Kwon Youngjoo, Magnuson Bernadene A
Department of Nutrition and Food Science, University of Maryland, College Park, MD, USA.
Food Chem Toxicol. 2009 Feb;47(2):377-85. doi: 10.1016/j.fct.2008.11.035. Epub 2008 Dec 6.
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.
姜黄素是一种广泛使用的膳食补充剂，也是一种针对多种癌症的化学预防剂。临床前化学预防研究很少考虑衰老的影响。我们之前报道过，与年轻动物不同，姜黄素对中年大鼠的结肠化学预防无效。本研究调查了癌症起始过程中对凋亡的抗性是否导致了这种年龄依赖性效应。给年轻、中年和老年的F344大鼠喂食姜黄素（0.6%）或对照饮食。在注射偶氮甲烷（AOM）后0、8和16小时评估结肠凋亡情况。测量结肠Hsp70 mRNA水平、半胱天冬酶-9活性、细胞增殖和隐窝形态。在AOM处理的大鼠中，只有中年大鼠对姜黄素诱导的凋亡具有抗性，而姜黄素在所有年龄段都能降低细胞增殖。姜黄素诱导的凋亡在年轻大鼠中由半胱天冬酶-9介导，而在老年大鼠中则不然。转录性Hsp70表达仅在年轻大鼠中被诱导，且被姜黄素抑制。因此，姜黄素化学预防中与年龄相关的差异是由于凋亡诱导的不同反应所致。线粒体依赖性途径似乎介导了姜黄素在年轻而非老年动物中诱导的凋亡。Hsp70表达与对姜黄素诱导凋亡的抗性无关。了解凋亡反应中与年龄相关的差异可能会改善从临床前动物研究到人类研究的转化。
