Vielanin K enhances doxorubicin-induced apoptosis via activation of IRE1α-TRAF2-JNK pathway and increases mitochondrial Ca2+influx in MCF-7 and MCF-7/MDR cells

Background: Therapeutic failure and drug resistance are common and have important implications in the poor prognosis of advanced breast cancer. It is necessary to acquire a natural product to overcome the resistance of cancer and increase the sensitivity of drug-resistant cells to anticancer agents. Purpose: To demonstrate whether the compound Vielanin K (VK) has the potential to increase the sensitivity of MCF-7 and MCF-7/MDR cells to anticancer agents. Methods: Cell viability and proliferative capacity were determined by MIT, colony formation and EdU assays. Apoptosis and Ca2+ accumulation were evaluated by flow cytometry. Then, proteins were detected by immunoblotting, and gene expression levels were explored by qRT-PCR. Results: In MCF-7 and corresponding MDR cells, VK increased the fluorescence intensity of Rho123, but not CFDA. VK treatment did not affect the protein expression of P-gp, MRP1 or BCRP. VK treatment enhanced the DOX-induced apoptotic cascade, while VK combined with DOX increased JNK phosphorylation by activating the IRE1 alpha-TRAF2 signaling pathway. In addition, Ca2+ was released from the endoplasmic reticulum following combination treatment, thereby giving rise to mitochondrial apoptosis. Silencing IRE1 alpha and JNK with small interfering RNA (siRNA) efficiently attenuated combination treatment-induced apoptosis. These effects caused mitochondrial depolarization and reduced viability in MCF-7 and corresponding MCF-7/MDR cells. Conclusion: VK combined with DOX increases the apoptosis of MCF-7 and corresponding MCF-7/MDR cells by activating ER stress and mitochondrial apoptosis via IRE1 alpha-TRAF2-JNK signaling.