Yang Yan, Du Ling-Qi, Huang Yan, Liang Chun-Jie, Qin Qi-Pin, Liang Hong
Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin 537000, PR China.
Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin 537000, PR China.
J Inorg Biochem. 2023 Apr;241:112152. doi: 10.1016/j.jinorgbio.2023.112152. Epub 2023 Jan 28.
For the first time, two new mononuclear platinum(II) coordination compounds, [Pt(L1)(DMSO)Cl] (PtL1) and [Pt(L2)(DMSO)Cl] (PtL2) with the 5-(ethoxymethyl)-8-hydroxyquinoline hydrochloride (H-L1) and 5-bromo-8-hydroxyquinoline (H-L2) have been synthesized and characterized. The cytotoxic activity of PtL1 and PtL2 were screened in both healthy HL-7702 cell line and cancer cell lines, human lung adenocarcinoma A549 cancer cells and cisplatin-resistant lung adenocarcinoma A549/DDP cancer cells (A549R), and were compared to that of the H-L1, H-L2, H-L3 ligands and 8-hydroxyquinoline (H-L3) platinum(II) complex [Pt(L3)(DMSO)Cl] (PtL3). MTT results showed that PtL1 bearing one deprotonated L1 ligand against A549R was more potent by 8.8-48.6 fold than that of PtL2 and PtL3 complexes but was more selective toward healthy HL-7702 cells. In addition, PtL1 and PtL3 overcomes tumour drug resistance by significantly inducing mitophagy and causing the change of the related proteins expression, which leads to cell apoptosis. Moreover, the inhibitory effect of PtL1 on A549 xenograft tumour was 68.2%, which was much higher than that of cisplatin (cisPt, ca. 50.0%), without significantly changing nude mice weight in comparison with the untreated group. This study helps to explore the potential of the platinum(II) 5-substituted-8-hydroxyquinoline coordination compounds for the new Pt-resistant cancer therapy.
首次合成并表征了两种新型单核铂（II）配位化合物，即[Pt(L1)(DMSO)Cl]（PtL1）和[Pt(L2)(DMSO)Cl]（PtL2），它们分别与5-（乙氧基甲基）-8-羟基喹啉盐酸盐（H-L1）和5-溴-8-羟基喹啉（H-L2）配位。在健康的HL-7702细胞系以及癌细胞系、人肺腺癌A549癌细胞和顺铂耐药肺腺癌A549/DDP癌细胞（A549R）中筛选了PtL1和PtL2的细胞毒性活性，并与H-L1、H-L2、H-L3配体以及8-羟基喹啉（H-L3）铂（II）配合物[Pt(L3)(DMSO)Cl]（PtL3）进行了比较。MTT结果表明，带有一个去质子化L1配体的PtL1对A549R的活性比PtL2和PtL3配合物高8.8至48.6倍，但对健康的HL-7702细胞更具选择性。此外，PtL1和PtL3通过显著诱导线粒体自噬并导致相关蛋白表达变化来克服肿瘤耐药性，从而导致细胞凋亡。此外，PtL1对A549异种移植肿瘤的抑制作用为68.2%，远高于顺铂（cisPt，约50.0%），与未治疗组相比，对裸鼠体重无显著影响。本研究有助于探索铂（II）5-取代-8-羟基喹啉配位化合物在新型铂耐药癌症治疗中的潜力。
