Colorectal cancer chemoprevention by 2 beta-cyclodextrin inclusion compounds of auraptene and 4'-geranyloxyferulic acid.
The inhibitory effects of novel prodrugs, inclusion complexes of 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans propenoic acid (GOFA) and auraptene (AUR) with beta-cyclodextrin (CD), on colon carcinogenesis were investigated using an azoxymethane (AOM)/dextran sodium sulfate (DSS) model. Male CD-1 (ICR) mice initiated with a single intraperitoneal injection of AOM (10 mg/kg body weight) were promoted by the addition of 1.5% (w/v) DSS to their drinking water for 7 days. They were then given a basal diet containing 2 dose levels (100 and 500 ppm) of GOFA/beta-CD or AUR/beta-CD for 15 weeks. At Week 18, the development of colonic adenocarcinoma was significantly inhibited by feeding with GOFA/beta-CD at dose levels of 100 ppm (63% reduction in multiplicity, p < 0.05) and 500 ppm (83% reduction in the multiplicity, p < 0.001), when compared with the AOM/DSS group (multiplicity: 3.36 +/- 3.34). In addition, feeding with 100 and 500 ppm (p < 0.01) of AUR/beta-CD suppressed the development of colonic adenocarcinomas. The dietary administration with GOFA/beta-CD and AUR/beta-CD inhibited colonic inflammation and also modulated proliferation, apoptosis and the expression of several proinflammatory cytokines, such as nuclear factor-kappaB, tumor necrosis factor-alpha, Stat3, NF-E2-related factor 2, interleukin (IL)-6 and IL-1beta, which were induced in the adenocarcinomas. Our findings indicate that GOFA/beta-CD and AUR/beta-CD, especially GOFA/beta-CD, are therefore able to inhibit colitis-related colon carcinogenesis by modulating inflammation, proliferation and the expression of proinflammatory cytokines in mice.
Tanaka
Takuji
T
Department of Oncologic Pathology, Kanazawa Medical University, Uchinada, Ishikawa, Japan. takutt@kanazawa-med.ac.jp
de Azevedo
Mariangela B M
MB
Durán
Nelson
N
Alderete
Joel B
JB
Epifano
Francesco
F
Genovese
Salvatore
S
Tanaka
Mayu
M
Tanaka
Takahiro
T
Curini
Massimo
M
D000818:Animals; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000453:epidemiology / Q000401:mortality / Q000517:prevention & control*; D003374:Coumarins / Q000627:therapeutic use*; D004224:Diterpenes / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D015994:Incidence; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D015212:Inflammatory Bowel Diseases / Q000150:complications; D051034:Inhibitor of Apoptosis Proteins; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011422:Propionates / Q000627:therapeutic use; D012097:Repressor Proteins; D000077022:Survivin; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000627:therapeutic use*
C506371:3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoic acid; C117749:Birc5 protein, mouse; D003374:Coumarins; D004224:Diterpenes; D051034:Inhibitor of Apoptosis Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D011422:Propionates; D012097:Repressor Proteins; D000077022:Survivin; D014409:Tumor Necrosis Factor-alpha; D047392:beta-Cyclodextrins; C105832:aurapten