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

ABSTRACT

BACKGROUND: Multidrug 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. PURPOSE: To prove that tooniliatone A (TA), a novel typical limonoid, can effectively reverse the MDR of tumor cells and to explore its mechanism of action. METHODS: The 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. RESULTS: TA 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. CONCLUSION: Our 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.