基于糖代谢调控的四价铂-氨基己糖配合物的设计、合成及其抗前列腺癌作用机制研究

Poor targeting and innate resistance of cisplatin has significantly restricted its application for therapy of prostate cancer. Abnormal expression of highly branched N-glycans, such as tri- and tetra-antennary structures on the cell membrane surface of prostate cancer, especially for androgen-independent prostate cancer, will promote the tolerance to cisplatin. However, how to regulate the biosynthesis of N-glycans and improve the sensitivity of the prostate cancer cells to cisplatin are still unknown. Our initial synthetic platinum-fluorinated glucosamine complexes Pt(IV)-FGN exhibited effective anti-tumor activity and dramatically inhibited PC3 cell migration when compared to parent platinum. In addition, preliminary mechanism analysis showed that FGN can prominently decrease the expression level of UDP-GlcNAc. Thus, it is considered that Pt(IV)-FGN has the potentials for targeting cancer cell. Moreover, the reduced product of FGN may regulate the glycometabolism to enhance the anti-tumor activity by increasing cross-linking of platinum drugs and DNA. In this study, a library of platinum(IV)-FGN complexes will be prepared and screened to obtain the leading compounds and explore their targeting mechanism, which will provide theoretical and experimental basis for further development of targeting platinum drugs.

固有耐药性和缺乏靶向性是限制顺铂治疗前列腺癌的主要原因。前列腺癌细胞膜表面异常表达高分支N-glycan使其对顺铂等抗癌药物的耐受能力增强，而如何降低N-glycan的生物合成并提高对顺铂的敏感性尚不清楚。我们前期结果表明，四价铂-氟代氨基己糖配合物Pt(IV)-FGN在体外表现出比母体铂更好的抗肿瘤生长和转移效果，初步机制探讨发现FGN可降低细胞内UDP-GlcNAc的表达水平。我们推测Pt(IV)-FGN不但可以靶向肿瘤细胞，其还原产物FGN可能通过调控UDP-GlcNAc的表达抑制N-glycan的生物合成，从而增强前列腺癌细胞对铂类药物的敏感性，提高铂类药物与DNA的结合，进而发挥抗肿瘤作用。本课题拟基于四价铂与可调控细胞糖代谢的FGN糖基配体制备系列化合物并进行结构优化，通过细胞、动物等模型评价其抗肿瘤效果并阐明作用机制，为具有靶向性铂类药物的研究提供理论基础和实验依据。

前列腺癌是男性中发病率较高的一种恶性肿瘤。然而固有耐药性和缺乏靶向性是限制顺铂治疗前列腺癌的主要原因。前列腺癌细胞膜表面异常表达高分支N-glycan使其对顺铂等抗癌药物的耐受能力增强，而如何降低N-glycan的生物合成并提高对顺铂的敏感性尚不清楚。此外，化疗药物通过激活TCR（T cell receptor）和IL-2/STAT5信号通路诱导产生T-reg及MDSCs两大免疫抑制细胞，与CRPC的不良预后、复发、转移及免疫逃逸均密切相关。因此，设计新型四价铂化合物调控N-glycan糖代谢水平，同时靶向调控免疫抑制型T-reg及MDSCs等将为解除晚期CRPC免疫抑制开辟新的道路。.本课题开发了一系列新型四价铂氨基己糖配合物，其中化合物R19表现出良好的抗肿瘤活性，结论如下：（1）R19对前列腺癌细胞有较高的细胞毒性，IC50值约为0.74 μM；（2）R19发挥细胞毒性依赖细胞膜表面糖转运蛋白跨膜；（3）R19的抗肿瘤和抗转移能力高达80%，高于顺铂和奥沙利铂，生物安全性高；（4）与顺铂相比，R19可以调控TXNIP和SGT1的表达，增强凋亡蛋白p53的稳定性，靶向核DNA诱导细胞凋亡，阻滞细胞G1/S期，抑制快速生长的前列腺癌细胞；（5）R19可以显著降低前列腺癌细胞内的UDP-GlcNA的含量，抑制前列腺癌细胞膜表面高分支的N-glycan；（6）R19还可以通过降低葡萄糖和谷氨酰胺的含量，抑制糖酵解增加GFAT1和PGM3的蛋白表达，升高4F-UDP-GlcNAc的含量；（7）最后，R19可以降低T-reg细胞O-GlcNAc糖基化，降低T-reg细胞的比例，控制免疫抑制细胞T-reg的分化，增强其抗肿瘤活性。

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