Elias Maria George, Fatima Shadma, Mann Timothy J, Karan Shawan, Mikhael Meena, de Souza Paul, Gordon Christopher P, Scott Kieran F, Aldrich-Wright Janice R
School of Science, Western Sydney University, Sydney, NSW 2751, Australia.
Medical Oncology, Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia.
Cancers (Basel). 2024 Jul 15;16(14):2544. doi: 10.3390/cancers16142544.
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)(1,2-diaminocyclohexane) (), Pt(5-methyl-1,10-phenanthroline)(1,2-diaminocyclohexane) () and Pt(5,6-dimethyl-1,10-phenanthroline)(1,2-diaminocyclohexane) () 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.
对顺铂、奥沙利铂和卡铂产生耐药性仍然是它们作为化疗药物使用时面临的一项挑战，尤其是在乳腺癌和结直肠癌中。在此，我们比较了新型配合物Pt(1,10 - 菲咯啉)(1,2 - 二氨基环己烷) ()、Pt(5 - 甲基 - 1,10 - 菲咯啉)(1,2 - 二氨基环己烷) ()和Pt(5,6 - 二甲基 - 1,10 - 菲咯啉)(1,2 - 二氨基环己烷) ()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中，这些配合物的效力比顺铂高11倍以上，对癌细胞的选择性高于基因稳定细胞。电感耦合等离子体质谱研究表明，细胞摄取是通过主动转运机制进行的，24小时后在所有配合物中，细胞骨架中的铂浓度发生了显著变化。观察到显著的活性氧生成，在处理72小时时线粒体膜电位降低。膜联蛋白V - FITC/PI流式细胞术检测显示晚期凋亡/坏死，与未处理细胞相比，亚G0/G1期细胞增加。所有配合物处理后均可见S期和G2 + M期细胞增加。处理导致肌动蛋白和微管蛋白染色发生显著变化。通过蛋白质印迹法，内在和外在凋亡标志物、MAPK/ERK和PI3K/AKT激活标志物以及自噬标志物显示这些信号通路均有显著激活。处理72小时后进行的蛋白质组学分析确定了通过质谱定量的1597种MDA - MB - 231蛋白和1859种HT29蛋白，相对于未处理有几种差异表达蛋白。基因本体富集分析显示，在这两种细胞系中，RNA/DNA相关蛋白有统计学意义的富集，并且每种药物还有特定的其他过程。这项研究表明，这些新型药物作为多机制化疗药物发挥作用，具有有前景的抗癌潜力，从而支持对其作为癌症治疗药物应用的进一步研究。
