearchQ4 · MEDICINE

Bile Acid Promotes the Proliferation of Squamous Cell Carcinoma of the Esophagus, Independent of its Inducing COX-2 Expression

Q4 · MEDICINE

Article

Author: Kentaro Kishi ; Takushi Yasuda ; Yutaka Kimura ; Yuichiro Doki ; Masahiko Yano ; Hiroshi Miyata ; Yoshiyuki Fujiwara ; Morito Monden ; Kiyonori Nishioka ; Koji Yoshida ; Shigeyuki Tamura

BACKGROUNDWe have reported G1 progression and cyclooxygenase-2 (COX-2) induction during carcinogenesis of the squamous epithelium of the esophagus. As bile acid induces COX-2 expression and promotes carcinogenesis in the digestive tract, we investigated the effect of bile acid on the proliferation of squamous cell carcinoma of the esophagus (ESCC).MATERIALS AND METHODSMTT assay, Western blot analysis of COX-2 and cell cycle-related molecules in the G1 phase (Rb, CDC25A, cyclin D1), and CDK2 kinase assay were performed on chenodeoxycholic acid (CDCA) exposure to ESCC cell lines (TE2R, TE3, TE13, TE15).RESULTSIn the presence of gradient bile acid concentration (up to 100 microm), growth of ESCC cell lines was stimulated at a low concentration (maximally at 20-30 microm), but suppressed at a higher concentration. Only a low dose of bile acid induced the expression of cyclin D1 and CDC25A and showed high Rb phosphorylation and high CDK2 kinase activity. In contrast, bile acid progressively induced COX-2 expression in a dose-dependent manner, regardless of its biphasic effects on cell proliferation, and a COX-2 specific inhibitor (JTE-522) did not suppress growth stimulation by a low dose of bile acid.CONCLUSIONSBile acid at a low dose stimulates the proliferation of ESCC by inducing G1-regulating molecules. However, COX-2 expression, which is also induced by bile acid, does not affect cell proliferation. Further work is needed to elucidate its role in carcinogenesis.

100 Deals associated with Tilmacoxib

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Indication	Highest Phase	Country/Location	Organization	Date
Adenomatous Polyposis Coli	Phase 2	-	Japan Tobacco (Hong Kong) Ltd.	-
Adenomatous Polyposis Coli	Phase 2	-	Janssen Global Services LLC	-
Adenomatous Polyposis Coli	Phase 2	JP	Japan Tobacco, Inc.	-
Osteoarthritis	Phase 2	-	Japan Tobacco (Hong Kong) Ltd.	-
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Pain, Postoperative	Phase 2	-	Janssen Global Services LLC	-
Pain, Postoperative	Phase 2	-	Japan Tobacco (Hong Kong) Ltd.	-
Rheumatoid Arthritis	Phase 2	JP	-	-
Osteoarthritis	Phase 1	-	Janssen Global Services LLC	-

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