Inhibition of haematogenous metastasis of colon cancer in mice by a selective COX-2 inhibitor, JTE-522

Tomozawa, Shigeru; Nagawa, Hirokazu; Tsuno, Nelson H.; Hatano, Kenji; Osada, Taro; Kitayama, Joji; Sunami, Eiji; Nita, Marcelo Eidi; Ishihara, Soichiro; Yano, Hideaki; Tsuruo, Takashi; Shibata, Yoichi; Muto, Tetsuichiro

doi:10.1038/sj.bjc.6694262

Cited by 106 publications

(80 citation statements)

References 28 publications

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“…A previous in vitro study using cell lines of CRC origin by Tsujii et al (1997) suggested that COX-2 inhibition may be beneficial in preventing the expression of genes associated with metastatic progression. Furthermore, a recent study by Tomozawa et al (1999) demonstrated that the COX-2 selective inhibitor JTE-522 might decrease the rate of haematogenous metastasis of CRC.…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2 selective inhibition with NS-398 suppresses proliferation and invasiveness and delays liver metastasis in colorectal cancer

et al. 2004

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Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to reduce the risk and mortality of colorectal cancer (CRC) by inhibiting the activity of cyclooxygenase (COX). The present studies were directed to determine whether selective COX-2 inhibition reduces CRC tumour cell proliferation and invasion/migration, and the possible cellular and molecular mechanisms involved. The MC-26 cells are a highly invasive mouse CRC cell line expressing COX-2 protein. NS-398 (100 mM), a highly selective COX-2 inhibitor, decreased cell proliferation by B35% of control, as determined using [ 3 H]-thymidine incorporation. This reduction in cell proliferation was associated with decreased expression of cyclin D1 and proliferating cell nuclear antigen (PCNA). Furthermore, NS-398 inhibited cell invasion/migration through Matrigel extracellular matrix components at 24 h by B60%. The addition of exogenous prostaglandin E 2 partially attenuated the inhibition of cell invasion by 10 mM NS-398, but failed to reverse the effect of 100 mM NS-398. Matrix metalloproteinases-2 (MMP-2) and -9 (MMP-9) are two enzymes that facilitate cell invasion/migration by degrading the extracellular matrix. In the presence of 100 mM NS-398, Western blot hybridisation analysis and zymography demonstrated that both MMP-2 and MMP-9 protein levels and enzyme activity were decreased by B25 -30%. In separate studies, NS-398 also inhibited tumour growth in vivo and retarded the formation of liver metastasis. The results of these studies indicate that the expression and activity of COX-2 appear to be associated with both the proliferative and invasive properties of CRC. Cyclooxygenase-2 inhibition suppresses tumour cell growth and invasion/migration, and retards liver metastasis in a mouse colon cancer model, via multiple cellular and molecular mechanisms.

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Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2 selective inhibition with NS-398 suppresses proliferation and invasiveness and delays liver metastasis in colorectal cancer

et al. 2004

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“…In the mouse model, JTE-522 has been found to inhibit liver and lung metastases of colon cancer that show COX-2 expression but lack an effect on those lacking COX-2 expression. 16,17 Considering that COX-2 is the best-known target for NSAIDs in colon carcinogenesis, lack of inhibitory effects of JTE-522 on signet-ring cell and mucinous carcinomas could be explained at least in part by a lack of COX-2 expression in those cancers. Furthermore, Park et al 25 have suggested that tubular adenocarcinoma follows the ACF-adenoma-carcinoma sequence, whereas poorly differentiated carcinoma may arise de novo without passing through the stage of ACF in DMH-induced colon carcinogenesis in rats.…”

Section: Discussionmentioning

confidence: 99%

“…14,15 This compound also inhibited liver and lung metastases of colon cancer expressing COX-2 but lacked effect on those lacking COX-2 expression in the nude mouse xenograft model. 16,17 In chemically induced colon carcinogenesis, we have previously shown that JTE-522 inhibited the development of aberrant crypt foci (ACF), the putative precursors of both human and experimental colon cancer, 18,19 when administered throughout the study. 20 In the present study, to evaluate the chemopreventive properties of JTE-522, we have investigated the efficacy of JTE-522 during different stages of rat colon carcinogenesis using colon tumor formation as an endpoint, including its effects on histopathologic pattern and growth, as well as invasion of colon tumors.…”

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confidence: 99%

JTE‐522, a selective cyclooxygenase‐2 inhibitor, inhibits induction but not growth and invasion of 1,2‐dimethylhydrazine‐induced tubular adenocarcinomas of colon in rats

