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Protective effects of 1,2,3-triazole derivative KPR-A020 against cisplatin-induced ototoxicity in murine cochlear cultures.

Abstract Cisplatin (cis-diaminedichloridoplatinum(II), cis-[PtCl2(NH3)2]) is an effective chemotherapeutic agent in the treatment of several types of malignant solid tumors but its clinical use is associated with ototoxicity. Several studies have investigated the effect of antioxidants on cisplatin-induced ototoxicity in mice. The triazole KPR-A020 has been shown to play a protective role against mitochondrial dysfunction by reducing the production of mitochondrial reactive oxygen species (ROS). The effect of KPR-A020 on cisplatin-induced ototoxicity was examined using cultures of cochlear explants. Healthy mice were randomly divided into 4 groups: control, treated with cisplatin alone (CP), treated with cisplatin and KPR-A020 (CP + KPR-A020), and treated with KPR-A020 alone (KPR-A020). The cochlear explants were harvested for histological and immunohistochemical examinations. Biochemical analyses of the explants revealed that pre-treatment with KPR-A020 prevented an increase in mitochondrial ROS levels. Moreover, the CP + KPR-A020 group showed better hair cell survival than the CP group. Immunohistochemical examinations of cochlear explants stained with anti-caspase-3 revealed greater immunopositivity in the CP group. The CP + KPR-A020 group showed significantly less immunopositivity than the CP group (P < 0.05). Thus, it appears that KPR-A020 protects hair cells in the organ of Corti from cisplatin-induced toxicity by decreasing the production of mitochondrial ROS. The results of this study suggest that KPR-A020 can be used as an antioxidant and antiapoptotic agent to prevent hearing loss caused by cisplatin induced-oxidative stress.
PMID
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Authors

Mayor MeshTerms
Keywords

Antioxidants

Cisplatin

Cochlear explants

KPR-A020

Ototoxicity

Triazole

Journal Title international journal of pediatric otorhinolaryngology
Publication Year Start




PMID- 28390615
OWN - NLM
STAT- MEDLINE
DA  - 20170409
DCOM- 20170517
LR  - 20170517
IS  - 1872-8464 (Electronic)
IS  - 0165-5876 (Linking)
VI  - 96
DP  - 2017 May
TI  - Protective effects of 1,2,3-triazole derivative KPR-A020 against
      cisplatin-induced ototoxicity in murine cochlear cultures.
PG  - 59-64
LID - S0165-5876(17)30088-5 [pii]
LID - 10.1016/j.ijporl.2017.02.028 [doi]
AB  - Cisplatin (cis-diaminedichloridoplatinum(II), cis-[PtCl2(NH3)2]) is an effective 
      chemotherapeutic agent in the treatment of several types of malignant solid
      tumors but its clinical use is associated with ototoxicity. Several studies have 
      investigated the effect of antioxidants on cisplatin-induced ototoxicity in mice.
      The triazole KPR-A020 has been shown to play a protective role against
      mitochondrial dysfunction by reducing the production of mitochondrial reactive
      oxygen species (ROS). The effect of KPR-A020 on cisplatin-induced ototoxicity was
      examined using cultures of cochlear explants. Healthy mice were randomly divided 
      into 4 groups: control, treated with cisplatin alone (CP), treated with cisplatin
      and KPR-A020 (CP + KPR-A020), and treated with KPR-A020 alone (KPR-A020). The
      cochlear explants were harvested for histological and immunohistochemical
      examinations. Biochemical analyses of the explants revealed that pre-treatment
      with KPR-A020 prevented an increase in mitochondrial ROS levels. Moreover, the CP
      + KPR-A020 group showed better hair cell survival than the CP group.
      Immunohistochemical examinations of cochlear explants stained with anti-caspase-3
      revealed greater immunopositivity in the CP group. The CP + KPR-A020 group showed
      significantly less immunopositivity than the CP group (P &lt; 0.05). Thus, it
      appears that KPR-A020 protects hair cells in the organ of Corti from
      cisplatin-induced toxicity by decreasing the production of mitochondrial ROS. The
      results of this study suggest that KPR-A020 can be used as an antioxidant and
      antiapoptotic agent to prevent hearing loss caused by cisplatin induced-oxidative
      stress.
CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
FAU - Kim, Ye-Ri
AU  - Kim YR
AD  - Department of Biology, College of Natural Sciences, Kyungpook National
      University, Daegu, Republic of Korea; School of Life Sciences, BK21 Plus KNU
      Creative BioResearch Group, Kyungpook National University, Daegu, Republic of
      Korea. Electronic address: [email protected]
FAU - Jung, Da Jung
AU  - Jung DJ
AD  - Department of Otorhinolaryngology-Head and Neck Surgery, Kyungpook National
      University Hospital, Kyungpook National University School of Medicine, Daegu,
      Republic of Korea. Electronic address: [email protected]
FAU - Oh, Se-Kyung
AU  - Oh SK
AD  - Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu,
      Republic of Korea. Electronic address: [email protected]
FAU - Lee, Taeho
AU  - Lee T
AD  - Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook
      National University, Daegu, Republic of Korea. Electronic address:
      [email protected]
FAU - Lee, In-Kyu
AU  - Lee IK
AD  - Department of Internal Medicine, Kyungpook National University Hospital,
      Kyungpook National University School of Medicine, Daegu, Republic of Korea;
      Leading-edge Research Center for Drug Discovery and Development for Diabetes and 
      Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of
      Korea. Electronic address: [email protected]
FAU - Lee, Kyu-Yup
AU  - Lee KY
AD  - Department of Otorhinolaryngology-Head and Neck Surgery, Kyungpook National
      University Hospital, Kyungpook National University School of Medicine, Daegu,
      Republic of Korea. Electronic address: [email protected]
FAU - Kim, Un-Kyung
AU  - Kim UK
AD  - Department of Biology, College of Natural Sciences, Kyungpook National
      University, Daegu, Republic of Korea; School of Life Sciences, BK21 Plus KNU
      Creative BioResearch Group, Kyungpook National University, Daegu, Republic of
      Korea. Electronic address: [email protected]
LA  - eng
PT  - Journal Article
DEP - 20170228
PL  - Ireland
TA  - Int J Pediatr Otorhinolaryngol
JT  - International journal of pediatric otorhinolaryngology
JID - 8003603
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Antioxidants)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Triazoles)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*adverse effects
MH  - Antioxidants/*pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Survival/drug effects
MH  - Cisplatin/*adverse effects
MH  - Cochlea/*drug effects
MH  - Hearing Loss/*chemically induced/prevention &amp; control
MH  - Immunohistochemistry
MH  - Mice
MH  - Oxidative Stress/drug effects
MH  - Reactive Oxygen Species/metabolism
MH  - Triazoles/*pharmacology
OTO - NOTNLM
OT  - Antioxidants
OT  - Cisplatin
OT  - Cochlear explants
OT  - KPR-A020
OT  - Ototoxicity
OT  - Triazole
EDAT- 2017/04/10 06:00
MHDA- 2017/05/18 06:00
CRDT- 2017/04/10 06:00
PHST- 2016/12/16 [received]
PHST- 2017/02/24 [revised]
PHST- 2017/02/25 [accepted]
AID - S0165-5876(17)30088-5 [pii]
AID - 10.1016/j.ijporl.2017.02.028 [doi]
PST - ppublish
SO  - Int J Pediatr Otorhinolaryngol. 2017 May;96:59-64. doi:
      10.1016/j.ijporl.2017.02.028. Epub 2017 Feb 28.

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