The principal urinary metabolites of dietary isothiocyanates, N-acetylcysteine conjugates, elicit the same anti-proliferative response as their parent compounds in human bladder cancer cells
The principal urinary metabolites of dietary isothiocyanates, N-acetylcysteine conjugates, elicit the same anti-proliferative response as their parent compounds in human bladder cancer cells
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DOI：
10.1097/00001813-200603000-00008
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发表时间：
2006-03-01
影响因子：
2.3
通讯作者：
Zhang, Yuesheng
中科院分区：
文献类型：
--
作者：
Tang, Li;Li, Guolin;Zhang, Yuesheng
异硫氰酸酯（ITC）是一类众所周知的癌症预防植物化学物质，但在体内主要以N-乙酰半胱氨酸缀合物（NAC-ITC）的形式在尿液中被处理和浓缩。因为人膀胱癌几乎完全发生在膀胱上皮中，其直接暴露于储存在膀胱中的尿液，所以我们着手检查NAC-ITC在培养的人膀胱癌细胞中的抗癌活性。在本文中，我们报告了四种天然存在的ITC的NAC缀合物，包括烯丙基ITC、苄基ITC（BITC）、苯乙基ITC和萝卜硫素，有效地抑制来自低级别浅表性和高级别浸润性人膀胱癌和耐药膀胱癌细胞的细胞生长。此外，生长抑制效力之间的共轭物和它们的母体化合物是相似的。以NAC-BITC和BITC为模型化合物的进一步研究表明，这两种化合物主要以BITC的谷胱甘肽结合物的形式在细胞中积累，但前者的积累较慢。此外，这两种化合物也表现出相同的抗增殖机制：导致同一组半胱天冬酶的分裂（半胱天冬酶-3、-8和-9）在凋亡诱导中的作用，将细胞阻滞在相同的时相（S和G（2）/M）并靶向相同的细胞周期调节剂（Cdc 25 C），尽管NAC-BITC需要更长的处理时间或略高的剂量以实现与BITC相同的效果，推测是由于NAC-BITC的细胞摄取较慢。这些数据表明，NAC-ITC在生物学上与其母体化合物相似，并且对人膀胱癌细胞非常有效。
Isothiocyanates (ITCs) are a class of well-known cancerpreventive phytochemicals, but are primarily disposed of and concentrated in the urine as N-acetylcysteine conjugates (NAC-ITCs) in vivo. Because human urinary bladder cancers occur almost exclusively in the bladder epithelium, which is directly exposed to the urine stored in the bladder, we undertook to examine the anti-cancer activity of NAC-ITCs in cultured human bladder cancer cells. In this paper, we report that the NAC conjugates of four naturally occurring ITCs, including allyl ITC, benzyl ITC (BITC), phenethyl ITC and sulforaphane, potently inhibited the growth of cells derived from both low-grade superficial and high-grade invasive human bladder cancers and drug-resistant bladder cancer cells. Moreover, the growth-inhibitory potencies were similar between the conjugates and their parent compounds. Further study of NAC-BITC and BITC as model compounds showed that both compounds accumulated in cells predominantly as the glutathione conjugate of BITC, but the accumulation of the former was slower. Moreover, both compounds also demonstrated the same anti-proliferative mechanisms: causing the cleavage of the same set of caspases (caspase -3, -8 and -9) in apoptosis induction, arresting cells in the same phases (S and G(2)/M) and targeting the same cell cycle regulator (Cdc25C), although a longer treatment time or slightly higher doses were needed for NAC-BITC to achieve the same effect as BITC, presumably due to slower cellular uptake of NAC-BITC. These data show that the NAC-ITCs are biologically similar to their parent compounds and are highly effective against human bladder cancer cells.