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Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy.

التفاصيل البيبلوغرافية
العنوان: Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy.
المؤلفون: Alcalá S; Department of Biochemistry, Autónoma University of Madrid, School of Medicine and Department of Cancer, Instituto de Investigaciones Biomédicas (IIBm) Sols-Morreale (CSIC-UAM), Madrid, Spain.; Biomarkers and Personalized Approach to Cancer (BIOPAC) Group, Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain., Villarino L; Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS), and Departamento de Química Orgánica, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain., Ruiz-Cañas L; Department of Biochemistry, Autónoma University of Madrid, School of Medicine and Department of Cancer, Instituto de Investigaciones Biomédicas (IIBm) Sols-Morreale (CSIC-UAM), Madrid, Spain.; Biomarkers and Personalized Approach to Cancer (BIOPAC) Group, Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain., Couceiro JR; Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS), and Departamento de Química Orgánica, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain., Martínez-Calvo M; Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS), and Departamento de Química Orgánica, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain., Palencia-Campos A; Department of Biochemistry, Autónoma University of Madrid, School of Medicine and Department of Cancer, Instituto de Investigaciones Biomédicas (IIBm) Sols-Morreale (CSIC-UAM), Madrid, Spain.; Biomarkers and Personalized Approach to Cancer (BIOPAC) Group, Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain., Navarro D; Department of Biochemistry, Autónoma University of Madrid, School of Medicine and Department of Cancer, Instituto de Investigaciones Biomédicas (IIBm) Sols-Morreale (CSIC-UAM), Madrid, Spain.; Biomarkers and Personalized Approach to Cancer (BIOPAC) Group, Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain., Cabezas-Sainz P; Department of Zoology, Genetics and Physical Anthropology, Veterinary Faculty, USC, Lugo, Spain., Rodriguez-Arabaolaza I; Department of Biochemistry, Autónoma University of Madrid, School of Medicine and Department of Cancer, Instituto de Investigaciones Biomédicas (IIBm) Sols-Morreale (CSIC-UAM), Madrid, Spain.; Facultad de Ciencia y Técnología, Universidad del País Vasco, 48940, Leioa (Bizkaia), Spain., Cordero-Barreal A; Department of Biochemistry, Autónoma University of Madrid, School of Medicine and Department of Cancer, Instituto de Investigaciones Biomédicas (IIBm) Sols-Morreale (CSIC-UAM), Madrid, Spain.; Biomarkers and Personalized Approach to Cancer (BIOPAC) Group, Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain., Trilla-Fuertes L; Molecular Oncology and Pathology Lab, Instituto de Genética Médica y Molecular-INGEMM, Instituto de Investigación Hospital Universitario La Paz-IdiPAZ, Madrid, Spain.; Biomedica Molecular Medicine SL, Madrid, Spain., Rubiolo JA; Department of Zoology, Genetics and Physical Anthropology, Veterinary Faculty, USC, Lugo, Spain., Batres-Ramos S; Department of Biochemistry, Autónoma University of Madrid, School of Medicine and Department of Cancer, Instituto de Investigaciones Biomédicas (IIBm) Sols-Morreale (CSIC-UAM), Madrid, Spain.; Biomarkers and Personalized Approach to Cancer (BIOPAC) Group, Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain., Vallespinos M; Department of Biochemistry, Autónoma University of Madrid, School of Medicine and Department of Cancer, Instituto de Investigaciones Biomédicas (IIBm) Sols-Morreale (CSIC-UAM), Madrid, Spain.; Biomarkers and Personalized Approach to Cancer (BIOPAC) Group, Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain., González-Páramos C; Department of Biochemistry, Autónoma University of Madrid, School of Medicine and Department of Cancer, Instituto de Investigaciones Biomédicas (IIBm) Sols-Morreale (CSIC-UAM), Madrid, Spain.; Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain.; Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain., Rodríguez J; Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS), and Departamento de Química Orgánica, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain., Gámez-Pozo A; Molecular Oncology and Pathology Lab, Instituto de Genética Médica y Molecular-INGEMM, Instituto de Investigación Hospital Universitario La Paz-IdiPAZ, Madrid, Spain.; Biomedica Molecular Medicine SL, Madrid, Spain., Vara JÁF; Molecular Oncology and Pathology Lab, Instituto de Genética Médica y Molecular-INGEMM, Instituto de Investigación Hospital Universitario La Paz-IdiPAZ, Madrid, Spain.; Centro de Investigación Biomédica en Red, Área Cáncer, CIBERONC, ISCIII, Madrid, Spain., Fernández SF; Servicio de Cirugía Torácica, Hospital Universitario Ramón y Cajal, Madrid, Spain., Berlinches AB; Biomarkers and Personalized Approach to Cancer (BIOPAC) Group, Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.; Servicio de Anatomía Patológica, Hospital Universitario Ramón y Cajal, Madrid, Spain., Moreno-Mata N; Servicio de Cirugía Torácica, Hospital Universitario Ramón y Cajal, Madrid, Spain., Redondo AMT; Biobanco Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain., Carrato A; Biomarkers and Personalized Approach to Cancer (BIOPAC) Group, Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.; Centro de Investigación Biomédica en Red, Área Cáncer, CIBERONC, ISCIII, Madrid, Spain.; Pancreatic Cancer Europe (PCE) Chairperson, Brussels, Belgium., Hermann PC; Department of Internal Medicine I, Ulm University, Ulm, Germany., Sánchez L; Department of Zoology, Genetics and Physical Anthropology, Veterinary Faculty, USC, Lugo, Spain., Torrente S; Valuation, Transfer and Entrepreneurship Area, USC, Santiago de Compostela, Spain., Fernández-Moreno MÁ; Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain.; Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain.; Department of Biochemistry, Autónoma University of Madrid, School of Medicine and Department of Rare Diseases, Instituto de Investigaciones Biomédicas (IIBm) Sols-Morreale (CSIC-UAM), Madrid, Spain., Mascareñas JL; Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS), and Departamento de Química Orgánica, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain. joseluis.mascarenas@usc.es., Sainz B Jr; Department of Biochemistry, Autónoma University of Madrid, School of Medicine and Department of Cancer, Instituto de Investigaciones Biomédicas (IIBm) Sols-Morreale (CSIC-UAM), Madrid, Spain. bsainz@iib.uam.es.; Biomarkers and Personalized Approach to Cancer (BIOPAC) Group, Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain. bsainz@iib.uam.es.; Centro de Investigación Biomédica en Red, Área Cáncer, CIBERONC, ISCIII, Madrid, Spain. bsainz@iib.uam.es.
