Abstract: TH-PO291
Dose Finding Safety Study for Bardoxolone Methyl and 6-Gingerol as Nephroprotectants against Cisplatin Induced Kidney Injury
Session Information
- AKI Basic: Oxidative Injury and Nephrotoxins
November 02, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Acute Kidney Injury
- 001 AKI: Basic
Authors
- Tuey, Stacey, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Brown, Carolyn Nicole, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Edelstein, Charles L., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Joy, Melanie S., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
Background
Nephrotoxicity is a major adverse effect that limits cisplatin (CIS) clinical use. CIS induced kidney injury is in part due to reactive oxygen species. Bardoxolone methyl (BARD) and 6-gingerol (6GNG), have shown nephroprotective potential through antioxidant properties. The purpose of this study was to conduct a dose finding safety study for use of BARD and 6-GNG as nephroprotectants against CIS induced kidney in a mouse model of cancer and cisplatin nephrotoxicity.
Methods
Study mice were injected with CMT167 lung cancer cells. In the first study, BARD (5, 10, or 20 mg/kg) or BARD vehicle (VEH) was given daily for 6 days and one dose of CIS (25mg/kg) was given on day 3 of BARD treatment. In the second study, mice were dosed with 6GNG (25, 50, or 100 mg/kg) or 6GNG VEH 3x weekly and CIS (12.5 mg/kg) or CIS VEH was given 1x weekly for 2 weeks. Treatments were compared to VEH using one-way analysis of variance with Dunnett’s post-hoc test.
Results
See Table 1
Conclusion
The 10 mg/kg BARD and 50 mg/kg 6GNG demonstrated the best performance in terms of no potential adverse effects on ALT, BUN, and hematocrit and no discernable increases in tumor size. Additionally, these doses appear promising for protection of kidney function and cisplatin-induced anemia as demonstrated by the reduction in BUN and increase in hematocrit, respectively. Future studies will be conducted to confirm safety and efficacy in this mouse model relevant to human CIS induced nephrotoxicity.
Results:
| BARD | 6GNG | |||||||
| CIS+VEH | CIS+5mg/kg | CIS+10mg/kg | CIS+20mg/kg | CIS+VEH | CIS+25mg/kg | CIS+50mg/kg | CIS+100mg/kg | |
| ALT (mU/mL) | 14±5.3 | 21±9.1 | 7±2.3 | 56±12.3* | 56±8.4 | 51±14.7 | 31±2.6 | 25±5.3 |
| BUN (mg/dL) | 37.5±2.22 | 25.3±3.84* | 29.0±2.65 | 175.5±3.50* | 30.3±2.10 | 26.3±0.47 | 25.6±1.15 | 30.7±5.66 |
| Hematocrit (%) | 34±0.7 | 35±2.9 | 41±0.8 | 38±1.2 | 37±1.9 | 40±1.2 | 40±3.3 | 38±1.8 |
*: p<0.05 compared to CIS+VEH
Funding
- NIDDK Support