Luteolin inhibits the TGF-β signaling pathway to overcome bortezomib resistance in multiple myeloma

Multiple myeloma (MM) is an incurable condition and the second most common hematological malignancy. Over the past few years, there has been progress in the treatment of MM, but most patients still relapse. Multiple myeloma stem-like cells (MMSCs) are believed to be the main reason for drug resistance and eventual relapse. Currently, there are not enough therapeutic agents that have been identified for eradication of MMSCs, and thus, identification of the same may alleviate the issue of relapse in patients. In the present study, we showed that luteolin (LUT), a natural compound obtained from different plants, such as vegetables, medicinal herbs, and fruits, effectively inhibits the proliferation of MM cells and overcomes bortezomib (BTZ) resistance in them in vitro and in vivo, mainly by decreasing the proportion of ALDH1+ cells. Furthermore, RNA sequencing after LUT treatment of MM cell lines and an MM xenograft mouse model revealed that the effects of the compound are mediated through inhibition of transforming growth factor-β signaling. Similarly, we found that LUT also significantly reduced the proportion of ALDH1+ cells in primary CD138+ plasma cells. In addition, LUT could overcome the BTZ treatment-induced increase in the proportion of ALDH1+ cells, and the combination of LUT and BTZ had a synergistic effect against myeloma cells. Collectively, our findings suggested that LUT is a promising agent that manifests MMSCs to overcome BTZ resistance, alone or in combination with BTZ, and thus, is a potential therapeutic drug for the treatment of MM.