المصدر: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2024 Jan 27; Vol. 43 (1), pp. 33. Date of Electronic Publication: 2024 Jan 27.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 8308647 Publication Model: Electronic Cited Medium: Internet ISSN: 1756-9966 (Electronic) Linking ISSN: 03929078 NLM ISO Abbreviation: J Exp Clin Cancer Res Subsets: MEDLINE
أسماء مطبوعة: Publication: 2009- : London : BioMed Central
Original Publication: [Roma] : APSIT,
مواضيع طبية MeSH: Ruthenium*/pharmacology , Pancreatic Neoplasms*/drug therapy , Pancreatic Neoplasms*/metabolism, Humans ; Oxidative Phosphorylation ; Mitochondria/metabolism ; Neoplastic Stem Cells/metabolism
مستخلص: Background: Previous studies by our group have shown that oxidative phosphorylation (OXPHOS) is the main pathway by which pancreatic cancer stem cells (CSCs) meet their energetic requirements; therefore, OXPHOS represents an Achille's heel of these highly tumorigenic cells. Unfortunately, therapies that target OXPHOS in CSCs are lacking.
Methods: The safety and anti-CSC activity of a ruthenium complex featuring bipyridine and terpyridine ligands and one coordination labile position (Ru1) were evaluated across primary pancreatic cancer cultures and in vivo, using 8 patient-derived xenografts (PDXs). RNAseq analysis followed by mitochondria-specific molecular assays were used to determine the mechanism of action.
Results: We show that Ru1 is capable of inhibiting CSC OXPHOS function in vitro, and more importantly, it presents excellent anti-cancer activity, with low toxicity, across a large panel of human pancreatic PDXs, as well as in colorectal cancer and osteosarcoma PDXs. Mechanistic studies suggest that this activity stems from Ru1 binding to the D-loop region of the mitochondrial DNA of CSCs, inhibiting OXPHOS complex-associated transcription, leading to reduced mitochondrial oxygen consumption, membrane potential, and ATP production, all of which are necessary for CSCs, which heavily depend on mitochondrial respiration.
Conclusions: Overall, the coordination complex Ru1 represents not only an exciting new anti-cancer agent, but also a molecular tool to dissect the role of OXPHOS in CSCs. Results indicating that the compound is safe, non-toxic and highly effective in vivo are extremely exciting, and have allowed us to uncover unprecedented mechanistic possibilities to fight different cancer types based on targeting CSC OXPHOS.
(© 2024. The Author(s).)
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معلومات مُعتمدة: RYC-2012-12104 Ministerio de Ciencia e Innovación; PID2019-110320RB-I00 Ministerio de Ciencia e Innovación; PID2019-108624RB-I00 Ministerio de Ciencia e Innovación; PDC2021-121508-I00 Ministerio de Ciencia e Innovación; CTQ2016-81797-REDC Ministerio de Ciencia e Innovación; GC16173694BARB Fundación Científica Asociación Española Contra el Cáncer; IDEAS222917FERN Fundación Científica Asociación Española Contra el Cáncer; PI18/00757 Instituto de Salud Carlos III; PI21/01110 Instituto de Salud Carlos III; PT20/00045 Instituto de Salud Carlos III; 340055 H2020 European Research Council; 899334 H2020 European Research Council; 111746 Deutsche Kinderkrebsstiftung; CRC 1279 Deutsche Bundesstiftung Umwelt; IN855A-2018/16 Agencia Gallega de Innovación; CC21-20122 'la Caixa' Foundation
فهرسة مساهمة: Keywords: Anti-cancer agents; Cancer stem cells; Colon cancer; Mitochondrial DNA; Oxidative phosphorylation; Pancreatic ductal adenocarcinoma; Patient-derived xenografts; Ruthenium complexes
المشرفين على المادة: 7UI0TKC3U5 (Ruthenium)
تواريخ الأحداث: Date Created: 20240127 Date Completed: 20240129 Latest Revision: 20240130
رمز التحديث: 20240130
مُعرف محوري في PubMed: PMC10821268
DOI: 10.1186/s13046-023-02931-7
PMID: 38281027
قاعدة البيانات: MEDLINE
الوصف
تدمد:1756-9966
DOI:10.1186/s13046-023-02931-7