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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 compounds, namely PMC79, PMC78, LCR134 and LCR220, in two CRC-derived cell lines (SW480 and RKO). Biological assays were performed on these CRC cell lines to evaluate cellular distribution, colony formation, cell cycle, proliferation, apoptosis, and motility, as well as cytoskeleton and mitochondrial alterations. Our results show that all the compounds displayed high bioactivity and selectivity, as shown by low half-maximal inhibitory concentrations (IC50) against CRC cells. We observed that all the Ru compounds have different intracellular distributions. In addition, they inhibit to a high extent the proliferation of CRC cells by decreasing clonogenic ability and inducing cell cycle arrest. PMC79, LCR134, and LCR220 also induce apoptosis, increase the levels of reactive oxygen species, lead to mitochondrial dysfunction, induce actin cytoskeleton alterations, and inhibit cellular motility. A proteomic study revealed that these compounds cause modifications in several cellular proteins associated with the phenotypic alterations observed. Overall, we demonstrate that Ru compounds, especially PMC79 and LCR220, display promising anticancer activity in CRC cells with a high potential to be used as new metallodrugs for CRC therapy.<\/jats:p>","DOI":"10.3390\/pharmaceutics15061731","type":"journal-article","created":{"date-parts":[[2023,6,15]],"date-time":"2023-06-15T01:32:57Z","timestamp":1686792777000},"page":"1731","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["New Ruthenium-Cyclopentadienyl Complexes Affect Colorectal Cancer Hallmarks Showing High Therapeutic Potential"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3585-4623","authenticated-orcid":false,"given":"Ana Rita","family":"Br\u00e1s","sequence":"first","affiliation":[{"name":"Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"Institute of Science and Innovation for Bio-Sustainability (IB-S), University of Minho, 4710-057 Braga, Portugal"},{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences and Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3920-8194","authenticated-orcid":false,"given":"Pedro","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"Institute of Science and Innovation for Bio-Sustainability (IB-S), University of Minho, 4710-057 Braga, Portugal"}]},{"given":"Tiago","family":"Moreira","sequence":"additional","affiliation":[{"name":"Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"Institute of Science and Innovation for Bio-Sustainability (IB-S), University of Minho, 4710-057 Braga, Portugal"}]},{"given":"Julia","family":"Morales-Sanfrutos","sequence":"additional","affiliation":[{"name":"Proteomics Unit, Centre de Regulaci\u00f3 Gen\u00f2mica (CRG), Barcelona Institute of Science and Technology (BIST), Catalonia, 08003 Barcelona, Spain"},{"name":"Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain"}]},{"given":"Eduard","family":"Sabid\u00f3","sequence":"additional","affiliation":[{"name":"Proteomics Unit, Centre de Regulaci\u00f3 Gen\u00f2mica (CRG), Barcelona Institute of Science and Technology (BIST), Catalonia, 08003 Barcelona, Spain"},{"name":"Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1827-7369","authenticated-orcid":false,"given":"Alexandra M. M.","family":"Antunes","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural (CQE), Institute of Molecular Sciences, Departamento de Engenharia Qu\u00edmica, Instituto Superior T\u00e9cnico (IST), Universidade de Lisboa, 1049-001 Lisboa, Portugal"}]},{"given":"Andreia","family":"Valente","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences and Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7302-0630","authenticated-orcid":false,"given":"Ana","family":"Preto","sequence":"additional","affiliation":[{"name":"Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"Institute of Science and Innovation for Bio-Sustainability (IB-S), University of Minho, 4710-057 Braga, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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