Sunitinib versus Pazopanib Dilemma in Renal Cell Carcinoma:New Insights into the In Vitro Metabolic Impact, Efficacy, and Safety
| Autor: | Filipa Amaro, Carolina Pisoeiro, Maria João Valente, Maria de Lourdes Bastos, Paula Guedes de Pinho, Márcia Carvalho, Joana Pinto |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Indazoles
Metastatic renal cell carcinoma Antineoplastic Agents Glycerophospholipids metastatic renal cell carcinoma tyrosine kinase inhibitors toxicity oxidative stress metabolomics 1H NMR spectroscopy endometabolome exometabolome Endometabolome Catalysis Inorganic Chemistry Exometabolome SDG 3 - Good Health and Well-being Sunitinib Humans Metabolomics Pyrroles Physical and Theoretical Chemistry Amino Acids Molecular Biology Carcinoma Renal Cell Spectroscopy Tyrosine kinase inhibitors Sulfonamides Toxicity Organic Chemistry General Medicine Kidney Neoplasms Computer Science Applications Pyrimidines Oxidative stress |
| Zdroj: | Amaro, F, Pisoeiro, C, Valente, M J, Bastos, M D L, Guedes de Pinho, P, Carvalho, M & Pinto, J 2022, ' Sunitinib versus Pazopanib Dilemma in Renal Cell Carcinoma : New Insights into the In Vitro Metabolic Impact, Efficacy, and Safety ', International Journal of Molecular Sciences, vol. 23, no. 17, 9898 . https://doi.org/10.3390/ijms23179898 International Journal of Molecular Sciences; Volume 23; Issue 17; Pages: 9898 |
| DOI: | 10.3390/ijms23179898 |
| Popis: | Sunitinib and pazopanib are tyrosine kinase inhibitors (TKIs) used as first-line therapy for metastatic renal cell carcinoma (RCC). Although these TKIs are associated with similar survival outcomes, some differences have been reported in their safety profiles. In this work, traditional toxicological endpoints (cell viability and growth, oxidative stress, and nuclear morphology) and 1H NMR spectroscopy-based metabolomics analysis were used to provide new insights into the cytotoxicity and metabolic mechanisms underlying sunitinib and pazopanib treatments. Tumoral (Caki-1) and non-tumoral (HK-2) human renal cells were exposed to clinically relevant concentrations of sunitinib (2 µM) or pazopanib (50 µM). Sunitinib showed selectivity for cancer cells, inhibiting proliferation, and inducing apoptotic death of Caki-1 cells, whereas pazopanib had a similar cytotoxic effect in both tumoral and non-tumoral cells. 1H-NMR metabolomics unveiled a higher impact of sunitinib on the levels of intracellular metabolites of Caki-1 cells (seven dysregulated metabolites), suggesting dysregulations on amino acid, glutathione and glycerophospholipid metabolisms. In contrast, pazopanib had a higher impact on the levels of extracellular metabolites of Caki-1 cells (seven dysregulated metabolites in culture medium), unveiling alterations on amino acid and energetic metabolisms. In HK-2 cells, sunitinib caused only a minor increase in intracellular isoleucine levels, whereas pazopanib induced several alterations on the intracellular (three dysregulated metabolites) and extracellular (three dysregulated metabolites) compartments suggesting changes on amino acid, glycerophospholipid, and energy metabolisms. Our results demonstrate that these TKIs elicit distinct cellular and metabolic responses, with sunitinib showing better in vitro efficacy against target RCC cells and lesser nephrotoxic potential than pazopanib. |
| Databáze: | OpenAIRE |
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