title: Shikonin, a component of chinese herbal medicine, inhibits chemokine receptor function and suppresses human immunodeficiency virus type 1.
abstract: Shikonin is a major component of zicao (purple gromwell, the dried root of Lithospermum erythrorhizon), a Chinese herbal medicine with various biological activities, including inhibition of human immunodeficiency virus (HIV) type 1 (HIV-1). G protein-coupled chemokine receptors are used by HIV-1 as coreceptors to enter the host cells. In this study, we assessed the effects of shikonin on chemokine receptor function and HIV-1 replication. The results showed that, at nanomolar concentrations, shikonin inhibited monocyte chemotaxis and calcium flux in response to a variety of CC chemokines (CCL2 [monocyte chemoattractant protein 1], CCL3 [macrophage inflammatory protein 1alpha], and CCL5 [regulated upon activation, normal T-cell expressed and secreted protein]), the CXC chemokine (CXCL12 [stromal cell-derived factor 1alpha]), and classic chemoattractants (formylmethionyl-leucine-phenylalanine and complement fraction C5a). Shikonin down-regulated surface expression of CCR5, a primary HIV-1 coreceptor, on macrophages to a greater degree than the other receptors (CCR1, CCR2, CXCR4, and the formyl peptide receptor) did. CCR5 mRNA expression was also down-regulated by the compound. Additionally, shikonin inhibited the replication of a multidrug-resistant strain and pediatric clinical isolates of HIV in human peripheral blood mononuclear cells, with 50% inhibitory concentrations (IC(50)s) ranging from 96 to 366 nM. Shikonin also effectively inhibited the replication of the HIV Ba-L isolate in monocytes/macrophages, with an IC(50) of 470 nM. Our results suggest that the anti-HIV and anti-inflammatory activities of shikonin may be related to its interference with chemokine receptor expression and function. Therefore, shikonin, as a naturally occurring, low-molecular-weight pan-chemokine receptor inhibitor, constitutes a basis for the development of novel anti-HIV therapeutic agents.
authors.affiliation: Basic Research Program, SAIC-Frederick, Inc, National Cancer Institute-Frederick, Frederick, Maryland 21702-1201, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Jim A
authors.initials: JA
authors.lastname: Turpin
authors.forename: Robert W
authors.initials: RW
authors.lastname: Buckheit
authors.forename: Clay
authors.initials: C
authors.lastname: Osterling
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Oppenheim
authors.forename: O M Zack
authors.initials: OM
authors.lastname: Howard
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D009285:Naphthoquinones / Q000494:pharmacology*; D012367:RNA, Viral / Q000096:biosynthesis / Q000235:genetics; D019713:Receptors, CCR5 / Q000096:biosynthesis; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D000893:Anti-Inflammatory Agents; D004365:Drugs, Chinese Herbal; D009285:Naphthoquinones; D012367:RNA, Viral; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; C016101:shikonin