Downregulation of GSTπ expression by tryptanthrin contributing to sensitization of doxorubicin-resistant MCF-7 cells through c-jun NH2-terminal kinase-mediated apoptosis

Overexpression of GSTπ 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 GSTπ expression and reduces glutathione S-transferase (GST) activity, but has no effect on Topo II expression. Less production of GSTπ decomposes the protein―protein interactions of GSTπ and c-jun NH 2 -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 GSTπ-related pathway, a nontransporter pathway, in MCF-7/adr cells. It indicates that tryptanthrin may act as a potential chemoadjuvant agent through multiple targets.