Chemoprevention of familial adenomatous polyposis by natural dietary compounds sulforaphane and dibenzoylmethane alone and in combination in ApcMin/+ mouse.
Cancer chemopreventive agent sulforaphane (SFN) and dibenzoylmethane (DBM) showed antitumorigenesis effects in several rodent carcinogenesis models. In this study, we investigated the cancer chemopreventive effects and the underlying molecular mechanisms of dietary administration of SFN and DBM alone or in combination in the ApcMin/+ mice model. Male ApcMin/+ mice (12 per group) at age of 5 weeks were given control AIN-76A diet, diets containing 600 ppm SFN and 1.0% DBM, or a combination of 300 ppm SFN and 0.5% DBM for 10 weeks. Mice were then sacrificed, and tumor numbers and size were examined. Microarray analysis, Western blotting, ELISA, and immunohistochemical staining were done to investigate the underlying molecular mechanisms of cancer chemopreventive effects of SFN and DBM. Dietary administrations of SFN and DBM alone or in combination significantly inhibited the development of intestinal adenomas by 48% (P=0.002), 50% (P=0.001), and 57% (P<0.001), respectively. Dietary administration of 600 ppm SFN and 1.0% DBM also reduced colon tumor numbers by 80% (P=0.016) and 60% (P=0.103), respectively, whereas the combination of SFN and DBM treatment blocked the colon tumor development (P=0.002). Both SFN and DBM treatments resulted in decreased levels of prostaglandin E2 or leukotriene B4 in intestinal polyps or apparently normal mucosa. Treatments also led to the inhibition of cell survival and growth-related signaling pathways (such as Akt and extracellular signal-regulated kinase) or biomarkers (such as cyclooxygenase-2, proliferating cell nuclear antigen, cleaved caspases, cyclin D1, and p21). In conclusion, our results showed that both SFN and DBM alone as well as their combination are potent natural dietary compounds for chemoprevention of gastrointestinal cancers.
Shen
Guoxiang
G
Center for Cancer Prevention Research, Department of Pharmaceutics, and Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Khor
Tin Oo
TO
Hu
Rong
R
Yu
Siwang
S
Nair
Sujit
S
Ho
Chi-Tang
CT
Reddy
Bandaru S
BS
Huang
Mou-Tuan
MT
Newmark
Harold L
HL
Kong
Ah-Ng Tony
AN
D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016718:Arachidonic Acid / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D047188:Chalcones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004032:Diet; D020869:Gene Expression Profiling; D007421:Intestine, Small / Q000378:metabolism; D017879:Isothiocyanates; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013454:Sulfoxides; D013861:Thiocyanates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D018797:Cell Cycle Proteins; D047188:Chalcones; D017879:Isothiocyanates; D013454:Sulfoxides; D013861:Thiocyanates; D016718:Arachidonic Acid; C061481:dibenzoylmethane; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; C016766:sulforaphane