The principal urinary metabolite of allyl isothiocyanate, N-acetyl-S-(N-allylthiocarbamoyl)cysteine, inhibits the growth and muscle invasion of bladder cancer
The principal urinary metabolite of allyl isothiocyanate, N-acetyl-S-(N-allylthiocarbamoyl)cysteine, inhibits the growth and muscle invasion of bladder cancer
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DOI：
10.1093/carcin/bgr283
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发表时间：
2012-02-01
期刊：
影响因子：
4.7
通讯作者：
Zhang, Yuesheng
中科院分区：
文献类型：
--
作者：
Bhattacharya, Arup;Li, Yun;Zhang, Yuesheng
最近发现，天然的异硫氰酸烯丙基酯(AITC)通过尿液排泄选择性地输送到膀胱癌组织中，并在动物模型中抑制膀胱癌的生长和肌肉侵袭。AITC在尿液中主要以N-乙酰基-S-(N-烯丙基硫代氨基甲酰基)半胱氨酸的形式排泄，通常被称为N-乙酰半胱氨酸偶合物(NaC-AITC)。我们发现，15 mM的NAC-AITC对人膀胱癌UM-UC-3细胞和大鼠膀胱癌AY-27细胞的生长和增殖有明显的抑制作用，并伴有细胞周期停滞和细胞凋亡。在大鼠原位膀胱癌模型中，口服10 mU/kg体重的NAC-AITC对肿瘤生长和肌肉侵袭的抑制率分别为40%和49%。此外，NAC-AITC的抗癌活性与几个重要的分子靶点的调节有关，包括下调α-微管蛋白和β-微管蛋白，激活caspase-3和下调血管内皮生长因子。这些结果与以前对AITC显示的结果相似，并与NAC-AITC是AITC携带者的理解一致。此外，对NAC-AITC和AITC的药代动力学和物理性质的比较表明，NAC-AITC在预防和治疗膀胱癌方面优于AITC。
Naturally occurring allyl isothiocyanate (AITC) was recently shown to be selectively delivered to bladder cancer tissue via urinary excretion and to inhibit bladder cancer growth and muscle invasion in an animal model. AITC is excreted in urine mainly as N-acetyl-S-(N-allylthiocarbamoyl)cysteine, more commonly known as the N-acetylcysteine conjugate (NAC-AITC). We show here that treatment of human bladder cancer UM-UC-3 cells or rat bladder cancer AY-27 cells with NAC-AITC at 15 mu M results in significant inhibition of cell growth and proliferation, together with cell cycle arrest and apoptosis. We also show that NAC-AITC administered orally at 10 mu mol/kg body wt inhibits cancer growth by 40% and muscle invasion by 49% in an orthotopic rat bladder cancer model. Furthermore, the anticancer activity of NAC-AITC is associated with the modulation of several important molecular targets, including downregulation of both alpha-tubulin and beta-tubulin, activation of caspase-3 and downregulation of vascular endothelial growth factor. These results are similar to those shown previously for AITC and are consistent with the understanding that NAC-AITC is a carrier of AITC. Furthermore, comparison of the pharmacokinetic and physical properties of NAC-AITC with those of AITC suggests that NAC-AITC is superior to AITC for potential use for prevention and therapy of bladder cancer.