Disruption of redox homeostasis for combinatorial drug efficacy in K-Ras tumors as revealed by metabolic connectivity profiling
| Autor: | Daniela Gaglio 1, 2, Marcella Bonanomi 2, 3, Silvia Valtorta 1, 4, Rohit Bharat 23, Marilena Ripamonti 1, Federica Conte 2, 5, Giulia Fiscon 2, Nicole Righi 2, Elisabetta Napodano 1, Federico Papa 2, Isabella Raccagni 1, 6, Seth J Parker 7, 8, Ingrid Cifola 9, Tania Camboni 9, Paola Paci 2, Anna Maria Colangelo 2, Marco Vanoni 2, Christian M Metallo 7, Rosa Maria Moresco 1, Lilia Alberghina 2 |
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| Přispěvatelé: | Gaglio., D, Bonanomi, M, Valtorta, S, Bharat, R, Ripamonti, M, Conte, F, Fiscon, G, Righi, N, Napodano, E, Papa, F, Raccagni, I, J Parker, S, Cifola, I, Camboni, T, Paci, P, Colangelo, A, Vanoni, M, M Metallo, C, Moresco, R, Alberghina, L |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Glutamine
Metabolic rewiring metabolic cancer therapy metabolic signature glycolysis glutamine combinatorial drugs treatment precision oncology metabolic connectivity Metabolic cancer therapy lcsh:RC254-282 Nucleic acid metabolism chemistry.chemical_compound Metabolic connectivity Metabolomics Metabolic signature Combinatorial drug treatment Glycolysis Metabolic rewiring Precision oncology Cancer Metabolism Chemistry Cell growth Glutaminase Research Metabolism lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Cell biology Psychiatry and Mental health Metabolic pathway Cancer cell Growth inhibition |
| Zdroj: | Cancer & Metabolism, Vol 8, Iss 1, Pp 1-15 (2020) Cancer & metabolism 8 (2020): 22. doi:10.1186/s40170-020-00227-4 info:cnr-pdr/source/autori:Daniela Gaglio 1,2, Marcella Bonanomi 2,3, Silvia Valtorta 1,2,4, Rohit Bharat 23, Marilena Ripamonti 1,2, Federica Conte 2,5, Giulia Fiscon 2,5, Nicole Righi 2,3, Elisabetta Napodano 1,2, Federico Papa 2,5, Isabella Raccagni 1,2,6, Seth J Parker 7,8, Ingrid Cifola 9, Tania Camboni 9, Paola Paci 2,5,10, Anna Maria Colangelo 2,3, Marco Vanoni 2,3, Christian M Metallo 7,8, Rosa Maria Moresco 1,2,4, Lilia Alberghina 2,3/titolo:Disruption of redox homeostasis for combinatorial drug efficacy in K-Ras tumors as revealed by metabolic connectivity profiling/doi:10.1186%2Fs40170-020-00227-4/rivista:Cancer & metabolism/anno:2020/pagina_da:22/pagina_a:/intervallo_pagine:22/volume:8 Cancer & Metabolism |
| ISSN: | 2049-3002 |
| DOI: | 10.1186/s40170-020-00227-4 |
| Popis: | Abstract Background Rewiring of metabolism induced by oncogenic K-Ras in cancer cells involves both glucose and glutamine utilization sustaining enhanced, unrestricted growth. The development of effective anti-cancer treatments targeting metabolism may be facilitated by the identification and rational combinatorial targeting of metabolic pathways. Methods We performed mass spectrometric metabolomics analysis in vitro and in vivo experiments to evaluate the efficacy of drugs and identify metabolic connectivity. Results We show that K-Ras-mutant lung and colon cancer cells exhibit a distinct metabolic rewiring, the latter being more dependent on respiration. Combined treatment with the glutaminase inhibitor CB-839 and the PI3K/aldolase inhibitor NVP-BKM120 more consistently reduces cell growth of tumor xenografts. Maximal growth inhibition correlates with the disruption of redox homeostasis, involving loss of reduced glutathione regeneration, redox cofactors, and a decreased connectivity among metabolites primarily involved in nucleic acid metabolism. Conclusions Our findings open the way to develop metabolic connectivity profiling as a tool for a selective strategy of combined drug repositioning in precision oncology. |
| Databáze: | OpenAIRE |
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