Tooniliatone A sensitizes multidrug resistant cancer cells by decreasing Bcl-xL via activation of JNK MAPK signaling

Abstract

BackgroundMultidrug resistance (MDR) refers to the phenotype of tumor cells that are resistant to various chemotherapeutic drugs with different structures and functions, which is clearly disadvantageous for patients. Finding a natural product that can effectively reverse the MDR of tumor cells is important for the treatment of patients. PurposeTo prove that tooniliatone A (TA), a novel typical limonoid, can effectively reverse the MDR of tumor cells and to explore its mechanism of action. MethodsThe MTT, CCK-8 and monoclonal formation assays, as well as flow cytometry, were used to evaluate the role of TA in reversing tumor multidrug resistance; then the mechanism of action for TA was explored by western blotting and real-time fluorescent quantitative PCR. ResultsTA significantly reversed the MDR of the K562/MDR and MCF-7/MDR cell lines. TA can inhibit the anti-apoptotic protein Bcl-xL to make cells sensitive to common chemotherapeutic drugs and activate the SAPK/JNK pathway to promote phosphorylation of JNK and its downstream cJun protein. Small interfering RNA-mediated knockdown of JNK and cJun could antagonize the MDR reversal effect of TA and the inhibition of Bcl-xL by TA. Therefore, we hypothesized that TA activates the JNK pathway to increase the transcription of the proapoptotic protein Bim, thereby inhibiting Bcl-xL and reversing MDR in tumor cells. ConclusionOur study suggests that TA reverses tumor MDR by activating the SAPK/JNK pathway to inhibit the action of Bcl-xL. TA may be an effective tumor MDR reversal agent.