An Integrated In Silico and In Vivo Approach to Identify Protective Effects of Palonosetron in Cisplatin-Induced Nephrotoxicity
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 or...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-12-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/13/12/480 |
| _version_ | 1797544058873184256 |
|---|---|
| author | Eri Wakai Yuya Suzumura Kenji Ikemura Toshiro Mizuno Masatoshi Watanabe Kazuhiko Takeuchi Yuhei Nishimura |
| author_facet | Eri Wakai Yuya Suzumura Kenji Ikemura Toshiro Mizuno Masatoshi Watanabe Kazuhiko Takeuchi Yuhei Nishimura |
| author_sort | Eri Wakai |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T13:55:06Z |
| format | Article |
| id | doaj.art-4f72399f336c4bc7b2eda665db9d0b2f |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T13:55:06Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-4f72399f336c4bc7b2eda665db9d0b2f2023-11-21T01:43:54ZengMDPI AGPharmaceuticals1424-82472020-12-01131248010.3390/ph13120480An Integrated In Silico and In Vivo Approach to Identify Protective Effects of Palonosetron in Cisplatin-Induced NephrotoxicityEri Wakai0Yuya Suzumura1Kenji Ikemura2Toshiro Mizuno3Masatoshi Watanabe4Kazuhiko Takeuchi5Yuhei Nishimura6Department of Integrative Pharmacology, Mie University Graduate School of Medicine, Tsu 514-8507, JapanDepartment of Integrative Pharmacology, Mie University Graduate School of Medicine, Tsu 514-8507, JapanDepartment of Pharmacy, Osaka University Hospital, Suita 565-0871, JapanDepartment of Medical Oncology, Mie University Graduate School of Medicine, Tsu 514-8507, JapanDepartment of Oncologic Pathology, Mie University Graduate School of Medicine, Tsu 514-8507, JapanDepartment of Otorhinolaryngology—Head and Neck Surgery, Mie University Graduate School of Medicine, Tsu 514-8507, JapanDepartment of Integrative Pharmacology, Mie University Graduate School of Medicine, Tsu 514-8507, JapanCisplatin 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.https://www.mdpi.com/1424-8247/13/12/480cisplatinnephrotoxicitydrug repositioningdata-driven approachgene expression signatureadverse events |
| spellingShingle | Eri Wakai Yuya Suzumura Kenji Ikemura Toshiro Mizuno Masatoshi Watanabe Kazuhiko Takeuchi Yuhei Nishimura An Integrated In Silico and In Vivo Approach to Identify Protective Effects of Palonosetron in Cisplatin-Induced Nephrotoxicity Pharmaceuticals cisplatin nephrotoxicity drug repositioning data-driven approach gene expression signature adverse events |
| title | An Integrated In Silico and In Vivo Approach to Identify Protective Effects of Palonosetron in Cisplatin-Induced Nephrotoxicity |
| title_full | An Integrated In Silico and In Vivo Approach to Identify Protective Effects of Palonosetron in Cisplatin-Induced Nephrotoxicity |
| title_fullStr | An Integrated In Silico and In Vivo Approach to Identify Protective Effects of Palonosetron in Cisplatin-Induced Nephrotoxicity |
| title_full_unstemmed | An Integrated In Silico and In Vivo Approach to Identify Protective Effects of Palonosetron in Cisplatin-Induced Nephrotoxicity |
| title_short | An Integrated In Silico and In Vivo Approach to Identify Protective Effects of Palonosetron in Cisplatin-Induced Nephrotoxicity |
| title_sort | integrated in silico and in vivo approach to identify protective effects of palonosetron in cisplatin induced nephrotoxicity |
| topic | cisplatin nephrotoxicity drug repositioning data-driven approach gene expression signature adverse events |
| url | https://www.mdpi.com/1424-8247/13/12/480 |
| work_keys_str_mv | AT eriwakai anintegratedinsilicoandinvivoapproachtoidentifyprotectiveeffectsofpalonosetronincisplatininducednephrotoxicity AT yuyasuzumura anintegratedinsilicoandinvivoapproachtoidentifyprotectiveeffectsofpalonosetronincisplatininducednephrotoxicity AT kenjiikemura anintegratedinsilicoandinvivoapproachtoidentifyprotectiveeffectsofpalonosetronincisplatininducednephrotoxicity AT toshiromizuno anintegratedinsilicoandinvivoapproachtoidentifyprotectiveeffectsofpalonosetronincisplatininducednephrotoxicity AT masatoshiwatanabe anintegratedinsilicoandinvivoapproachtoidentifyprotectiveeffectsofpalonosetronincisplatininducednephrotoxicity AT kazuhikotakeuchi anintegratedinsilicoandinvivoapproachtoidentifyprotectiveeffectsofpalonosetronincisplatininducednephrotoxicity AT yuheinishimura anintegratedinsilicoandinvivoapproachtoidentifyprotectiveeffectsofpalonosetronincisplatininducednephrotoxicity AT eriwakai integratedinsilicoandinvivoapproachtoidentifyprotectiveeffectsofpalonosetronincisplatininducednephrotoxicity AT yuyasuzumura integratedinsilicoandinvivoapproachtoidentifyprotectiveeffectsofpalonosetronincisplatininducednephrotoxicity AT kenjiikemura integratedinsilicoandinvivoapproachtoidentifyprotectiveeffectsofpalonosetronincisplatininducednephrotoxicity AT toshiromizuno integratedinsilicoandinvivoapproachtoidentifyprotectiveeffectsofpalonosetronincisplatininducednephrotoxicity AT masatoshiwatanabe integratedinsilicoandinvivoapproachtoidentifyprotectiveeffectsofpalonosetronincisplatininducednephrotoxicity AT kazuhikotakeuchi integratedinsilicoandinvivoapproachtoidentifyprotectiveeffectsofpalonosetronincisplatininducednephrotoxicity AT yuheinishimura integratedinsilicoandinvivoapproachtoidentifyprotectiveeffectsofpalonosetronincisplatininducednephrotoxicity |