State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325027, China.
Department of Urology, Xiangya Hospital, Central South University, Changsha 410008, China.
Int J Biol Macromol. 2023 Jan 1;224:797-809. doi: 10.1016/j.ijbiomac.2022.10.167. Epub 2022 Oct 23.
Recently, it was newly revealed that the DNA damage induced by cis‑platinum (Cis-Pt) mediated chemotherapy was significantly impaired by the highly expressed programmed death ligand-1 (PD-L1) in tumor cells. Besides, the efficacy of Cis-Pt was also limited due to its severe side effects, especially enhanced drug efflux induced by multidrug resistance protein 1 (MDR-1) and increased tumor metastasis. Up to now, few drugs or carbohydrates could simultaneously solve these defects of Cis-Pt mediated chemotherapy. Here, we newly found that metformin-modified chitosan (Ch-Met) possessed ideal selective mitochondria accumulation capacity, leading to the further disrupted mitochondrial function, which then effectively inhibited the upregulated PD-L1 expression to inhibit DNA damage repair in tumor cells, as well as impaired drug efflux and lowered tumor metastasis. Therefore, it was demonstrated that Ch-Met could sensitize the chemotherapy efficacy of Cis-Pt.
最近有新发现表明，肿瘤细胞中高表达的程序性死亡配体 1（PD-L1）显著削弱了顺铂（Cis-Pt）介导的化疗引起的 DNA 损伤。此外，由于其严重的副作用，尤其是多药耐药蛋白 1（MDR-1）诱导的药物外排增加和肿瘤转移增加，Cis-Pt 的疗效也受到限制。到目前为止，很少有药物或碳水化合物能够同时解决 Cis-Pt 介导的化疗的这些缺陷。在这里，我们新发现二甲双胍修饰壳聚糖（Ch-Met）具有理想的选择性线粒体积累能力，导致线粒体功能进一步受损，从而有效抑制上调的 PD-L1 表达，抑制肿瘤细胞中的 DNA 损伤修复，并削弱药物外排和降低肿瘤转移。因此，证明了 Ch-Met 可以增强 Cis-Pt 的化疗疗效。
