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Int Immunopharmacol. 2015 Sep;28(1):399-408. doi: 10.1016/j.intimp.2015.06.020. Epub 2015 Jun 26.

Saikosaponin-D reduces cisplatin-induced nephrotoxicity by repressing ROS-mediated activation of MAPK and NF-κB signalling pathways.

Author information

1
Department of Oncology, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710000, PR China.
2
Department of Oncology, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710000, PR China.
3
Department of Oncology, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710000, PR China. Electronic address: huiwentaoedu@163.com.

Abstract

The nephrotoxicity induced by cisplatin (DDP) severely limits the clinical efficacy of this widely used anticancer agent. The observed nephrotoxicity may be the result of DDP-induced inflammation and apoptosis. Saikosaponin-D (SSD), a triterpenoid saponin, has numerous pharmacological properties. The goal of the present study was to investigate whether and how SSD protected against DDP-induced nephrotoxicity. Non-cytotoxic levels of SSD significantly increased the viability rate, improved the nuclear morphology, and attenuated the caspase-3 activation and programmed apoptosis of DDP-treated HK-2 cells. In addition, SSD treatment markedly inhibited the release of tumour necrosis factor (TNF)-α, interleukin-1β (IL-1β), and interleukin-6 (IL-6), as well as the production of nitric oxide and the expression of inducible nitric oxide synthase (iNOS) by these cells. More importantly, SSD effectively blocked the DDP-induced activation of NF-κB, P38, JNK, and MAPKs. Furthermore, we found that U0126 (a specific inhibitor of MAPKs) strongly inhibited the IKK/IκB/NF-κB-dependent release of pro-inflammatory cytokines and iNOS gene expression. Finally, we demonstrated that SSD decreased the level of reactive oxygen species (ROS) accumulation and that the specific ROS scavenger N-acetylcysteine (NAC) markedly inhibited the DDP-induced activation of MAPK and phosphorylation of the downstream signal NF-κB, which in turn reduced the levels of pro-inflammatory cytokine release and iNOS gene expression. Our results suggest that the SSD-mediated alleviation of DDP-induced nephrotoxicity was due to uncoupling of the ROS, P38, and JNK/NF-κB signalling pathways.

KEYWORDS:

Cisplatin nephrotoxicity; MAPKs; NF-κB; ROS; Saikosaponin-D

PMID:
26118633
DOI:
10.1016/j.intimp.2015.06.020
[Indexed for MEDLINE]

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