Abstract
Cisplatin is widely used to treat various types of cancers, but it is often limited by nephrotoxicity. Here, we employed an integrated in silico and in vivo approach to identify potential treatments for cisplatin-induced nephrotoxicity (CIN). Using publicly available mouse kidney and human kidney organoid transcriptome datasets, we first identified a 208-gene expression signature for CIN and then used the bioinformatics database Cmap and Lincs Unified Environment (CLUE) to identify drugs expected to counter the expression signature for CIN. We also searched the adverse event database, Food and Drug Administration. Adverse Event Reporting System (FAERS), to identify drugs that reduce the reporting odds ratio of developing cisplatin-induced acute kidney injury. Palonosetron, a serotonin type 3 receptor (5-hydroxytryptamine receptor 3 (5-HT3R)) antagonist, was identified by both CLUE and FAERS analyses. Notably, clinical data from 103 patients treated with cisplatin for head and neck cancer revealed that palonosetron was superior to ramosetron in suppressing cisplatin-induced increases in serum creatinine and blood urea nitrogen levels. Moreover, palonosetron significantly increased the survival rate of zebrafish exposed to cisplatin but not to other 5-HT3R antagonists. These results not only suggest that palonosetron can suppress CIN but also support the use of in silico and in vivo approaches in drug repositioning studies.
Highlights
Cisplatin, an inorganic platinum derivative, is one of the most effective anticancer drugs and is widely used for the treatment of many malignancies, including brain, head and neck, lung, breast, and ovarian cancers [1,2]
We identified a gene expression signature (GES) characteristic of cisplatin-treated kidney cells and employed bioinformatics tools to search for drugs that might counter the cisplatin-associated GES, thereby preventing Cisplatin-induced nephrotoxicity (CIN)
To identify a GES associated with CIN, which we termed GES-CIN, we analyzed transcriptome datasets of cisplatin-exposed mouse kidneys [20,21] and human kidney organoid [22] from the Gene Expression Omnibus [23]
Summary
An inorganic platinum derivative, is one of the most effective anticancer drugs and is widely used for the treatment of many malignancies, including brain, head and neck, lung, breast, and ovarian cancers [1,2]. In addition to DNA repair pathways, cisplatin activates other signaling cascades that lead to oxidative stress and inflammation in renal proximal tubule epithelial cells, tubular cell death, decline of glomerular filtration rate, and acute kidney failure [3,7,8]. CIN is generally treated and/or prevented by increasing hydration through the administration of isotonic saline, magnesium supplementation, or by mannitol-induced forced diuresis [9]. The latter approach is considered for patients treated with high doses of cisplatin, but mannitol itself may cause dehydration by over-diuresis [9]. We identified a GES characteristic of cisplatin-treated kidney cells and employed bioinformatics tools to search for drugs that might counter the cisplatin-associated GES, thereby preventing CIN. Our data identify a potential novel use for palonosetron in suppressing CIN
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