Nanoscale Organisation and Dynamics Group, School of Science and Health, Western Sydney University, Locked Bag 2579, Penrith South DC, NSW 1797, Australia.
Nanoscale Organisation and Dynamics Group, School of Science and Health, Western Sydney University, Locked Bag 2579, Penrith South DC, NSW 1797, Australia.
J Inorg Biochem. 2018 Feb;179:97-106. doi: 10.1016/j.jinorgbio.2017.11.021. Epub 2017 Dec 1.
The cytotoxicity of platinum(II) complexes coordinated to a chiral diamine, 1S,2S-diaminocyclohexane or 1R,2R-diaminocyclohexane and 1,10-phenanthroline or 3,4,7,8-tetramethyl-1,10-phenanthroline has been investigated in the renal proximal tubule HK-2 cell line. All platinum(II) complexes exhibited lower cytotoxicity in HK-2 cells (IC 1.7-25μM) than in A2780 ovarian cancer cells or cisplatin-resistant A2780cisR cells (IC 0.2-2.1μM) (at 48h). PHENSS ([Pt(1,10-phenanthroline)(1S,2S-dach)]) induced apoptosis and necrosis in ovarian cancer cells at concentrations that are relatively cytostatic to renal cells. Cisplatin was similarly or more cytotoxic to renal cells than ovarian cancer cells. Similar trends were reflected with shorter term exposure (1.5h). PHENSS demonstrated a comparatively cytostatic mode of action in renal cell cultures than cisplatin, as demonstrated by lower toxicity at higher concentrations (90μM). PHENSS induced an elongated renal cell morphology, cytoskeletal stress fibre thickening, and increased β-galactosidase activity, but no detectable change in reactive oxygen species generation or cell cycle distribution. In contrast, cisplatin treatment was associated with increased oxidative stress, cellular enlargement, G2/M arrest and apoptosis. The cytotoxicity of all platinum(II) complexes in both renal and ovarian cell lines were reduced in the presence of organic cation transporter (OCT) inhibitors cimetidine, disopyramide and amantadine. PHENSS and analogues demonstrated low level genotoxicity in an in vitro micronuclei assay compared to cisplatin or etoposide. These findings highlight PHENSS and other phen-based unconventional platinum(II) complexes as promising anticancer agents with alternative modes of action that induce lower kidney cell toxicity and genotoxicity, while demonstrating greater cisplatin-resistant ovarian cancer cell toxicity.
已研究了手性二胺 1S,2S-二氨基环己烷或 1R,2R-二氨基环己烷与 1,10-菲咯啉或 3,4,7,8-四甲基-1,10-菲咯啉配位的铂(II)配合物在肾近端小管 HK-2 细胞系中的细胞毒性。所有铂(II)配合物在 HK-2 细胞中的细胞毒性均低于卵巢癌细胞 A2780 或顺铂耐药 A2780cisR 细胞（48h 时 IC 0.2-2.1μM）（IC 1.7-25μM）。在相对细胞生长抑制浓度下，PhenSS([Pt(1,10-菲咯啉)(1S,2S-dach)])诱导卵巢癌细胞凋亡和坏死。顺铂对肾细胞的细胞毒性与卵巢癌细胞相似或更高。短期暴露（1.5h）也反映出类似的趋势。与顺铂相比，PhenSS 在肾细胞培养物中表现出相对的细胞生长抑制作用，这表现为在较高浓度下毒性较低（90μM）。PhenSS 诱导肾细胞形态拉长，细胞骨架应力纤维变厚，β-半乳糖苷酶活性增加，但未检测到活性氧生成或细胞周期分布的变化。相比之下，顺铂处理与氧化应激增加、细胞增大、G2/M 期阻滞和凋亡有关。在有机阳离子转运体（OCT）抑制剂西咪替丁、双异丙吡胺和金刚烷胺存在的情况下，所有铂(II)配合物在肾和卵巢细胞系中的细胞毒性均降低。与顺铂或依托泊苷相比，PhenSS 及其类似物在体外微核试验中表现出低水平的遗传毒性。这些发现强调了 PhenSS 和其他基于 Phen 的非传统铂(II)配合物作为有前途的抗癌药物，具有替代作用机制，可降低肾细胞毒性和遗传毒性，同时对顺铂耐药的卵巢癌细胞毒性更大。
