Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2021-09-20 , DOI: 10.1016/j.bmcl.2021.128361 Yunshuo Zhao 1 , Xiaotong Chen 1 , Chuanjie He 1 , Guanfei Gao 1 , Zhenzhen Chen 1 , Jiangfeng Du 1
As a unique ligand gated ion channel in the P2-receptor family, P2X7R is highly expressed in various tumors. The activated P2X7R facilitates tumor growth and metastasis. Hypoxia, inflammation and necrosis in the tumor microenvironment (TME) cause a large amount of adenosine triphosphate (ATP) accumulated in the TME. High concentration of ATP can abnormally activate P2X7R, which induces pore formation and further facilitates the Ca2+ ion influx and non-specific substance intake. Therefore, inhibition of P2X7R activation can be applied as a potential anti-tumor therapy strategy. However, there is currently no FDA approved drugs for this target for anti-tumor treatment. In this study, we identified bilirubin as novel P2X7R antagonist by using structure based virtual screening combined with cell based assays. Molecular docking studies indicated that bilirubin probably interacted with P2X7R by forming hydrogen-π interactions with residues V173, E174 and K311. The compound bilirubin inhibited the P2X7R gated EB intake by cancer cells. Meanwhile, bilirubin was capable to inhibit the cell proliferation and migration of P2X7R expressed HT29 cells. The phosphorylation of mTOR, STAT3 and GSK3β were significantly decreased when bilirubin was present. Finally, in vivo experiment exhibited the anti-tumor effect of bilirubin in the MC38 bearing mice model, but did not show tissue damage in different organs. In conclusion, bilirubin was identified as a novel P2X7R antagonist and it may have potential for anti-cancer treatment, although various functions of the molecule should be considered.
中文翻译:
发现胆红素作为具有抗肿瘤活性的新型 P2X7R 拮抗剂
作为 P2 受体家族中独特的配体门控离子通道,P2X7R 在各种肿瘤中高度表达。活化的 P2X7R 促进肿瘤生长和转移。肿瘤微环境(TME)中的缺氧、炎症和坏死导致TME中积累了大量的三磷酸腺苷(ATP)。高浓度 ATP 可异常激活 P2X7R,从而诱导孔形成并进一步促进 Ca 2+离子流入和非特异性物质摄入。因此,抑制 P2X7R 激活可用作潜在的抗肿瘤治疗策略。然而,目前还没有 FDA 批准的针对这一目标的抗肿瘤治疗药物。在这项研究中,我们通过使用基于结构的虚拟筛选结合基于细胞的测定将胆红素鉴定为新型 P2X7R 拮抗剂。分子对接研究表明,胆红素可能通过与残基 V173、E174 和 K311 形成氢-π 相互作用而与 P2X7R 相互作用。复合胆红素抑制癌细胞对 P2X7R 门控 EB 的摄入。同时,胆红素能够抑制P2X7R表达的HT29细胞的增殖和迁移。当胆红素存在时,mTOR、STAT3 和 GSK3β 的磷酸化显着降低。最后,体内实验显示胆红素在荷MC38小鼠模型中的抗肿瘤作用,但未显示不同器官的组织损伤。总之,胆红素被鉴定为一种新型 P2X7R 拮抗剂,它可能具有抗癌治疗的潜力,尽管应考虑该分子的各种功能。