Inhibitory effects of retinoic acid metabolism blocking agents (RAMBAs) on the growth of human prostate cancer cells and LNCaP prostate tumour xenografts in SCID mice.
Inhibitory effects of retinoic acid metabolism blocking agents (RAMBAs) on the growth of human prostate cancer cells and LNCaP prostate tumour xenografts in SCID mice.
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DOI：
10.1038/sj.bjc.6602971
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发表时间：
2006-02-27
影响因子：
8.8
通讯作者：
Njar, VCO
中科院分区：
文献类型：
--
作者：
Huynh, CK;Brodie, AMH;Njar, VCO
在最近的研究中，我们发现了几种高效的全反式视黄酸（ATRA）代谢阻断剂（RAMBA）。根据之前利阿唑（第一代 RAMBA）对 ATRA 分解代谢和大鼠 Dunning R3227G 前列腺肿瘤生长的影响，我们评估了我们的新型 RAMBA 对人前列腺肿瘤 (PCA) 细胞系的影响。我们检查了三种不同的 PCA 细胞系，以确定它们诱导 P450 介导的 ATRA 氧化的能力。在三种不同的细胞系中，在 LNCaP 中检测到分解代谢增强，而在 PC-3 和 DU-145 中未发现。这种分解代谢被我们的 RAMBA 强烈抑制，最有效的是 VN/14-1、VN/50-1、VN/66-1 和 VN/69-1，IC50 值分别为 6.5、90.0、62.5 和 90.0nM。 RAMBA 抑制 LNCaP 细胞的生长，IC50 值在 μM 范围内。在 LNCaP 细胞增殖测定中，VN/14-1、VN/50-1、VN/66-1 和 VN/69-1 也分别将 ATRA 介导的抗增殖活性增强了 47、60、70 和 65 倍。然后我们研究了单独使用 ATRA 以及与 RAMBA 联合使用时抑制生长的分子机制。该机制似乎涉及诱导分化、细胞周期停滞和诱导凋亡 (TUNEL)，涉及 Bad 表达增加和 Bcl-2 表达减少。用 VN/66-1 和 VN/69-1 治疗 SCID 小鼠中生长的 LNCaP 肿瘤，分别产生适度但统计学显着的肿瘤生长抑制，分别为 44% 和 47%，而用 VN/14-1 治疗却出乎意料地无效。这些结果表明我们的一些新型 RAMBA 可能是治疗前列腺癌的有用药物。
In recent studies, we have identified several highly potent all-trans-retinoic acid (ATRA) metabolism blocking agents (RAMBAs). On the basis of previous effects of liarozole (a first-generation RAMBA) on the catabolism of ATRA and on growth of rat Dunning R3227G prostate tumours, we assessed the effects of our novel RAMBAs on human prostate tumour (PCA) cell lines. We examined three different PCA cell lines to determine their capacity to induce P450-mediated oxidation of ATRA. Among the three different cell lines, enhanced catabolism was detected in LNCaP, whereas it was not found in PC-3 and DU-145. This catabolism was strongly inhibited by our RAMBAs, the most potent being VN/14-1, VN/50-1, VN/66-1, and VN/69-1 with IC50 values of 6.5, 90.0, 62.5, and 90.0 nM, respectively. The RAMBAs inhibited the growth of LNCaP cells with IC50 values in the μM-range. In LNCaP cell proliferation assays, VN/14-1, VN/50-1, VN/66-1, and VN/69-1 also enhanced by 47-, 60-, 70-, and 65-fold, respectively, the ATRA-mediated antiproliferative activity. We then examined the molecular mechanism underlying the growth inhibitory properties of ATRA alone and in combination with RAMBAs. The mechanism appeared to involve the induction of differentiation, cell-cycle arrest, and induction of apoptosis (TUNEL), involving increase in Bad expression and decrease in Bcl-2 expression. Treatment of LNCaP tumours growing in SCID mice with VN/66-1 and VN/69-1 resulted in modest but statistically significant tumour growth inhibition of 44 and 47%, respectively, while treatment with VN/14-1 was unexpectedly ineffective. These results suggest that some of our novel RAMBAs may be useful agents for the treatment of prostate cancer.
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新的17Alpha-羟化酶/C（17,20） - 溶剂抑制剂对体外和体内LNCAP前列腺癌细胞生长的影响。
影响因子：
8.8
作者：
Grigoryev, DN;Long, BJ;Nnane, IP;Njar, VCO;Liu, Y;Brodie, AMH
通讯作者：
Brodie, AMH
影响因子：
2.8
作者：
CARTER, BS;CARTER, HB;ISAACS, JT
通讯作者：
ISAACS, JT
影响因子：
4.8
作者：
Campbell, MJ;Park, S;Koeffler, HP
通讯作者：
Koeffler, HP
DOI：
10.1016/0960-0760(92)90208-z
发表时间：
1992-09-01
影响因子：
4.1
作者：
DECOSTER, R;WOUTERS, W;BOWDEN, C
通讯作者：
BOWDEN, C
影响因子：
2.9
作者：
FROLIK, CA;ROBERTS, AB;SPORN, MB
通讯作者：
SPORN, MB