Dataset Information

New ruthenium-cyclopentadienyl complexes affect colorectal cancer hallmarks showing high therapeutic potential

ABSTRACT: Colorectal cancer (CRC) is one of the most lethal cancers worldwide. Current therapeutic strategies are accompanied by low success rates and several side effects, representing a relevant clinical problem and requiring the discovery of new and more effective therapeutic alternatives. Ruthenium drugs emerged as one of the most promising metallodrugs due to their high selectivity to cancer cells. In this work, we studied for the first time the anticancer properties and mechanisms of action of four lead Ru-cyclopentadienyl compounds, namely PMC79, PMC78, LCR134 and LCR220, in CRC-derived cell lines. Biological assays were performed in CRC cell lines to evaluate cellular distribution, colony formation, cell cycle, proliferation, apoptosis, motility as well as cytoskeleton and mitochondrial alterations. Our results showed that all compounds displayed high bioactivity and selectivity, as shown by low IC50 concentrations against CRC cells. We observed that all Ru compounds had different intracellular distributions and inhibited to a high extent the clonogenic ability and proliferation of CRC cells. In addition, PMC79, LCR134 and LCR220 induced apoptosis, increased the levels of reactive oxygen species, induced mitochondrial alterations and affected F-actin cytoskeleton organization and cellular motility. A proteomic analysis showed that these compounds induce alterations in several cellular proteins related to the phenotypic alterations induced. Overall, we demonstrated that Ru compounds, in special PMC79 and LCR220, present promising anticancer activity in CRC cells and potential to be used as new metallodrugs for CRC therapy.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Colorectal Cancer

SUBMITTER: Eduard Sabidó

LAB HEAD: Eduard Sabidó

PROVIDER: PXD041324 | Pride | 2023-07-20

REPOSITORIES: Pride

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			Action	DRS
	2020MQ001_ANVA_001_03_45pto.raw	Raw
	2020MQ001_ANVA_002_03_45pto.raw	Raw
	2020MQ001_ANVA_003_03_45pto.raw	Raw
	2020MQ001_ANVA_004_03_45pto.raw	Raw
	2020MQ001_ANVA_005_03_45pto.raw	Raw

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New Ruthenium-Cyclopentadienyl Complexes Affect Colorectal Cancer Hallmarks Showing High Therapeutic Potential.

Brás Ana Rita AR Fernandes Pedro P Moreira Tiago T Morales-Sanfrutos Julia J Sabidó Eduard E Antunes Alexandra M M AMM Valente Andreia A Preto Ana A

Pharmaceutics 20230614 6

Colorectal cancer (CRC) is among the most deadly cancers worldwide. Current therapeutic strategies have low success rates and several side effects. This relevant clinical problem requires the discovery of new and more effective therapeutic alternatives. Ruthenium drugs have arisen as one of the most promising metallodrugs, due to their high selectivity to cancer cells. In this work we studied, for the first time, the anticancer properties and mechanisms of action of four lead Ru-cyclopentadienyl ...[more]

PMID: 37376178

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Project description:Background. Most colorectal cancers (CRC) arise in a progression through adenoma to carcinoma phenotypes as a consequence of altered genetic information. Clinical progression of CRC may occur in parallel with distinctive signaling alterations. We designed multidirectional analyses integrating microarray-based data with biostatistics and bioinformatics to elucidate the signaling and metabolic alterations underlying CRC development in the adenoma-carcinoma sequence. Methodology/Principal Findings. Studies were performed on normal mucosa, adenoma, and CRC samples obtained during surgery or colonoscopy. Collections of cryostat sections prepared from the tissue samples were evaluated by a pathologist to control the relative cell type content. RNA was isolated from 105 macro- and 40 microdissected specimens. The measurements were done using Affymetrix GeneChip HG-U133plus2, and probe set data were generated using two normalization algorithms: MAS5 and GCRMA with LVS. The data were evaluated using pair-wise comparisons and data decomposition into SVD modes. The method selected for the functional analysis used the Kolmogorov-Smirnov test. Based on a consensus of the results obtained by two tissue handling procedures, two normalization algorithms, and two probe set sorting criteria, we identified six KEGG signaling and metabolic pathways (cell cycle, DNA replication, p53 signaling pathway, purine metabolism, pyrimidine metabolism, and RNA polymerase) that are significantly altered in both macro- and microdissected tumor samples compared to normal colon. On the other hand, pathways altered between benign and malignant tumors were identified only in the macrodissected tissues. Conclusion/Significance. Multidirectional analyses of microarray data allow the identification of essential signaling alterations underlying CRC development. Although the proposed strategy is computationally complex and labor–intensive, it may reduce the number of false results. Gene expression profiles of 40 tissue samples representing distant full-thickness normal colon, normal colon mucosa dissected from tumor, adenoma, and carcinoma. Gene expression profiles of 105 tissue samples representing colon carcinomas, adenocarcinomas, and normal colon samples.