title: Downregulation of GSTpi expression by tryptanthrin contributing to sensitization of doxorubicin-resistant MCF-7 cells through c-jun NH2-terminal kinase-mediated apoptosis.
abstract: Overexpression of GSTpi and underexpression of Topo II expression are associated with multidrug resistance (MDR) phenotype through nontransporter pathway. Tryptanthrin, a quinazoline derivative, was reported to sensitize resistant cells to doxorubicin by downregulation of MDR1 expression. This study aims to extendedly investigate the effect of tryptanthrin on the role of nontransporter-based genes in determining the MDR response in doxorubicin-resistant MCF-7 cells (MCF-7/adr). Results show that tryptanthrin downregulates GSTpi expression and reduces glutathione S-transferase (GST) activity, but has no effect on Topo II expression. Less production of GSTpi decomposes the protein-protein interactions of GSTpi and c-jun NH2-terminal kinase (JNK). The resulting free-form JNK undergoes phosphorylation upon elevated intracellular doxorubicin accumulation and subsequently activates JNK-mediated apoptosis. In conclusion, in addition to transporter pathway, tryptanthrin reverses MDR partly by modulating GSTpi-related pathway, a nontransporter pathway, in MCF-7/adr cells. It indicates that tryptanthrin may act as a potential chemoadjuvant agent through multiple targets.
authors.affiliation: Graduate Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Sung-Tsai
authors.initials: ST
authors.lastname: Yu
authors.forename: Tzer-Ming
authors.initials: TM
authors.lastname: Chen
authors.forename: Ji-Wang
authors.initials: JW
authors.lastname: Chern
authors.forename: Shih-Yun
authors.initials: SY
authors.lastname: Tseng
authors.forename: Yen-Hui
authors.initials: YH
authors.lastname: Chen