title: Shikonin exerts antitumor activity via proteasome inhibition and cell death induction in vitro and in vivo.
abstract: Dysregulation of the ubiquitin-proteasome pathway plays an essential role in tumor growth and development. Shikonin, a natural naphthoquinone isolated from the traditional Chinese medicine Zi Cao (gromwell), has been reported to possess tumor cell-killing activity, and results from a clinical study using a shikonin-containing mixture demonstrated its safety and efficacy for the treatment of late-stage lung cancer. In this study, we reported that shikonin is an inhibitor of tumor proteasome activity in vitro and in vivo. Our computational modeling predicts that the carbonyl carbons C(1) and C(4) of shikonin potentially interact with the catalytic site of beta 5 chymotryptic subunit of the proteasome. Indeed, shikonin potently inhibits the chymotrypsin-like activity of purified 20S proteasome (IC(50) 12.5 micromol/L) and tumor cellular 26S proteasome (IC(50) between 2-16 micromol/L). Inhibition of the proteasome by shikonin in murine hepatoma H22, leukemia P388 and human prostate cancer PC-3 cultures resulted in accumulation of ubiquitinated proteins and several proteasome target proapoptotic proteins (I kappaB-alpha, Bax and p27), followed by induction of cell death. Shikonin treatment resulted in tumor growth inhibition in both H22 allografts and PC-3 xenografts, associated with suppression of the proteasomal activity and induction of cell death in vivo. Finally, shikonin treatment significantly prolonged the survival period of mice bearing P388 leukemia. Our results indicate that the tumor proteasome is one of the cellular targets of shikonin and inhibition of the proteasome activity by shikonin contributes to its antitumor property.
authors.affiliation: Department of Pathophysiology, Guangzhou Medical College, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Huanjie
authors.initials: H
authors.lastname: Yang
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Hongbiao
authors.initials: H
authors.lastname: Huang
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.forename: Ningfang
authors.initials: N
authors.lastname: Ma
authors.forename: Qiuzhi Cindy
authors.initials: QC
authors.lastname: Cui
authors.forename: Shouxing
authors.initials: S
authors.lastname: Shen
authors.forename: Weihua
authors.initials: W
authors.lastname: Dong
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.forename: Wen
authors.initials: W
authors.lastname: Lian
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
authors.forename: Jinbao
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D009374:Neoplasms, Experimental / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D015996:Survival Rate
chemical_list: D000970:Antineoplastic Agents; D009285:Naphthoquinones; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; C016101:shikonin