title: Licorice and its active compound glycyrrhizic acid ameliorates cisplatin-induced nephrotoxicity through inactivation of p53 by scavenging ROS and overexpression of p21 in human renal proximal tubular epithelial cells.
abstract: Nephrotoxicity is one of the major side effects that limit the use of cisplatin in cancer therapy. Cisplatin-induced apoptosis in renal cells is associated with reactive oxygen species (ROS)-mediated p53 activation. Licorice (Glycyrrhiza uralensis Fischer) is one of the most widely used medicinal herbs in Korea, China and Japan. The aim of the study was to evaluate the protective effects of licorice extract (LE) and its active compound glycyrrhizic acid (GA) against cisplatin-induced nephrotoxicity in human renal proximal tubular epithelial (HK-2) cells.
  
  
  
  HK-2 cells were pretreated with LE or GA for 1 h and then treated with 40 μM of cisplatin for indicated times under the serum-free condition. Cell viability was evaluated by MTT assay. Apoptosis was evaluated by flow cytometric analysis and caspase-3 activity. The intracellular ROS levels were determined by DCFH-DA assay. The expression and phosphorylation levels of protein were evaluated by Western blot and densitometry analysis.
  
  
  
  When treating HK-2 cells with LE or GA, both of them alleviated cisplatin-induced cytotoxicity and apoptosis. LE and GA inhibited caspase-3 activity and polymerase (PARP) cleavage in cisplatin-treated cells. LE and GA also inhibited p53 expression and its phosphorylation as well as ROS production in cells exposed to cisplatin. Meanwhile, LE and GA enhanced cisplatin-induced p21 expression, which then led to S-phase arrest in cell cycle and limited cell growth. Presumably, increased p21 expression may contribute to cellular prevention from cisplatin-induced apoptosis, because p21 is the key molecule to cytoprotection during cisplatin-induced nephrotoxicity.
  
  
  
  These results suggest that LE and GA ameliorate cisplatin-induced apoptosis through reduction of ROS-mediating p53 activation and promotion of p21 expression in HK-2 cells.
authors.affiliation: Department of Pathology, College of Korean Medicine, Wonkwang University, Iksan, Jeonbuk, Republic of Korea. omdjbh@wku.ac.kr.
authors.forename: S-M
authors.initials: SM
authors.lastname: Ju
authors.forename: M-S
authors.initials: MS
authors.lastname: Kim
authors.forename: Y-S
authors.initials: YS
authors.lastname: Jo
authors.forename: Y-M
authors.initials: YM
authors.lastname: Jeon
authors.forename: J-S
authors.initials: JS
authors.lastname: Bae
authors.forename: H-O
authors.initials: HO
authors.lastname: Pae
authors.forename: B-H
authors.initials: BH
authors.lastname: Jeon
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002945:Cisplatin / Q000009:adverse effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006035:Glycyrrhiza / Q000737:chemistry; D019695:Glycyrrhizic Acid / Q000494:pharmacology*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology; D010936:Plant Extracts / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D010936:Plant Extracts; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019695:Glycyrrhizic Acid; D002945:Cisplatin