Anticancer Effect of PtIIPHENSS, PtII5MESS, PtII56MESS and Their Platinum(IV)-Dihydroxy Derivatives against Triple-Negative Breast Cancer and Cisplatin-Resistant Colorectal Cancer DOI Open Access
Maria George Elias, Shadma Fatima,

Timothy J. Mann

et al.

Cancers, Journal Year: 2024, Volume and Issue: 16(14), P. 2544 - 2544

Published: July 15, 2024

Development of resistance to cisplatin, oxaliplatin and carboplatin remains a challenge for their use as chemotherapies, particularly in breast colorectal cancer. Here, we compare the anticancer effect novel complexes [Pt(1,10-phenanthroline)(1S,2S-diaminocyclohexane)](NO3)2 (PtIIPHENSS), [Pt(5-methyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)](NO3)2 (PtII5MESS) [Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)](NO3)2 (PtII56MESS) platinum(IV)-dihydroxy derivatives with cisplatin. Complexes are greater than 11-fold more potent cisplatin both 2D 3D cell line cultures increased selectivity cancer cells over genetically stable cells. ICP-MS studies showed cellular uptake occurred through an active transport mechanism considerably altered platinum concentrations found cytoskeleton across all after 24 h. Significant reactive oxygen species generation was observed, reduced mitochondrial membrane potential at 72 h treatment. Late apoptosis/necrosis shown by Annexin V-FITC/PI flow cytometry assay, accompanied sub-G0/G1 compared untreated An increase S G2+M seen complexes. Treatment resulted significant changes actin tubulin staining. Intrinsic extrinsic apoptosis markers, MAPK/ERK PI3K/AKT activation together autophagy markers these pathways Western blot. The proteomic profile investigated post-72 treatment identified 1597 MDA−MB−231 1859 HT29 proteins quantified mass spectroscopy, several differentially expressed relative no GO enrichment analysis revealed statistically RNA/DNA-associated lines specific additional processes individual drugs. This study shows that agents function multi-mechanistic chemotherapeutics, offering promising potential, thereby supporting further research into application therapeutics.

Language: Английский

Chemotherapeutic Potential of Chlorambucil-Platinum(IV) Prodrugs against Cisplatin-Resistant Colorectal Cancer Cells DOI Open Access
Maria George Elias, Angelico D. Aputen, Shadma Fatima

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(15), P. 8252 - 8252

Published: July 28, 2024

Chlorambucil-platinum(IV) prodrugs exhibit multi-mechanistic chemotherapeutic activity with promising anticancer potential. The platinum(II) precursors of the have been previously found to induce changes in microtubule cytoskeleton, specifically actin and tubulin HT29 colon cells, while chlorambucil alkylates DNA. These demonstrate significant 2D cell 3D spheroid viability assays. A notable production reactive oxygen species has observed cells 72 h post treatment this type, mitochondrial membrane potential was substantially reduced. cellular uptake chlorambucil-platinum(IV) prodrugs, assessed by ICP-MS, confirmed that active transport primary mechanism, platinum localisation identified primarily cytoskeletal fraction. Apoptosis necrosis were at as demonstrated Annexin V-FITC/PI assay using flow cytometry. Immunofluorescence measured via confocal microscopy showed intensity architecture. Western blot analysis intrinsic extrinsic pathway apoptotic markers, cytoskeleton proliferation well autophagy markers studied treatment. proteomic profile also a total 1859 proteins quantified mass spectroscopy, several dysregulated proteins. Network revealed dysregulation transcription, MAPK microtubule-associated dysfunction. This study confirms are candidates act chemotherapeutics.

Language: Английский

Citations

2
Anticancer Effect of PtIIPHENSS, PtII5MESS, PtII56MESS and Their Platinum(IV)-Dihydroxy Derivatives against Triple-Negative Breast Cancer and Cisplatin-Resistant Colorectal Cancer DOI Open Access
Maria George Elias, Shadma Fatima,

Timothy J. Mann

et al.

Cancers, Journal Year: 2024, Volume and Issue: 16(14), P. 2544 - 2544

Published: July 15, 2024

Development of resistance to cisplatin, oxaliplatin and carboplatin remains a challenge for their use as chemotherapies, particularly in breast colorectal cancer. Here, we compare the anticancer effect novel complexes [Pt(1,10-phenanthroline)(1S,2S-diaminocyclohexane)](NO3)2 (PtIIPHENSS), [Pt(5-methyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)](NO3)2 (PtII5MESS) [Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)](NO3)2 (PtII56MESS) platinum(IV)-dihydroxy derivatives with cisplatin. Complexes are greater than 11-fold more potent cisplatin both 2D 3D cell line cultures increased selectivity cancer cells over genetically stable cells. ICP-MS studies showed cellular uptake occurred through an active transport mechanism considerably altered platinum concentrations found cytoskeleton across all after 24 h. Significant reactive oxygen species generation was observed, reduced mitochondrial membrane potential at 72 h treatment. Late apoptosis/necrosis shown by Annexin V-FITC/PI flow cytometry assay, accompanied sub-G0/G1 compared untreated An increase S G2+M seen complexes. Treatment resulted significant changes actin tubulin staining. Intrinsic extrinsic apoptosis markers, MAPK/ERK PI3K/AKT activation together autophagy markers these pathways Western blot. The proteomic profile investigated post-72 treatment identified 1597 MDA−MB−231 1859 HT29 proteins quantified mass spectroscopy, several differentially expressed relative no GO enrichment analysis revealed statistically RNA/DNA-associated lines specific additional processes individual drugs. This study shows that agents function multi-mechanistic chemotherapeutics, offering promising potential, thereby supporting further research into application therapeutics.

Language: Английский

Citations

1