title: Age-related differential responses to curcumin-induced apoptosis during the initiation of colon cancer in rats.
abstract: Curcumin is a widely-used dietary supplement and a chemopreventive agent for various cancers. Pre-clinical chemopreventive studies rarely consider the effect of aging. We previously reported that unlike young animals, curcumin is ineffective in middle-aged rats for colon chemoprevention. This study investigated whether resistance to apoptosis during cancer initiation contributes to this age-dependent effect. Young, middle-aged, and old F344 rats were fed either curcumin (0.6%) or control diet. Colonic apoptosis was evaluated 0, 8, and 16 h after azoxymethane (AOM) injection. Colonic Hsp70 mRNA levels, caspase-9 activity, cell proliferation, and crypt morphology were measured. In AOM-treated rats, only middle-aged rats were resistant to curcumin-induced apoptosis whereas cell proliferation was reduced by curcumin in all ages. Curcumin-induced apoptosis was mediated by caspase-9 in young but not older rats. Transcriptional Hsp70 expression was induced in only young rats and was suppressed by curcumin. Therefore, the age-related difference in curcumin chemoprevention is due to a differential response in induction of apoptosis. The mitochondria-dependent pathway seems to mediate curcumin-induced apoptosis in young but not older animals. Hsp70 expression was not related with resistance to curcumin-induced apoptosis. Understanding age-related differences in the apoptotic response may lead to improved translation from pre-clinical animal studies to humans.
authors.affiliation: Department of Nutrition and Food Science, University of Maryland, College Park, MD, USA.
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Kwon
authors.forename: Bernadene A
authors.initials: BA
authors.lastname: Magnuson
mesh_terms: D000367:Age Factors; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D053453:Caspase 9 / Q000378:metabolism; D018890:Chemoprevention; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D003474:Curcumin / Q000494:pharmacology*; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D050957:HSP110 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D000970:Antineoplastic Agents; D002273:Carcinogens; D050957:HSP110 Heat-Shock Proteins; C494655:Hspa4 protein, rat; D012333:RNA, Messenger; D053453:Caspase 9; D003474:Curcumin