Graduate Program in Pharmaceutical Science, Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA.
Carcinogenesis. 2010 May;31(5):880-5. doi: 10.1093/carcin/bgp285. Epub 2009 Dec 3.
Previously, phenethyl isothiocyanate (PEITC) and dibenzoylmethane (DBM) had been shown to inhibit intestinal carcinogenesis in Apc(Min/+) mice. In this study, we investigated the chemopreventive efficacy of PEITC and DBM in the azoxymethane (AOM)-initiated and dextran sodium sulfate (DSS)-promoted colon cancer mouse model and to compare their potential in vivo mechanisms leading to chemoprevention. The mice were fed with diet supplemented with 0.05% PEITC or 1% DBM before or after AOM initiation. Our results showed that AOM/DSS mice fed with PEITC- or DBM-supplemented diet had lower tumor incidence, lower colon tumor multiplicities and smaller polyps as compared with mice fed with the standard AIN-76A diet. PEITC was effective even after AOM initiation, whereas DBM was not as effective when fed after AOM initiation. Hematoxylin and eosin staining showed that mice fed with PEITC or DBM had attenuated loss of crypt, a marker of inflammation. To examine potential in vivo mechanisms involved in chemoprevention, western blotting was performed and showed that inhibition of growth of adenomas by PEITC was associated with an increase of apoptosis (increased cleaved caspase-3 and-7) and cell cycle arrest (increased p21). In contrast DBM's effect on cell cycle arrest and apoptosis markers was not as substantial as PEITC. Instead, DBM showed increased induction of NF-E2-related factor-2 (Nrf2) transcription factor and phase II detoxifying enzymes, which appears to correlate with in vitro cell lines results that DBM is a more potent Nrf2 activator than PEITC. In summary, our present study shows that PEITC and DBM are potent natural dietary compounds for chemoprevention of colon cancer induced by AOM/DSS and appears to be associated with different in vivo mechanism of actions. PEITC's chemopreventive effect appears to be due to induction of apoptosis and cell cycle arrest, whereas DBM's effect is due to prevention of AOM initiation via induction of Nrf2 and phase II detoxifying enzymes.
先前的研究表明，苯乙基异硫氰酸酯（PEITC）和二苯甲酰甲烷（DBM）可抑制 Apc（Min/+）小鼠的肠道癌变。在这项研究中，我们研究了 PEITC 和 DBM 在氧化偶氮甲烷（AOM）诱导和葡聚糖硫酸钠（DSS）促进的结肠癌小鼠模型中的化学预防功效，并比较了它们在体内导致化学预防的潜在机制。在 AOM 诱导前或诱导后，将小鼠喂食含 0.05%PEITC 或 1%DBM 的饮食。结果显示，与喂食标准 AIN-76A 饮食的小鼠相比，喂食 PEITC 或 DBM 饮食的 AOM/DSS 小鼠的肿瘤发生率更低，结肠肿瘤数量更少，息肉更小。PEITC 甚至在 AOM 诱导后仍有效，而 DBM 在 AOM 诱导后喂食则效果不佳。苏木精和伊红染色显示，喂食 PEITC 或 DBM 的小鼠的隐窝丢失减轻，这是炎症的标志物。为了研究化学预防中涉及的潜在体内机制，进行了 Western blot 分析，结果显示，PEITC 抑制腺瘤生长与凋亡增加（增加 cleaved caspase-3 和 -7）和细胞周期停滞（增加 p21）有关。相比之下，DBM 对细胞周期停滞和凋亡标志物的作用不如 PEITC 明显。相反，DBM 显示出 NF-E2 相关因子-2（Nrf2）转录因子和 II 相解毒酶的诱导增加，这似乎与 DBM 是比 PEITC 更有效的 Nrf2 激活剂的体外细胞系结果相关。总之，本研究表明，PEITC 和 DBM 是 AOM/DSS 诱导的结肠癌化学预防的有效天然膳食化合物，并且似乎与不同的体内作用机制有关。PEITC 的化学预防作用似乎是由于诱导凋亡和细胞周期停滞，而 DBM 的作用是通过诱导 Nrf2 和 II 相解毒酶来预防 AOM 诱导。
