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FDA‐approved PARP Inhibitors are Cytoprotective against Cisplatin Injury in Renal Proximal Tubular Cells
Author(s) -
Kim Jinu,
Ha Ligyeom,
Noh Mi Ra,
Jang Hee-Seong,
Padanilam Babu J.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.09561
Subject(s) - cisplatin , nephrotoxicity , viability assay , pharmacology , olaparib , parp inhibitor , propidium iodide , poly adp ribose polymerase , medicine , chemistry , kidney , apoptosis , chemotherapy , programmed cell death , biochemistry , enzyme , polymerase
Cisplatin is a potent chemotherapeutic drug used to treat many solid cancers. However, its dose‐limiting side effect is nephrotoxicity, leading to acute kidney injury and chronic kidney disease. We previously reported that genetic or pharmacologicial inhibition of poly (ADP‐ribose) polymerase 1 (PARP1) protects against cisplatin nephrotoxicity. PARP1 inhibitors including olaparib, niraparib, and rucaparib are currently FDA approved for treatment of ovarian cancer. In this study, we tested the effect of the above FDA‐approved PARP inhibitors in cisplatin nephrotoxicity. Human HK‐2, pig LLC‐PK1, and mouse HUMPT renal proximal tubular cells (PTC) were subjected to one cycle of treatment with high‐dose cisplatin (1 to 1.5 mM) or four cycles of treatment with low‐dose cisplatin (1 to 3 μM). Each cycle consisted of 6 hours of treatment with cisplatin and 18 hours of recovery in cisplatin‐free medium. The FDA‐approved PARP inhibitors (300 pM to 1 μM) or the same volume of dimethylformamide (vehicle) were added immediately before the first treatment cycle and incubated continuously. The 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay performed to determine cell viability, lactate dehydrogenase (LDH) release assay to determine cell membrane disruption, and propidium iodide (PI) staining to determine necrotic cell death. All of the PARP inhibitors improved cell viability after the high‐dose cisplatin treatment in renal PTC. Increased percentages of LDH release and PI‐positive cells observed after one cycle of treatment with high‐dose cisplatin were significantly abrogated by the PARP inhibitors. Moreover, combined treatment with the PARP inhibitors showed an additive effect on cell viability in renal PTC treated with high‐dose cisplatin. The PARP inhibitors also enhanced cell viability after the four cycles of treatment with low‐dose cisplatin in renal PTC. Thus, our findings suggest that the FDA‐approved PARP inhibitors can protect efficaciously against death of PTC during cisplatin nephrotoxicity and could be developed as potential therapeutic agents to improve cisplatin nephrotoxicity. Support or Funding Information This study is supported by NIH grants DK‐116987, DK‐120533, AHA grants 15GRNT25080031 (BJP), 15POST25130003 (HSJ), and NRF grant NRF‐2019R1F1A1041410 (JK).