Kava chalcone, flavokawain A, inhibits urothelial tumorigenesis in the UPII-SV40T transgenic mouse model.
Kava chalcone, flavokawain A, inhibits urothelial tumorigenesis in the UPII-SV40T transgenic mouse model.
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DOI：
10.1158/1940-6207.capr-13-0219
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发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
Zi X
中科院分区：
文献类型：
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作者：
Liu Z;Xu X;Li X;Liu S;Simoneau AR;He F;Wu XR;Zi X
Flavokawain A （FKA）是从卡瓦植物中鉴定出的主要查尔酮。我们之前已经证明，FKA优先抑制p53缺陷膀胱癌细胞系的生长。在UPII-SV40T转基因模型中，我们研究了FKA是否可以抑制膀胱癌的体内发生和进展，该模型类似于p53和视网膜母细胞瘤（RB）蛋白通路缺陷的人类尿路上皮细胞癌（UCC）。从28日龄开始，用载药对照（AIN-93M）或FKA （6 g/kg食物；0.6%）口服UPII-SV40T基因型小鼠318 d。饲喂含fka食物的雄性小鼠存活超过318日龄的比例超过64%，而饲喂载体对照食物的雄性小鼠存活超过318日龄的比例仅为38% （p= 0.0383）。存活雄性转基因小鼠的膀胱重量分别为234.6±72.5 mg和96.1±69.4 mg （P=0.0002）。FKA主要通过尿路排泄，尿中浓度最高可达8.4 μmol/L，平均为血浆浓度的38倍（男性）和15倍（女性）（P=0.0001）。FKA治疗抑制了高级别乳头状UCC（侵袭性尿路上皮癌的前兆）的发生，降低了42.1%。fka喂养小鼠尿路上皮组织中Ki67、survivin和XIAP的表达降低，p27和DR5的表达增加，tunel阳性凋亡细胞数量增加。这些结果表明，FKA在预防非肌肉侵袭性UCC的复发和进展方面具有潜力。
Flavokawain A (FKA) is the predominant chalcone identified from the kava plant. We have previously demonstrated that FKA preferentially inhibits the growth of p53 defective bladder cancer cell lines. Here we examined whether FKA could inhibit bladder cancer development and progression in vivo in the UPII-SV40T transgenic model that resembles human urothelial cell carcinoma (UCC) with defects in the p53 and the retinoblastoma (RB) protein pathways. Genotyped UPII-SV40T mice were fed orally with vehicle control (AIN-93M) or FKA (6 g/kg food; 0.6%) for 318 days starting at 28 days of age. More than 64% of the male mice fed with FKA-containing food survived beyond 318 days of age, whereas only about 38% of the male mice fed with vehicle control food survived to that age (p= 0.0383). The mean bladder weights of surviving male transgenic mice with the control diet versus the FKA diet were 234.6 ± 72.5 versus 96.1±69.4 mg (P=0.0002). FKA was excreted primarily through the urinary tract and concentrated in the urine up to 8.4 μmol/L, averaging about 38 times (males) and 15 times (females) more concentrated than in the plasma (P=0.0001). FKA treatment inhibited the occurrence of high-grade papillary UCC, a precursor to invasive urothelial cancer, by 42.1%. A decreased expression of Ki67, survivin and XIAP and increased expression of p27 and DR5 and number of TUNEL-positive apoptotic cells were observed in the urothelial tissue of FKA-fed mice. These results suggest a potential of FKA in preventing the recurrence and progression of non-muscle invasive UCC.