Center for Cancer Prevention and Drug Development, Hematology/Oncology Section, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Oncol Rep. 2013 Aug;30(2):952-60. doi: 10.3892/or.2013.2483. Epub 2013 May 23.
Inducible nitric oxide synthase (iNOS) is a potential target for the treatment of inflammation and cancer. Previously, we showed that the selective iNOS inhibitor S,S'-1,4-phenylenebis(1,2-ethanediyl)bis-isothiourea (PBIT) caused significant inhibition of colon carcinogenesis induced by azoxymethane (AOM), although it did not completely abrogate NO production due to the exogenous bioavailability of NO and NO generation by eNOS in tumor tissues. To create an iNOS-targeting molecule that may have additional benefits, a novel isosteric analog of PBIT, PBI-Se, was developed, in which sulfur was replaced with selenium. Chemopreventive efficacy of PBI-Se was evaluated in an AOM-induced rat colon carcinogenesis model using aberrant crypt foci (ACF) as the endpoint. At 7 weeks of age, rats (12/group) were fed the control diet (AIN 76A) and then colonic ACF were induced with two AOM treatments. Three days later, rats were fed diets containing PBI-Se (0-20 ppm) for 8 weeks, and then ACF were evaluated histopathologically. Dietary administration of 10 or 20 ppm of PBI-Se significantly suppressed AOM-induced total colonic ACF formation (32 or 41%, p<0.002-0.0003), and multi-crypt (4 or more) aberrant foci (29 or 47%, p<0.01-0.0004), respectively. The inhibition by PBI-Se was dose-dependent and was half the dose of PBIT for inhibiting total ACF in rats. Both PBIT and PBI-Se induced dose-dependent apoptosis in CaCo2 cells and caused a significant decrease in the cell cycle proteins cyclin D1 (70%, p<0.0001) and iNOS (99%, p<0.0001). Treatment with PBIT (30 and 60 µM) and PBI-Se (2 and 4 µM) significantly decreased the LPS-induced cytokine interleukin-6 level. Incorporation of selenium into the structure of PBIT provided the agent with additional novel cytotoxic and immunologic properties. Results from the in vitro and in vivo bioassays suggest that PBI-Se could be developed further for the prevention and treatment of colon cancer.
诱导型一氧化氮合酶 (iNOS) 是治疗炎症和癌症的潜在靶点。此前，我们表明选择性 iNOS 抑制剂 S,S'-1,4-亚苯基双(1,2-乙二基)双异硫脲 (PBIT) 可显著抑制氧化偶氮甲烷 (AOM) 诱导的结肠癌发生，尽管由于肿瘤组织中外源 NO 的生物利用度和 eNOS 生成的 NO，NO 产生并未完全被阻断。为了创造一种可能具有额外益处的 iNOS 靶向分子，开发了 PBIT 的新型等排体类似物 PBI-Se，其中硫被硒取代。使用异常隐窝病灶 (ACF) 作为终点，在 AOM 诱导的大鼠结肠癌发生模型中评估了 PBI-Se 的化学预防功效。在 7 周龄时，大鼠 (每组 12 只) 以对照饮食 (AIN 76A) 喂养，然后用两次 AOM 处理诱导结肠 ACF。3 天后，大鼠以含有 PBI-Se (0-20 ppm) 的饮食喂养 8 周，然后对 ACF 进行组织病理学评估。10 或 20 ppm 的 PBI-Se 饮食摄入显著抑制了 AOM 诱导的全结肠 ACF 形成 (32 或 41%，p<0.002-0.0003)，以及多隐窝 (4 个或更多) 异常病灶 (29 或 47%，p<0.01-0.0004)。PBI-Se 的抑制作用呈剂量依赖性，对大鼠总 ACF 的抑制作用是 PBIT 的一半。PBIT 和 PBI-Se 均诱导 CaCo2 细胞中剂量依赖性凋亡，并导致细胞周期蛋白 D1(70%，p<0.0001)和 iNOS(99%，p<0.0001)的显著减少。用 PBIT(30 和 60 µM) 和 PBI-Se(2 和 4 µM) 处理可显著降低 LPS 诱导的细胞因子白细胞介素 6 水平。将硒掺入 PBIT 的结构中为该药物提供了额外的新型细胞毒性和免疫特性。体外和体内生物测定的结果表明，PBI-Se 可进一步开发用于预防和治疗结肠癌。
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