Germacrone Reduces Cisplatin-Induced Toxicity of Renal Proximal Tubular Cells <i>via</i> Inhibition of Organic Cation Transporter

Abstract

Cisplatin is a widely used chemotherapy for solid tumors; however, its benefits are limited by serious nephrotoxicity, particularly in proximal tubular cells. The present study investigated the renoprotective effect and mechanisms of germacrone, a bioactive terpenoid compound found in Curcuma species on cisplatin-induced toxicity of renal cells. Germacrone (50 and 100 µM) attenuated apoptosis of human renal proximal tubular cells, RPTEC/TERT1 following treatment with 50 µM cisplatin and for 48 h. Co-treating RPTEC/TERT1 cells with cisplatin and germacrone significantly reduced cellular platinum content compared with cisplatin treatment alone. The effect of germacrone on organic cation transporter 2 (OCT2) which is a transporter responsible for cisplatin uptake was determined. Germacrone showed an inhibitory effect on OCT2-mediated methyl-4-phenylpyridinium acetate ( 3 H-MPP ) uptake with IC 50 of 15 µM with less effect on OCT1. The germacrone's protective effect on cisplatin-induced cytotoxicity was not observed in cancer cells; cisplatin's anti-cancer activity was preserved. In conclusion, germacrone prevents cisplatin-induced toxicity in renal proximal tubular cells via inhibition OCT2 transport function and reducing cisplatin accumulation. Thus germacrone may be a good candidate agent used for reducing cisplatin-induced nephrotoxicity.

miR-188-3p abolishes germacrone-mediated podocyte protection in a mouse model of diabetic nephropathy in type I diabetes through triggering mitochondrial injury

“…Germacrone plays a neuroprotective role by protecting against oxygen-glucose deprivation/reperfusion injury [ 23 ]. Germacrone reduces cisplatin-induced nephrotoxicity by inhibiting organic cation transporters [ 24 ]. Substantial evidence has shown that germacrone has strong antioxidant and anti-apoptotic effects, however, the role of germacrone in the development of DN remains unclear.…”

Protective Effect of Panduratin A on Cisplatin-Induced Apoptosis of Human Renal Proximal Tubular Cells and Acute Kidney Injury in Mice

“…14,15) Certain phytochemicals ameliorate cisplatin-induced neph-rotoxicity by inhibiting ROS accumulation and apoptosis. [16][17][18] Although nephroprotective effects of these phytochemicals have been reported in preclinical studies, there is still no approved drugs from phytochemicals for cisplatin's nephrotoxicity (see detail in review). 19) Current clinical practice only provides supportive treatments to recover renal function.…”

MicroRNAs Involved in Intrinsic Apoptotic Pathway during Cisplatin-Induced Nephrotoxicity: Potential Use of Natural Products against DDP-Induced Apoptosis

“…Likewise, terpenoids are a large and diverse group of lipids resulting from five-carbon isoprene units assembled in thousands of combinations and are isolated from plants and microbial sources. The following terpenoids have shown potential in some studies: anemoside B4 [ 126 ], carnosic acid [ 127 ], carvacrol [ 128 , 129 ], dioscin [ 130 ], germacrone [ 131 ], ginsenoside 20 (S)-RG3/Re/RG5/Rk1/Rh2 [ 132 , 133 , 134 , 135 , 136 ], linalool [ 137 ], Panax quinquefolius saponins [ 138 ], Panax notoginseng saponins [ 139 , 140 ], platycodin D [ 141 , 142 ], pseudoginsengenin DQ [ 53 ], red ginseng [ 143 ], saikosaponin D [ 144 ], and Terminalia arjuna triterpenoid saponins [ 145 ].…”