Abstract
One of the major adverse effects of cisplatin chemotherapy is hearing loss. Cisplatin-induced ototoxicity hampers treatment because it often necessitates dose reduction, which decreases cisplatin efficacy. This study was performed to investigate the effect of Tempol on cisplatin-induced ototoxicity in an auditory cell line, House Ear Institute-Organ of Corti 1 (HEI-OC1). Cultured HEI-OC1 cells were exposed to 30 μM cisplatin for 24 h with or without a 2 h pre-treatment with Tempol. Cell viability was determined using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and apoptotic cells were identified using terminal deoxynucleotidyl transferase dUTP nick end labeling of nuclei (TUNEL) assay and flow cytometry. The effects of Tempol on cisplatin-induced cleaved poly(ADP-ribose) polymerase, cleaved caspase, and mitochondrial inducible nitric oxide synthase expression were evaluated using western blot analysis. Levels of intracellular reactive oxygen species (ROS) were measured to assess the effects of Tempol on cisplatin-induced ROS accumulation. Mitochondria were evaluated by confocal microscopy, and the mitochondrial membrane potential was measured to investigate whether Tempol protected against cisplatin-induced mitochondrial dysfunction. Cisplatin treatment decreased cell viability, and increased apoptotic features and markers, ROS accumulation, and mitochondrial dysfunction. Tempol pre-treatment before cisplatin exposure significantly inhibited all these cisplatin-induced effects. These results demonstrate that Tempol inhibits cisplatin-induced cytotoxicity in HEI-OC1, and could play a preventive role against cisplatin-induced ototoxicity.
Highlights
Cisplatin is effective for the treatment of solid tumors in the ovaries, testes, lungs, and bladder, as well as for head and neck cancers
The mechanism of cisplatin-induced ototoxicity has not yet been completely elucidated, it can mostly be attributed to an increase in the level of reactive oxygen species (ROS), which causes a deficiency of intracochlear antioxidants [2] and induces calcium inflow into hair cells, resulting in apoptosis [3]
The present study showed that the cisplatin-induced expression of two apoptotic proteins, cleaved caspase-3 and cleaved PARP, was suppressed by Tempol pre-treatment, thereby demonstrating its anti-apoptotic effect
Summary
Cisplatin is effective for the treatment of solid tumors in the ovaries, testes, lungs, and bladder, as well as for head and neck cancers. Despite its excellent efficacy, cisplatin use is limited because of the hearing loss caused by its ototoxic effects [1], which necessitates dose reduction and reduces its efficacy as an anticancer agent. The mechanism of cisplatin-induced ototoxicity has not yet been completely elucidated, it can mostly be attributed to an increase in the level of reactive oxygen species (ROS), which causes a deficiency of intracochlear antioxidants [2] and induces calcium inflow into hair cells, resulting in apoptosis [3]. Tempol has been reported to restore the intracellular oxidative balance and reduce oxidative stress, resulting in alleviation of nephrotoxicity in mice [4], and reduced infarct size in rat and rabbit myocardial infarction modInetl.sJ.[M5]o.l. MSci.o2r0e1o6,v1e7,r1,9i3t1exerts a protective effect against lymphocyte genotoxicity [6]. Furth eofr1m3 ore, Temipnofal rccatnioneamsiloydpelesn[e5t]r.aMteotrheeovbelor,odit–ebxrearitns baarprrioetreactnivdeexefefretctneaugraoinpsrtoltyemctpivheoecyffteectgse[n7o]t.oSxiincictey T[e6m]. pol acts Fausrathnearmntoiroex,iTdeamnpt,oiltcmanaeyabsielyapbelneettorastue pthperbelsosocdi–sbprlaaitninb-ainrrdieurcaenddoexxeidrtantievuerosptrreostesc. tive effects [7]
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