Scutellarin circumvents chemoresistance, promotes apoptosis, and represses tumor growth by HDAC/miR-34a-mediated down-modulation of Akt/mTOR and NF-κB-orchestrated signaling pathways in multiple myeloma.

Multiple myeloma (MM) is a neoplastic dyscrasia of monoclonal immunoglobulin-secreting plasma cells culminating in multi-organ dysfunction. In this study, we sought to investigate whether scutellarin (STN), a flavonoid, could reduce MM progression, mitigate chemoresistance of MM cells to bortezomib (BTB), and cause MM cell apoptosis in a xenograft mouse model of MM. Epigenetic signalling plays a main role in the modulation of various pathways involved in multiple myeloma progression. At the outset, mechanistic analyses of the MM pathways indicated that key epigenetic molecules including HDAC1/3 and miR-34a were up-modulated and down-modulated respectively, in the MM mice. Besides, the downstream signalling analysis of miR-34a depicted that the c-Met/AKT/mTOR pathway was activated in the MM mice. We also investigated the expression of NF-κB, one of the major chemoresistance inducers in cancer treatment, in the MM mice. As anticipated, the tumor-bearing mice expressed more NF-κB along with elevated anti-apoptotic Bcl-xL protein, as well as reduced pro-apoptotic Bim protein. On the other hand, STN+BTB co-treatment effectively combated the MM tumor progression, and STN circumvented the MM tumor resistance to BTB and provoked apoptotic cell death in MM. Based on our study data, we deduce that STN, in combination with BTB, appears to be a reliable tumoricidal strategy.