Development of resistance to cisplatin, oxaliplatin and carboplatin remains a challenge for their use as chemotherapies, particularly in breast and colorectal cancer. Here, we compare the anticancer effect of novel complexes [Pt(1,10-phenanthroline)(1S,2S-diaminocyclohexane)](NO3)2(PtIIPHENSS), [Pt(5-methyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)](NO3)2(PtII5MESS) and [Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)](NO3)2(PtII56MESS) and their platinum(IV)-dihydroxy derivatives with cisplatin. Complexes are greater than 11-fold more potent than cisplatin in both 2D and 3D cell line cultures with increased selectivity for cancer cells over genetically stable cells. ICP-MS studies showed cellular uptake occurred through an active transport mechanism with considerably altered platinum concentrations found in the cytoskeleton across all complexes after 24 h. Significant reactive oxygen species generation was observed, with reduced mitochondrial membrane potential at 72 h of treatment. Late apoptosis/necrosis was shown by Annexin V-FITC/PI flow cytometry assay, accompanied by increased sub-G0/G1 cells compared with untreated cells. An increase in S and G2+M cells was seen with all complexes. Treatment resulted in significant changes in actin and tubulin staining. Intrinsic and extrinsic apoptosis markers, MAPK/ERK and PI3K/AKT activation markers, together with autophagy markers showed significant activation of these pathways by Western blot. The proteomic profile investigated post-72 h of treatment identified 1597 MDA−MB−231 and 1859 HT29 proteins quantified by mass spectroscopy, with several differentially expressed proteins relative to no treatment. GO enrichment analysis revealed a statistically significant enrichment of RNA/DNA-associated proteins in both the cell lines and specific additional processes for individual drugs. This study shows that these novel agents function as multi-mechanistic chemotherapeutics, offering promising anticancer potential, and thereby supporting further research into their application as cancer therapeutics.
顺铂、奥沙利铂和卡铂耐药性的产生，仍然是这些药物在化疗应用中面临的挑战，尤其在乳腺癌和结直肠癌治疗中。本研究对比了新型配合物[Pt(1,10-菲咯啉)(1S,2S-二氨基环己烷)](NO3)2（PtIIPHENSS）、[Pt(5-甲基-1,10-菲咯啉)(1S,2S-二氨基环己烷)](NO3)2（PtII5MESS）和[Pt(5,6-二甲基-1,10-菲咯啉)(1S,2S-二氨基环己烷)](NO3)2（PtII56MESS）及其铂(IV)-二羟基衍生物与顺铂的抗癌效果。在二维和三维细胞系培养模型中，这些配合物的抗癌效力均超过顺铂11倍以上，且对癌细胞的选择性显著高于遗传稳定细胞。ICP-MS研究表明，细胞摄取通过主动转运机制进行，处理24小时后所有配合物在细胞骨架中的铂浓度均发生显著改变。实验观察到显著的活性氧生成，并在处理72小时后线粒体膜电位降低。膜联蛋白V-FITC/PI流式细胞术检测显示晚期凋亡/坏死现象，同时亚G0/G1期细胞较未处理组增加。所有配合物均引起S期和G2+M期细胞比例上升。处理导致肌动蛋白和微管蛋白染色发生显著变化。通过Western blot检测发现，内源性及外源性凋亡标记物、MAPK/ERK和PI3K/AKT激活标记物以及自噬标记物均显示这些通路被显著激活。处理72小时后蛋白质组学分析鉴定出1597个MDA-MB-231细胞蛋白和1859个HT29细胞蛋白，质谱定量显示多个蛋白表达量相较于未处理组发生差异变化。GO富集分析揭示两个细胞系中RNA/DNA相关蛋白均出现统计学显著富集，且各药物具有特定的附加作用过程。本研究表明这些新型药物作为多机制化疗药物，展现出良好的抗癌潜力，为其作为癌症治疗药物的进一步研究提供了支持。
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