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Updated: Jun 13, 2025
Acute Kidney Injury Model Induced by Cisplatin in Adult Zebrafish
Published on: May 15, 2021
Discovery of Novel Potent Molecule for Treating Cisplatin-Induced Acute Kidney Injury Driven by Phenotypic Screening
Yan Lou1, Feilong Zhou1, Daxing Shi1
1School of Pharmacy, Anhui Medical University, Hefei 230032, P.R. China.
Abstract:
Cisplatin-induced acute kidney injury (cis-AKI) is the primary organ toxicity that occurs during cisplatin-based cancer treatment, and currently, there is a lack of effective treatment methods. The occurrence of cis-AKI involves complex pathophysiological processes, therefore, phenotypic screening-based drug discovery may be more applicable for identifying lead compounds to treat cis-AKI. In this study, a cascading phenotypic screening was designed and implemented. Through this protocol, a potent compound, CX116, was obtained, which exhibits potent anti-inflammatory activity and effectively protects cells from cisplatin toxicity. Mechanism studies indicated that CX116 exerts its effects by inhibiting the inflammatory response, reducing oxidative stress, protecting mitochondrial function, and counteracting apoptosis. In vivo studies showed that CX116 bears acceptable toxicity and appropriate pharmacokinetic properties, and significantly protects renal tissue from cisplatin-induced damage in a cis-AKI animal model. In conclusion, CX116 is a highly promising active molecule and holds great potential for the development of therapeutic drugs for cis-AKI.
Insights
A new compound, CX116, effectively protects against cisplatin-induced acute kidney injury (cis-AKI) by reducing inflammation and oxidative stress. This promising molecule shows potential for developing novel treatments for cis-AKI in cancer patients.
Area of Science:
- Nephrology
- Pharmacology
- Oncology
Background:
- Cisplatin-induced acute kidney injury (cis-AKI) is a significant dose-limiting toxicity in cancer chemotherapy.
- Current therapeutic options for cis-AKI are limited, necessitating the development of novel treatment strategies.
- Complex pathophysiological mechanisms underscore the need for innovative drug discovery approaches like phenotypic screening.
Purpose of the Study:
- To identify novel therapeutic compounds for cis-AKI using a cascading phenotypic screening approach.
- To evaluate the efficacy and mechanisms of action of a lead compound identified through screening.
- To assess the safety and pharmacokinetic profile of the lead compound in preclinical models.
Main Methods:
- Implementation of a cascading phenotypic screening protocol to identify cis-AKI protective compounds.
- In vitro assessment of compound efficacy on cisplatin-induced cellular toxicity.
- In vivo evaluation of compound safety, pharmacokinetics, and renoprotective effects in a cis-AKI animal model.
Main Results:
- Identification of CX116 as a potent compound exhibiting significant anti-inflammatory and cytoprotective effects against cisplatin toxicity.
- Mechanism studies revealed that CX116 inhibits inflammation, reduces oxidative stress, preserves mitochondrial function, and prevents apoptosis.
- In vivo studies demonstrated favorable toxicity and pharmacokinetic profiles for CX116, with significant protection of renal tissue in a cis-AKI model.
Conclusions:
- CX116 is a highly promising molecule for the treatment of cis-AKI.
- The compound's multifaceted mechanism of action offers a strong basis for therapeutic development.
- CX116 holds significant potential for clinical translation in managing cisplatin-related nephrotoxicity.
