A small molecule polyamine oxidase inhibitor blocks androgen-induced oxidative stress and delays prostate cancer progression in the transgenic adenocarcinoma of the mouse prostate model.
A small molecule polyamine oxidase inhibitor blocks androgen-induced oxidative stress and delays prostate cancer progression in the transgenic adenocarcinoma of the mouse prostate model.
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DOI：
10.1158/0008-5472.can-08-2472
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发表时间：
2009-10-01
期刊：
影响因子：
11.2
通讯作者：
Wilding G
中科院分区：
文献类型：
--
作者：
Basu HS;Thompson TA;Church DR;Clower CC;Mehraein-Ghomi F;Amlong CA;Martin CT;Woster PM;Lindstrom MJ;Wilding G
前列腺上皮细胞内高水平的活性氧（reactive oxygen species，ROS）是前列腺癌（prostate cancer，CaP）发生、复发和进展的重要致病因素。雄激素通过一种未知的机制诱导前列腺中的ROS产生。在这里，据我们所知，我们首次报告，雄激素诱导的亚精胺/精胺N1-乙酰转移酶（SSAT），多胺氧化途径中的限速酶的过度表达。由于前列腺上皮细胞产生大量过量的多胺，雄激素诱导的多胺氧化产生H2 O2可能是前列腺上皮细胞中高ROS水平的主要原因。一种小分子多胺氧化酶抑制剂N，N '-丁二烯基丁二胺（MDL 72，527或CPC-200）有效阻断人CaP细胞中雄激素诱导的ROS产生，并显著延迟自发性CaP动物的CaP进展和死亡。这些数据表明，多胺氧化不仅是前列腺中ROS产生的主要途径，而且抑制该途径还成功地延迟了前列腺癌的进展。
High levels of reactive oxygen species (ROS) present in human prostate epithelia are an important etiological factor in prostate cancer (CaP) occurrence, recurrence and progression. Androgen induces ROS production in the prostate by a yet unknown mechanism. Here, to the best of our knowledge, we report for the first time that androgen induces an overexpression of spermidine/spermine N1-acetyltransferase (SSAT), the rate-limiting enzyme in the polyamine oxidation pathway. As prostatic epithelia produce a large excess of polyamines, the androgen-induced polyamine oxidation that produces H2O2 could be a major reason for the high ROS levels in the prostate epithelia. A small molecule polyamine oxidase inhibitor N,N'-butanedienyl butanediamine (MDL 72,527 or CPC-200) effectively blocks androgen-induced ROS production in human CaP cells as well as significantly delays CaP progression and death in animals developing spontaneous CaP. These data demonstrate that polyamine oxidation is not only a major pathway for ROS production in prostate, but inhibiting this pathway also successfully delays prostate cancer progression.