Wei

Morimura

Wanibuchi

et al. 2004

Intl Journal of Cancer

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We have previously demonstrated that JTE-522, a selective cyclooxygenase-2 (COX-2) inhibitor, inhibited development of aberrant crypt foci (ACF) in rats, a putative preneoplastic lesion in colon, and suggested its inhibitory potential in rat colon carcinogenesis. To evaluate the chemopreventive properties of JTE-522, the present study was design to evaluate the inhibitory effects of JTE-522 on rat colon tumorigenesis induced by 1,2-dimethylhydrazine (DMH). Rats at 6 weeks of age were divided into 4 groups. One week after the start of the experiment, all rats received DMH by s.c. injection at a dose of 40 mg/kg body weight once a week for 4 successive weeks. As the initiation and postinitiation treatment groups, groups 1-3 were fed diets containing 0, 50, or 150 ppm JTE-522, respectively, from the start of the study to the end. As the postinitiation treatment group, group 4 was given 150 ppm JTE-522 from 1 week after the last DMH injection to the end of the study. Forty weeks after the start of the experiment, administration of 150 ppm JTE-522 during both initiation and postinitiation stages significantly inhibited the incidences of tubular adenocarcinomas and total carcinomas, as well as total tumors in the colon. The inhibitory effect of JTE-522 was most prominent for tubular adenocarcinomas, but was not observed in the nontubular carcinomas (signet-ring cell and mucinous carcinomas). Almost equal inhibitory effects on tubular adenocarcinomas were also observed in the rats given 150 ppm JTE-522 during the postinitiation stage, suggesting that its major anticancer action is at the postinitiation phase. However, JTE-522 had no effect on the size or invasive extent of tubular adenocarcinomas. Furthermore, microarray analyses revealed that JTE-522 had no effect on gene expression levels in DMH-induced tubular adenocarcinomas. These findings suggest that JTE-522 possesses chemopreventive activity against induction but not progression of tubular adenocarcinomas in rat colon. In view of the significant inhibitory effects of JTE-522 on ACF, its major anticancer action may occur in the postinitiation stage but before the malignant conversion stage of DMH-induced colon carcinogenesis.Key words: JTE-522; selective cyclooxynenase-2 inhibitor; colon carcinogenesis; tubular adenocarcinoma; chemoprevention Colorectal cancer leads to approximately 550,000 annual deaths worldwide 1 and is therefore a major public health problem and underlines the need for effective chemopreventive strategies. The protective effect of traditional nonsteroidal antiinflammatory drugs (NSAIDs), such as aspirin and sulindac, for colon cancer has been well documented in epidemiologic and animal studies. 2 However, their use for chemoprevention of colon cancer has been hindered by their potential gastrointestinal and renal toxicity. It is now known that nonselective NSAIDs inhibit activities of cyclooxygenases (COX), and inhibition of COX-2 may well explain their chemopreventive effect, whereas inhibition of COX-1 is believed to be responsible for man...

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“…In the treatment experiment, a hepatic metastasis model was constructed by infusing cancer cells in BALB/c or CDF1 male mice below the splenic capsule where etodolac and PSK were administered. Cells (5x10 5 ) of the mouse colon cancer 26 cell line (CT26) and its highly metastatic variant were implanted below the splenic capsule. Three days after implantation, a spleen-removed group and a non-spleen-removed one were produced and the hepatic metastasis model was designed.…”

Section: Methodsmentioning

confidence: 99%

A review of the anti-tumor effect of the combined administration of a cyclooxygenase-2 selective inhibitor and a non-specific immunostimulant protein-bound polysaccharide on an advanced colon cancer model using colon cancer cell lines

et al. 2011

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Abstract. The anti-tumor effect of a cyclooxygenase (COX)-2 selective inhibitor or a non-specific immunostimulant (PSK) alone, as well as the anti-tumor effect of their combined administration were examined on a hepatic metastasis model of colon cancer using a colon 26 cell line (CT26) and its highly metastatic variant. Anti-tumor effects were assessed by the number of hepatic metastases. Serum MMP-9, TGF-β and IL-6 were also measured. In a preliminary experiment, cells (5x10 5 ) of a mouse colon cancer 26 cell line (CT26) and its highly metastatic variant were implanted below the splenic capsule in BALB/c and CDF1 mice. The number of hepatic metastatic CT26 cell lesions in the CDF1 mice of the nonspleen-removed group at 2 weeks was found to be optimum for the experiments. Although no significant difference was found, etodolac treatment showed the highest inhibitory effect on the number of hepatic metastases at a concentration of 30 mg/kg. In contrast, intraperitoneal administration of 50 mg/ kg PSK showed an inhibitory effect on hepatic metastases, but a significant difference was not observed. PSK (p=0.002) or the combined use of etodolac and PSK (p=0.001) exhibited a significant inhibition of the number of hepatic metastases. In addition, MMP-9 was significantly inhibited by the single use of etodolac or PSK, and was inhibited with an additive effect by the combined use of etodolac and PSK. IL-6 and TGF-β were significantly inhibited following the combined use of etodolac and PSK. In conclusion, etodolac did not exhibit any significant hepatic metastasis inhibitory effect, whereas it significantly reduced the MMP-9 level. PSK reduced both the number of hepatic metastases and MMP-9. Combined use of etodolac and PSK did not show any additive effect in the inhibition of the number of hepatic metastases, whereas it inhibited MMP-9, TGF-β and IL-6, suggesting the benefit of a combined effect.

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Inhibition of haematogenous metastasis of colon cancer in mice by a selective COX-2 inhibitor, JTE-522

Cited by 106 publications

References 28 publications

Cyclooxygenase-2 selective inhibition with NS-398 suppresses proliferation and invasiveness and delays liver metastasis in colorectal cancer

Cyclooxygenase-2 selective inhibition with NS-398 suppresses proliferation and invasiveness and delays liver metastasis in colorectal cancer

JTE‐522, a selective cyclooxygenase‐2 inhibitor, inhibits induction but not growth and invasion of 1,2‐dimethylhydrazine‐induced tubular adenocarcinomas of colon in rats

A review of the anti-tumor effect of the combined administration of a cyclooxygenase-2 selective inhibitor and a non-specific immunostimulant protein-bound polysaccharide on an advanced colon cancer model using colon cancer cell lines

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