Thalidomide is a non-addictive and non-barbiturate sedative that inhibits cereblon with anti-inflammatory and anti-angiogenic properties [1]. Thalidomide binds to GC-rich promoter sites by intercalation and thereby decreases the transcription of IGF-1 and FGF-2 and inhibits angiogenesis to exert the teratogenic effects [2]. Thalidomide has been widely used to alleviate neural inflammation and inhibit the excessive vascularization, growth, and metastasis of tumors[3].
In vitro, Thalidomide treatment for 72 hours significantly inhibited the proliferation of MG-63 cells and U2OS cells, with IC50 values of 94.76µg/ml and 156.61µg/ml, respectively[4]. Thalidomide treatment (150µg/ml) for 12 hours significantly inhibited the formation of tubular structures in ECV 304 cells and induced cytoskeleton reorganization[5]. Thalidomide pretreatment (1mM) for 30 minutes inhibited the NFκB transcriptional activation induced by IL-1β in Caco-2 cells as well as the production of IL-8, and inhibited the nuclear translocation of NFκB and the degradation of IκB[6].
In vivo, Thalidomide treatment via oral administration at a dose of 200mg/kg/day for 30 days significantly inhibited the tumor growth and metastasis of A549 xenograft in mice [7].
References:
[1] Vargesson N. Thalidomide‐induced teratogenesis: History and mechanisms[J]. Birth Defects Research Part C: Embryo Today: Reviews, 2015, 105(2): 140-156.
[2] Stephens T D, Bunde C J W, Fillmore B J. Mechanism of action in thalidomide teratogenesis[J]. Biochemical pharmacology, 2000, 59(12): 1489-1499.
[3] Kim J H, Scialli A R. Thalidomide: the tragedy of birth defects and the effective treatment of disease[J]. Toxicological sciences, 2011, 122(1): 1-6.
[4] Zhu J, Yang Y, Liu S, et al. Anticancer effect of thalidomide in vitro on human osteosarcoma cells[J]. Oncology Reports, 2016, 36(6): 3545-3551.
[5] Tamilarasan K P, Kolluru G K, Rajaram M, et al. Thalidomide attenuates nitric oxide mediated angiogenesis by blocking migration of endothelial cells[J]. BMC Cell Biology, 2006, 7(1): 17.
[6] Jin S H, Kim T I, Han D S, et al. Thalidomide Suppresses the Interleukin 1β‐Induced NFκB Signaling Pathway in Colon Cancer Cells[J]. Annals of the New York Academy of Sciences, 2002, 973(1): 414-418.
[7] Lin Y C, Shun C T, Wu M S, et al. A novel anticancer effect of thalidomide: inhibition of intercellular adhesion molecule-1–mediated cell invasion and metastasis through suppression of nuclear factor-κB[J]. Clinical cancer research, 2006, 12(23): 7165-7173.
Thalidomide是一种非成瘾性、非巴比妥类镇静剂，可抑制cereblon蛋白，具有抗炎和抗血管生成特性[1]。Thalidomide通过嵌入方式结合到富含GC的启动子区域，从而降低IGF-1和FGF-2的转录，并通过抑制血管生成来发挥致畸作用[2]。Thalidomide已被广泛用于减轻神经炎症，抑制肿瘤的过度血管化、生长和转移[3]。
在体外，Thalidomide处理72小时显著抑制了MG-63细胞和U2OS细胞的增殖，IC50值分别为94.76µg/ml和156.61µg/ml[4]。150µg/ml的Thalidomide处理ECV 304细胞12小时，显著抑制了细胞管状结构的形成，并诱导了细胞骨架重组[5]。1mM的Thalidomide预处理Caco-2细胞30分钟，抑制了IL-1β诱导的NFκB转录激活及IL-8的产生，并抑制了NFκB的核转位和IκB的降解[6]。
在体内，每日口服200mg/kg剂量的Thalidomide，持续30天，显著抑制了小鼠A549异种移植瘤的生长和转移[7]。