Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues.
Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues.
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DOI：
10.1158/1535-7163.mct-15-0320
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发表时间：
2015-10
影响因子：
5.7
通讯作者：
Figg WD
中科院分区：
文献类型：
--
作者：
Beedie SL;Peer CJ;Pisle S;Gardner ER;Mahony C;Barnett S;Ambrozak A;Gütschow M;Chau CH;Vargesson N;Figg WD
沙利度胺在影响免疫调节和血管生成途径的各种恶性肿瘤中显示出临床活性。开发疗效更好、毒性更低的新型沙利度胺类似物是一项持续的研究工作。我们最近设计并合成了一类新的化合物，包括四氟沙利度胺类似物(Gu973和Gu998)和四氟苯甲酰胺(Gu1029和Gu992)。在这项研究中，我们展示了这些新合成的化合物的抗血管生成特性。我们以大鼠主动脉环为阳性对照，检测了其体外抗血管生成特性。此外，用5μM和10μM剂量的每种化合物处理人脐静脉内皮细胞和PC3细胞，进一步评估其体外疗效。与先前测试的沙利度胺类似物相比，所有化合物在较低的浓度下都能减少大鼠主动脉环微血管的生长，并在更大程度上抑制血管内皮细胞。这些化合物的抗血管生成特性也在体内的FLI1：EGFP斑马鱼胚胎中进行了测试，所有化合物都可以抑制新发育的血管的生长。此外，Gu1029和Gu973降低了MPO：GFP斑马鱼胚胎的抗炎反应，而Gu998和Gu992没有差异。利用人前列腺癌PC3异种移植瘤模型，研究了这些化合物的体内抗肿瘤作用。所有四种化合物也在鸡胚胎中进行了体内筛选，以研究它们的致畸潜力。这项研究确立了这些新型的沙利度胺类似物是一种有希望的免疫调节类化合物，具有抗癌作用，值得进一步开发，以表征它们的作用机制。
Thalidomide has demonstrated clinical activity in various malignancies affecting immunomodulatory and angiogenesis pathways. The development of novel thalidomide analogs with improved efficacy and decreased toxicity is an ongoing research effort. We recently designed and synthesized a new class of compounds, consisting of both tetrafluorinated thalidomide analogs (Gu973 and Gu998) and tetrafluorobenzamides (Gu1029 and Gu992). In this study, we demonstrate the anti-angiogenic properties of these newly synthesized compounds. We examined the specific anti-angiogenic characteristics in vitro using rat aortic rings with carboxyamidotriazole as a positive control. Additionally, further in vitro efficacy was evaluated using HUVECs and PC3 cells treated with 5μM and 10μM doses of each compound. All compounds were seen to reduce microvessel outgrowth in rat aortic rings as well as inhibit HUVECs to a greater extent, at lower concentrations than previously tested thalidomide analogs. The anti-angiogenic properties of the compounds was also examined in vivo in fli1:EGFP zebrafish embryos, where all compounds were seen to inhibit the extent of outgrowth of newly developing blood vessels. In addition, Gu1029 and Gu973 reduced the anti-inflammatory response in mpo:GFP zebrafish embryos, while Gu998 and Gu992 showed no difference. The compounds anti-tumor effects were also explored in vivo using the human prostate cancer PC3 xenograft model. All four compounds were also screened in vivo in chicken embryos to investigate their teratogenic potential. This study establishes these novel thalidomide analogs as a promising immunomodulatory class with anti-cancer effects that warrant further development to characterize their mechanisms of action.