title: Tanshinone-1 induces tumor cell killing, enhanced by inhibition of secondary activation of signaling networks.
abstract: Tumor multidrug resistance (MDR) can result from overexpression of drug transporters and deregulation of cellular signaling transduction. New agents and strategies are required for overcoming MDR. Here, we report that tanshinone-1, a bioactive ingredient in traditional Chinese medicine, directly killed MDR tumor cells and their corresponding parental cells, which was potentiated by inhibition of secondary activation of signaling networks. Tanshinone-1 was slightly more potent at inducing cytotoxicity and apoptosis in MDR cells than in corresponding parental cells. Tanshinone-1-induced MDR cell killing was independent of the function and expression of drug transporters but was partially correlated with the phosphatase-dependent reduction of phospho-705-Stat3, which secondarily activated p38-, AKT-, and ERK-involved signaling networks. Cotreatments with p38, AKT, and ERK inhibitors potentiated the anti-MDR effects of tanshinone-1. Our study presents a model for MDR cell killing using a compound of natural origin. This model could lead to new therapeutic strategies for targeting signaling network(s) in MDR cancers as well as new strategies for multitarget design.
authors.affiliation: Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.forename: J-M
authors.initials: JM
authors.lastname: Feng
authors.forename: J-X
authors.initials: JX
authors.lastname: Li
authors.forename: J-M
authors.initials: JM
authors.lastname: Zhu
authors.forename: S-S
authors.initials: SS
authors.lastname: Song
authors.forename: L-J
authors.initials: LJ
authors.lastname: Tong
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: X-Y
authors.initials: XY
authors.lastname: Yang
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Shen
authors.forename: F-L
authors.initials: FL
authors.lastname: Lian
authors.forename: Y-P
authors.initials: YP
authors.lastname: Li
authors.forename: D-H
authors.initials: DH
authors.lastname: Lin
authors.forename: J
authors.initials: J
authors.lastname: Ding
authors.forename: Z-H
authors.initials: ZH
authors.lastname: Miao
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D045784:Abietanes; D050796:STAT3 Transcription Factor; C021751:tanshinone; D051057:Proto-Oncogene Proteins c-akt