College of Pharmacy, University of Hawaii at Hilo, 34 Rainbow Drive, Hilo, HI 96720, USA.
Cancer Prev Res (Phila). 2011 Apr;4(4):592-607. doi: 10.1158/1940-6207.CAPR-10-0004.
Retinoid X receptor (RXR) has been targeted for the chemoprevention and treatment of cancer. To discover potential agents acting through RXRs, we utilized an RXR response element (RXRE)-luciferase reporter gene assay. Following extensive screening, 3-amino-6-(3-aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline dihydrochloride (AM6-36) was found to induce RXRE-luciferase activities. AM6-36 inhibited COX-2 expression and anchorage-independent growth with 12-O-tetradecanoylphorbol 13-acetate-stimulated JB6 Cl41 cells, induced the expression of CD38 in HL-60 cells, and attenuated the growth of N-methyl-N-nitrosourea-induced mammary tumors in rats. Consistent with other reports describing the antiproliferative effects of RXR agonists in breast cancers, AM6-36 showed growth inhibition with cultured MCF7 breast cancer cells, accompanied by G(2)/M-phase arrest at lower concentrations and enhanced S-phase arrest at higher concentrations. On the basis of DNA microarray analysis, AM6-36 upregulated the expression of CDKN1A, a target gene of RXR, by 35-fold. In accord with this response, the expression of the corresponding protein, p21(WAF1/CIP1), was increased in the presence of AM6-36. Induction of p21 by AM6-36 was abrogated following transient knockdown of RXRα, demonstrating that the effect of AM6-36 on the expression of p21 is closely related to modulation of RXRα transcriptional activity. Intestinal permeability was suggested with Caco-2 cells and limited metabolism resulted when AM6-36 was incubated with human liver microsomes. Oral administration with rats resulted in 0.8 μg/mL, 4.3 μg/g, and 0.3 μg/g in serum, liver, and mammary gland, respectively. In sum, these data suggest that AM6-36 is a promising lead for the treatment or prevention of breast cancer and provide a strong rationale for testing in more advanced antitumor systems.
视黄醇 X 受体（RXR）已成为癌症化学预防和治疗的靶标。为了发现通过 RXR 起作用的潜在药物，我们利用了 RXR 反应元件（RXRE）-荧光素酶报告基因检测法。经过广泛筛选，发现 3-氨基-6-(3-氨基丙基)-5,6-二氢-5,11-二氧代-11H-茚并[1,2-c]异喹啉二盐酸盐（AM6-36）可诱导 RXRE-荧光素酶活性。AM6-36 抑制 COX-2 表达和无锚定生长，用 12-O-十四烷酰佛波醇 13-乙酸刺激 JB6 Cl41 细胞，诱导 HL-60 细胞表达 CD38，并减弱 N-甲基-N-亚硝基脲诱导的大鼠乳腺肿瘤的生长。与其他描述 RXR 激动剂在乳腺癌中抗增殖作用的报告一致，AM6-36 对培养的 MCF7 乳腺癌细胞显示出生长抑制作用，较低浓度时表现为 G2/M 期阻滞，较高浓度时表现为 S 期阻滞增强。基于 DNA 微阵列分析，AM6-36 将 RXR 的靶基因 CDKN1A 的表达上调了 35 倍。与该反应一致，存在 AM6-36 时，相应蛋白 p21（WAF1/CIP1）的表达增加。在用 AM6-36 瞬时敲低 RXRα 后，p21 的诱导作用被阻断，表明 AM6-36 对 p21 表达的影响与调节 RXRα 转录活性密切相关。用 Caco-2 细胞提示肠通透性，用人肝微粒体孵育时代谢有限。用大鼠口服给药后，血清、肝脏和乳腺中的浓度分别为 0.8μg/mL、4.3μg/g 和 0.3μg/g。总之，这些数据表明 AM6-36 是治疗或预防乳腺癌的有前途的先导化合物，并为在更先进的抗肿瘤系统中进行测试提供了强有力的依据。
