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Anticancer Effect of Pt(II)PHENSS, Pt(II)5MESS, Pt(II)56MESS and Their Platinum(IV)-Dihydroxy Derivatives against Triple-Negative Breast Cancer and Cisplatin-Resistant Colorectal Cancer

Affiliations
  • 1School of Science, Western Sydney University, Sydney, NSW 2751, Australia.
  • 2Medical Oncology, Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia.
  • 3School of Medicine, Western Sydney University, Sydney, NSW 2751, Australia.
  • 4Nepean Clinical School, Faculty of Medicine and Health, University of Sydney, Kingswood, NSW 2747, Australia.

Published on:

July 27, 2024

Abstract

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)](NO) (), [Pt(5-methyl-1,10-phenanthroline)(1,2-diaminocyclohexane)](NO) () and [Pt(5,6-dimethyl-1,10-phenanthroline)(1,2-diaminocyclohexane)](NO) () 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.

Keywords:

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