Journal
GASTRIC CANCER
Volume 18, Issue 4, Pages 774-783Publisher
SPRINGER
DOI: 10.1007/s10120-014-0434-3
Keywords
Analog; beta-Catenin; Curcumin; Gastric cancer; Signal transducer and activator of transcription 3
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Funding
- Japan Society for the Promotion of Science [22501041]
- Cancer Research Institute of Kanazawa University
- Nippon Carbide Industries (Tokyo, Japan)
- Grants-in-Aid for Scientific Research [221S0001, 22501041, 24510062] Funding Source: KAKEN
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Potent chemotherapy for advanced gastric cancer has not been completely established. Many molecularly targeted therapies are under investigation, but their therapeutic outcomes are not promising because they do not target specific and/or critical targets of gastric carcinogenesis. Although the molecular basis of gastric carcinogenesis remains poorly understood, nuclear localization of beta-catenin was observed in approximately 50 % of gastric cancer specimens. Recent studies have suggested that activation of signal transducer and activator of transcription 3 (STAT3) contributes to gastric carcinogenesis in a mouse model. A newly synthesized curcumin analog has inhibitory potential against beta-catenin and STAT3. Using a transgenic mouse model of gastric cancer in which beta-catenin, cyclooxygenase 2, and microsomal prostaglandin E synthase 1 activation is induced, we examined a curcumin analog with the most enhanced potential for treating gastric cancer through oral administration. Inhibition of these targets was demonstrated using microarray and immunohistochemical analyses. The curcumin analog GO-Y031 decreased the incidence of gastric carcinogenesis to 54.5 % of that of the control (50.0 % vs 91.7 %, p = 0.043), and tumor size was reduced to 51.6 % of that of the control (1.6 mm vs 3.1 mm, p = 0.03). beta-Catenin and STAT3 levels were suppressed to 26.2 % (p = 0.00023) and 44.8 % (p = 0.025), respectively, of those of the control. Moreover, macrophage infiltration was suppressed with GO-Y031. beta-Catenin and STAT3 can be pharmacologically inhibited in vivo with a curcumin analog, which effectively inhibits beta-catenin and STAT3.
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