Bardoxolone methyl improves survival and reduces clinical measures of kidney injury in tumor-bearing mice treated with cisplatin
Abstract Objective Acute kidney injury (AKI) occurs in approximately one-third of patients treated with cisplatin and there is an outstanding need for mitigation strategies to decrease the frequency and severity of cisplatin-induced AKI. This study evaluated bardoxolone methyl (BARD) as a nephroprot...
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SpringerOpen
2025-03-01
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| Online Access: | https://doi.org/10.1186/s41120-025-00107-5 |
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| author | Lauren E. Thompson Stacey M. Tuey Paola Garcia Gonzalez Carly S. Chesterman Courtney D. McGinnis M. Scott Lucia Lauren M. Aleksunes Charles L. Edelstein Melanie S. Joy |
| author_facet | Lauren E. Thompson Stacey M. Tuey Paola Garcia Gonzalez Carly S. Chesterman Courtney D. McGinnis M. Scott Lucia Lauren M. Aleksunes Charles L. Edelstein Melanie S. Joy |
| author_sort | Lauren E. Thompson |
| collection | DOAJ |
| description | Abstract Objective Acute kidney injury (AKI) occurs in approximately one-third of patients treated with cisplatin and there is an outstanding need for mitigation strategies to decrease the frequency and severity of cisplatin-induced AKI. This study evaluated bardoxolone methyl (BARD) as a nephroprotectant in a multidose, tumor-bearing mouse model of cisplatin-induced AKI. BARD is an attractive therapeutic intervention due to its ability to protect against cisplatin-induced nephrotoxicity by activating Nrf2 and previous reports suggesting anti-tumorigenic effects. Methods In this study, CMT167 tumor-bearing mice were treated with four weekly doses of cisplatin with or without BARD and evaluated for survival, tumor growth, and clinical and histological measures of AKI. Kidney injury and/or function were evaluated by quantification of urinary kidney injury molecule-1 (KIM-1) and serum creatinine (SCr) levels as well as histopathology. Results Compared to mice receiving cisplatin alone, co-treatment with BARD significantly enhanced survival (p = 0.01). Moreover, BARD prevented elevation of urinary KIM-1 concentrations as early as one week after cisplatin treatment (p < 0.01) – a response that was observed throughout the 4-week study period. Cisplatin increased SCr concentrations by four weeks, which was prevented by BARD co-administration (p < 0.01). Cisplatin treatment significantly decreased tumor burden compared to vehicle-treated mice (p < 0.05 after two cisplatin doses) – a response that was not altered by BARD co-treatment. Conclusions Overall, the results of this study demonstrate that BARD has the potential to improve survival and reduce clinical measures of kidney injury in tumor-bearing mice treated with cisplatin, suggesting it could be used as a nephroprotectant to mitigate cisplatin-induced AKI. |
| format | Article |
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| institution | OA Journals |
| issn | 2364-9534 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | SpringerOpen |
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| series | AAPS Open |
| spelling | doaj-art-e150de590ea041029189fc12400f2f8a2025-08-20T01:57:45ZengSpringerOpenAAPS Open2364-95342025-03-0111111310.1186/s41120-025-00107-5Bardoxolone methyl improves survival and reduces clinical measures of kidney injury in tumor-bearing mice treated with cisplatinLauren E. Thompson0Stacey M. Tuey1Paola Garcia Gonzalez2Carly S. Chesterman3Courtney D. McGinnis4M. Scott Lucia5Lauren M. Aleksunes6Charles L. Edelstein7Melanie S. Joy8Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical CampusDepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical CampusDepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical CampusDepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical CampusDepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical CampusDepartment of Pathology, University of Colorado Anschutz Medical CampusEnvironmental and Occupational Health Sciences Institute, Rutgers UniversityDivision of Renal Diseases and Hypertension, University of Colorado Anschutz Medical CampusDepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical CampusAbstract Objective Acute kidney injury (AKI) occurs in approximately one-third of patients treated with cisplatin and there is an outstanding need for mitigation strategies to decrease the frequency and severity of cisplatin-induced AKI. This study evaluated bardoxolone methyl (BARD) as a nephroprotectant in a multidose, tumor-bearing mouse model of cisplatin-induced AKI. BARD is an attractive therapeutic intervention due to its ability to protect against cisplatin-induced nephrotoxicity by activating Nrf2 and previous reports suggesting anti-tumorigenic effects. Methods In this study, CMT167 tumor-bearing mice were treated with four weekly doses of cisplatin with or without BARD and evaluated for survival, tumor growth, and clinical and histological measures of AKI. Kidney injury and/or function were evaluated by quantification of urinary kidney injury molecule-1 (KIM-1) and serum creatinine (SCr) levels as well as histopathology. Results Compared to mice receiving cisplatin alone, co-treatment with BARD significantly enhanced survival (p = 0.01). Moreover, BARD prevented elevation of urinary KIM-1 concentrations as early as one week after cisplatin treatment (p < 0.01) – a response that was observed throughout the 4-week study period. Cisplatin increased SCr concentrations by four weeks, which was prevented by BARD co-administration (p < 0.01). Cisplatin treatment significantly decreased tumor burden compared to vehicle-treated mice (p < 0.05 after two cisplatin doses) – a response that was not altered by BARD co-treatment. Conclusions Overall, the results of this study demonstrate that BARD has the potential to improve survival and reduce clinical measures of kidney injury in tumor-bearing mice treated with cisplatin, suggesting it could be used as a nephroprotectant to mitigate cisplatin-induced AKI.https://doi.org/10.1186/s41120-025-00107-5CisplatinNephrotoxicityBardoxolone MethylAcute Kidney InjuryNrf2 |
| spellingShingle | Lauren E. Thompson Stacey M. Tuey Paola Garcia Gonzalez Carly S. Chesterman Courtney D. McGinnis M. Scott Lucia Lauren M. Aleksunes Charles L. Edelstein Melanie S. Joy Bardoxolone methyl improves survival and reduces clinical measures of kidney injury in tumor-bearing mice treated with cisplatin AAPS Open Cisplatin Nephrotoxicity Bardoxolone Methyl Acute Kidney Injury Nrf2 |
| title | Bardoxolone methyl improves survival and reduces clinical measures of kidney injury in tumor-bearing mice treated with cisplatin |
| title_full | Bardoxolone methyl improves survival and reduces clinical measures of kidney injury in tumor-bearing mice treated with cisplatin |
| title_fullStr | Bardoxolone methyl improves survival and reduces clinical measures of kidney injury in tumor-bearing mice treated with cisplatin |
| title_full_unstemmed | Bardoxolone methyl improves survival and reduces clinical measures of kidney injury in tumor-bearing mice treated with cisplatin |
| title_short | Bardoxolone methyl improves survival and reduces clinical measures of kidney injury in tumor-bearing mice treated with cisplatin |
| title_sort | bardoxolone methyl improves survival and reduces clinical measures of kidney injury in tumor bearing mice treated with cisplatin |
| topic | Cisplatin Nephrotoxicity Bardoxolone Methyl Acute Kidney Injury Nrf2 |
| url | https://doi.org/10.1186/s41120-025-00107-5 |
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