Xanthine oxidase inhibitory terpenoids of Amentotaxus formosana protect cisplatin-induced cell death by reducing reactive oxygen species (ROS) in normal human urothelial and bladder cancer cells.
The diterpenoids (+)-ferruginol (1), ent-kaur-16-en-15-one (2), ent-8(14),15-sandaracopimaradiene-2α,18-diol (3), 8(14),15-sandaracopimaradiene-2α,18,19-triol (4), and (+)-sugiol (5) and the triterpenoids 3β-methoxycycloartan-24(24(1))-ene (6), 3β,23β-dimethoxycycloartan-24(24(1))-ene (7), 3β,23β-dimethoxy-5α-lanosta-24(24(1))-ene (8), and 23(S)-23-methoxy-24-methylenelanosta-8-en-3-one (9), isolated from Amentotaxus formosana, showed inhibitory effects on xanthine oxidase (XO). Of the compounds tested, compound 5 was a potent inhibitor of XO activity, with an IC(50) value of 6.8±0.4 μM, while displaying weak ABTS radical cation scavenging activity. Treatment of the bladder cancer cell line, NTUB1, with 3-10 μM of compound 5 and 10 μM cisplatin, and immortalized normal human urothelial cell line, SV-HUC1, with 0.3-1 μM and 10-50 μM of compound 5 and 10 μM cisplatin, respectively, resulted in increased viability of cells compared with cytotoxicity induced by cisplatin. Treatment of NTUB1 with 20 μM cisplatin and 10 or 30 μM of compound 5 resulted in decreased ROS production compared with ROS production induced by cisplatin. These results indicate that 10 or 30 μM of compound 5 in NTUB1 cells may mediate through the suppression of XO activity and reduction of reactive oxygen species (ROS) induced by compound 5 cotreated with 20 μM cisplatin and protection of subsequent cell death.
Lin
Chun-Nan
CN
School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, San Min District, Kaohsiung 807, Taiwan.
Huang
A-Mei
AM
Lin
Kai-Wei
KW
Hour
Tzyh-Chyuan
TC
Ko
Horng-Huey
HH
Yang
Shyh-Chyun
SC
Pu
Yeong-Shiau
YS
D016923:Cell Death / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D006801:Humans; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D032490:Taxaceae / Q000737:chemistry*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
D004224:Diterpenes; D017382:Reactive Oxygen Species; C501333:sugiol; D014969:Xanthine Oxidase; D002945:Cisplatin