沙利度胺抗肿瘤机制及其作用靶点CRBN的研究进展

Research progress on the anticancer mechanism of thalidomide and the function of its target protein CRBN

沙利度胺及其衍生物(来那度胺、泊马度胺)为小分子谷氨酸衍生物,具有很强的免疫调节作用,此外,它们还具有其它重要的生物学作用,如抑制血管新生、致畸,更重要的是,它们具有明显的抗肿瘤活性,能够抑制肿瘤细胞增殖,促进细胞凋亡,特别是针对多发性骨髓瘤(multiple myeloma,MM)的临床治疗中已经发挥重要作用。近年来通过对沙利度胺分子靶标的筛选和其靶分子cereblon(CRBN)发现,为其药理机制的研究提供了新的思路,并为开发新一代无毒副作用和具有更高效抗肿瘤活性的新一代沙利度胺衍生物提供了新的线索。该文将从沙利度胺及其衍生物的作用机制、最新靶点及对MM的治疗作一简单综述。

Thalidomide and its analogues （ lenalidomide and po-malidomide） are small glutamic acid derivatives with strong immunomodulatory effects, belonging to immunomodulatory drug （ IMiD ） class . In addition , these thalidomide analogues demonstrate an overlapping and diverse range of biological activities, including anti-angiogenesis and anti-teratogenicity. Importantly, the IMiDs exert anticancer effects such as inhibiting tumor cell proliferation and promoting tumor cell apoptosis and play impor-tant roles especially in clinical treatment of multiple myeloma. Recently, the screening and discovery of thalidomide binding protein, CRBN provides new clues to the research of its pharma-cological mechanisms and the develop ment of new generation of thalidomide derivatives with less toxic side effects and more anti-tumor potency. This review briefly discusses the underlying mechanism of thalidomide and their derivatives’ action and their new identified target, as well as their contribution to the treat-ment of multiple myeloma.