Decrease in growth factor receptors after treatment with serine protease inhibitor ONO-3403

Hiwasa, Takaki; Shimada, Hideaki; Ochiai, Takenori; Liu, Tian-Ling; Yuasa, Yasuhito; Takao, Masaki; Ohkoshi, Masaaki

doi:10.3892/ijo.20.4.797

Cited by 2 publications

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“…This is the first report concerning a protective effect of ONO 3403 against LPS-mediated toxicity. ONO 3403 inhibits the growth of normal and transformed cells, 10,28 and induces apoptosis-like cell death via stimulating calpain activity. 29 However, the cytotoxic action is not observed at concentrations of 2-20 mg/ml in our study, excluding the possibility that the inhibition of pro-inflammatory mediators by ONO 3403 might be dependent on the cytotoxic action.…”

Section: Discussionmentioning

confidence: 99%

ONO 3403, a synthetic serine protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-α and nitric oxide production and protects mice from lethal endotoxic shock

et al. 2009

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ONO 3403, a new synthetic serine protease inhibitor, is a derivative of camostat mesilate and has a higher protease-inhibitory activity. The effect of ONO 3403 on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α and nitric oxide (NO) production in RAW 264.7 macrophage-like cells was examined. ONO 3403 significantly inhibited LPS-induced TNF-α production at a lower concentration than camostat mesilate. It also inhibited LPS-induced NO production. Their inhibition was responsible for the reduced mRNA expression of TNF-α and inducible NO synthase. In LPS-stimulated cells, ONO 3403 prevented the augmentation of MyD88 expression and inhibited the phosphorylation of IκB-α, stress-activated protein kinase (SAPK) and IRF-3, and the production of interferon-β. ONO 3403 abolished the elevation of the extracellular serine protease activity in response to LPS. Further, it reduced the circulating TNF-α level, hepatic injury and mortality in mice receiving an injection of D-galactosamine and LPS. ONO 3403 was suggested to inhibit LPS-induced inflammatory responses via inactivation of MyD88-dependent and independent pathways.

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Section: Discussionmentioning

confidence: 99%

ONO 3403, a synthetic serine protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-α and nitric oxide production and protects mice from lethal endotoxic shock

et al. 2009

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“…( 24 ) Transfection with calpain inhibitor calpastatin did not increase 5‐FU sensitivity (data not shown), possibly because the basal activity of calpain was sufficiently suppressed in the ras‐NIH3T3 cells. ( 30 ) Transfection with calpain/calpastatin cDNA into human gastric adenocarcinoma cells failed to produce any significant difference in the sensitivity to 5‐FU presumably because of the much lower transfection efficiency in human cells compared with that in mouse fibroblasts (data not shown).…”

Section: Discussionmentioning

confidence: 96%

“…In turn, the TS‐FdUMP complex, which was rapidly detectable in 5‐FU‐sensitive KATO‐III cells (Fig. 3E), remarkably decreased by pretreatment with calpain stimulator ONO‐3403 ( 28–30 ) for 1 h followed by 5‐FU treatment in the presence of ONO‐3403 for 2 h (Fig. 4B).…”

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Calpain regulates thymidylate synthase–5‐fluoro‐dUMP complex levels associated with response to 5‐fluorouracil in gastric cancer cells

Nabeya

Suzuki²,

Furuya

et al. 2011

Cancer Science

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Thymidylate synthase (TS) plays a major role in the response to 5-fluorouracil (5-FU) by binding directly to the 5-FU metabolite, 5-fluoro-dUMP (FdUMP). The change in the TS expression levels after 5-FU administration was examined in parallel to 5-FU responsiveness in six human gastric adenocarcinoma cell lines to elucidate the source of variability of 5-FU sensitivity. MKN-1, SH-10-TC and MKN-74 cells were more resistant to 5-FU than MKN-28, KATO III and MKN-45 cells. Western blotting analysis revealed that the 5-FU sensitivity of these cells did not correlate with the basal TS expression levels but did correlate with rapid detection of the TS-FdUMP complex after exposure to 5-FU. In 5-FU-resistant cells, very low levels of the TS-FdUMP complex early after 5-FU exposure were elevated by pretreatment with calpain inhibitors such as benzyloxycarbonyl-leucyl-leucinal (ZLLH), benzyloxycarbonyl-leucyl-leucyl-leucinal (ZLLLH) and ALLN, but not by other protease inhibitors. In contrast, ONO-3403, which causes calpain activation, stimulated downregulation of the TS-FdUMP complex in 5-FU-sensitive cells. The expression levels of calpastatin, an endogenous calpain inhibitor, were higher in 5-FU-sensitive cells than in 5-FUresistant cells. ZLLH increased the 5-FU sensitivity of 5-FU-resistant cells, whereas ONO-3403 decreased the sensitivity of 5-FU-sensitive cells. In addition, knockdown of m-calpain by siRNA increased the 5-FU sensitivity in 5-FU-resistant cells, while knockdown of calpastatin reduced the sensitivity in 5-FU-sensitive cells. These results suggest that calpain might reduce the chemosensitivity of human gastric cancer cells to 5-FU possibly by rapid degradation of the TS-FdUMP complex, a finding that is considered to have novel therapeutic implications. (Cancer Sci 2011; 102: 1509-1515 G astric cancer is one of the most common neoplasms worldwide.(1,2) Although surgery remains the mainstay of potentially curative treatment, the prognoses even for patients who undergo a complete resection are not satisfactory. Postoperative adjuvant chemotherapy with S-1, which includes tegafur as a prodrug of 5-FU, has recently been reported to be effective for curatively resected stage II ⁄ III gastric cancer.(3) At present, 5-FU is still a key drug for gastric cancer in both the adjuvant and primary settings, while numerous multidrug regimens have been developed for this treatment.(4,5) However, chemotherapeutic management is further complicated by the observation that, even among gastric cancers that share identical clinicopathological features, there are significant differences among individuals in the sensitivity to the same regimen.(6-9) Therefore, the clinical response to 5-FU-based chemotherapy is patient dependent, and it is important to select patients in whom the treatment is likely to be effective, namely, to predict the sensitivity of gastric cancer cells to 5-FU.(5,7-9) Gastric adenocarcinoma cells that have a mutant p53 are likely to be more resistant to the growth-inhibitory effect of 5-FU than cells with ...

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Decrease in growth factor receptors after treatment with serine protease inhibitor ONO-3403

Cited by 2 publications

References 0 publications

ONO 3403, a synthetic serine protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-α and nitric oxide production and protects mice from lethal endotoxic shock

ONO 3403, a synthetic serine protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-α and nitric oxide production and protects mice from lethal endotoxic shock

Calpain regulates thymidylate synthase–5‐fluoro‐dUMP complex levels associated with response to 5‐fluorouracil in gastric cancer cells

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