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Published on: January 7, 2013
Cisplatin Induces Kidney Cell Death via ROS-dependent MAPK Signaling Pathways by Targeting Peroxiredoxin I and II in
Hui-Na Zhang1, Wan-Qiu Xiao1, Dong Hun Lee2
1College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, P.R. China.
Background/Aim:
Cisplatin [cis-diamminedichloroplatinum(II), CDDP] is a widely used and effective antitumor drug in clinical settings, notorious for its nephrotoxic side effects. This study investigated the mechanisms of CDDP-induced damage in African green monkey kidney (Vero) cells, with a focus on the role of Peroxiredoxin I (Prx I) and Peroxiredoxin II (Prx II) of the peroxiredoxin (Prx) family, which scavenge reactive oxygen species (ROS).
Materials And Methods:
We utilized the Vero cell line derived from African green monkey kidneys and exposed these cells to various concentrations of CDDP. Cell viability, apoptosis, ROS levels, and mitochondrial membrane potential were assessed.
Results:
CDDP significantly compromised Vero cell viability by elevating both cellular and mitochondrial ROS, which led to increased apoptosis. Pretreatment with the ROS scavenger N-acetyl-L-cysteine (NAC) effectively reduced CDDP-induced ROS accumulation and subsequent cell apoptosis. Furthermore, CDDP reduced Prx I and Prx II levels in a dose- and time-dependent manner. The inhibition of Prx I and II exacerbated cell death, implicating their role in CDDP-induced accumulation of cellular ROS. Additionally, CDDP enhanced the phosphorylation of MAPKs (p38, ERK, and JNK) without affecting AKT. The inhibition of these pathways significantly attenuated CDDP-induced apoptosis.
Conclusion:
The study highlights the involvement of Prx proteins in CDDP-induced nephrotoxicity and emphasizes the central role of ROS in cell death mediation. These insights offer promising avenues for developing clinical interventions to mitigate the nephrotoxic effects of CDDP.
Insights
Cisplatin (CDDP) causes kidney damage by increasing reactive oxygen species (ROS) and reducing protective Peroxiredoxin (Prx) I and II levels. Restoring Prx levels may mitigate CDDP nephrotoxicity.
Area of Science:
- Cell Biology
- Toxicology
- Biochemistry
Background:
- Cisplatin (cis-diamminedichloroplatinum(II), CDDP) is an effective chemotherapy agent with significant nephrotoxic side effects.
- Peroxiredoxins (Prx) I and II are key enzymes involved in scavenging reactive oxygen species (ROS).
Purpose of the Study:
- To investigate the mechanisms underlying CDDP-induced kidney cell damage.
- To elucidate the role of Peroxiredoxin I (Prx I) and Peroxiredoxin II (Prx II) in CDDP nephrotoxicity.
Main Methods:
- African green monkey kidney (Vero) cells were exposed to varying concentrations of CDDP.
- Assessed cell viability, apoptosis, ROS levels, mitochondrial membrane potential, and MAPK/AKT phosphorylation.
- Utilized N-acetyl-L-cysteine (NAC) as a ROS scavenger and pathway inhibitors.
Main Results:
- CDDP treatment elevated cellular and mitochondrial ROS, leading to apoptosis and reduced cell viability.
- CDDP decreased Prx I and Prx II levels, and their inhibition exacerbated CDDP-induced cell death.
- N-acetyl-L-cysteine (NAC) pretreatment mitigated CDDP-induced ROS and apoptosis.
- CDDP activated p38, ERK, and JNK MAPKs, contributing to apoptosis.
Conclusions:
- Reactive oxygen species (ROS) play a critical role in mediating CDDP-induced kidney cell death.
- Peroxiredoxin (Prx) proteins are involved in protecting kidney cells against CDDP toxicity.
- Targeting ROS and Prx pathways may offer strategies to reduce CDDP nephrotoxicity.
