Tetsuya Tanigawa

Rebamipide Inhibits Gastric Cancer Cell Growth

Rebamipide is an antiulcer drug used in Japan, Korea, China, Philippines, and other Asian countries for treatment of gastritis and peptic ulcer. Its effect on gastric cancer cell growth and its regulatory mechanisms remain unknown. We examined whether rebamipide affects human gastric cancer cell proliferation and activation of Smad signaling pathway. Gastric cancer (AGS) cells were treated with either (a) medium (control), (b) medium-containing rebamipide (0.5–2xa0mg/mL), or (c) PD98059+rebamipide. We determined cell proliferation, expression of p21, phosphorylation of ERK2, JNK p38, and Smad2/3, formation of Smad2/3–Smad4 complex, and nuclear translocation of Smad2/3. Rebamipide treatment inhibited AGS cell proliferation and increased p21, Smad2/3 phosphorylation, and Smad2/3–Smad4 complex formation. Rebamipide induced phosphorylation of ERK2 but not JNK or p38. Inactivation of ERK2 by PD98059 partly attenuated rebamipide-induced p21 expression. These data demonstrate that rebamipide activates Smad signaling pathway and suppresses human gastric cancer cell growth. Inactivation of ERK2 partly inhibited rebamipide-induced p21 expression, indicating a crosstalk between ERK and Smad signaling pathways.

Selective cyclooxygenase (COX) inhibition causes damage to portal hypertensive gastric mucosa: roles of nitric oxide and NF-κB

Portal hypertension (PHT) is associated with increased susceptibility of the gastric mucosa to injury by a variety of factors, including nonsteroidal anti‐inflammatory drugs (NSAIDs) that nonselectively inhibit both isoforms of cyclooxygenase (COX‐1 and ‐2). PHT gastric mucosa also has excessive nitric oxide (NO) production that contributes to the general increased susceptibility to injury. Using a rat model of PHT, we studied whether selective COX inhibition, which does not damage normal (normotensive) gastric mucosa, is sufficient to cause PHT gastric damage and, if so, whether and how excessive NO is involved. Indomethacin, a nonselective NSAID, caused 2.4‐fold more gastric injury to PHT vs. normotensive sham‐operated (SO) control rats. Neither NS‐398 nor celecoxib, selective COX‐2 inhibitors, caused gastric damage in either SO or PHT rats. SC‐560, a selective COX‐1 inhibitor, did not cause gastric damage in SO rats but dose‐dependently caused gastric damage in PHT rats. There was a compensatory increase in COX‐2 expression and activity in SC‐560‐treated SO rats but not SC‐560‐treated PHT rats. Partial inhibition of NO production restored gastric COX‐2 expression and activity levels in SC‐560‐treated PHT rats to those of SC‐560‐treated SO rats, by a mechanism consistent with induction of NF‐κB, and significantly reduced gastric damage. These studies indicate that, in contrast to normotensive gastric mucosa, inhibition of COX‐1 alone is sufficient to cause PHT gastric damage as a result of excessive NO that prevents the induction of NF‐κB and the compensatory increase in COX‐2.