Lycorine targets multiple myeloma stem cell‐like cells by inhibition of Wnt/β‐catenin pathway

Abstract

Summary Multiple myeloma (MM) is characterised by the proliferation and accumulation of malignant plasma cells in the bone marrow. Despite the progress in treatment over the last few years, MM remains incurable and the majority of patients relapse. MM stem‐like cells (MMSCs) have been considered as the main reason for drug resistance and eventual relapse. Currently, therapeutic agents are not enough to eradicate MMSCs, and finding effective strategies to eradicate MMSCs may improve the outcome of patients. Here we showed that lycorine, a natural compound from the Amaryllidaceae species, effectively inhibits the proliferation of myeloma cells from cell lines or patients, mainly through decreasing ALDH1+ cells. Mechanistically, lycorine decreases the MMSC population through inhibition of the Wnt/β‐catenin pathway by reducing the β‐catenin protein level. Moreover, lycorine could overcome the increasing proportion of ALDH1+ cells caused by bortezomib (BTZ) treatment, and a combination BTZ and lycorine have a synergistic effect on anti‐myeloma cells. Furthermore, we found a similar reduction of MMSC characteristics by lycorine in BTZ‐resistant MM cells and primary CD138+ plasma cells. Collectively, our findings indicate lycorine as a promising agent to target MMSCs to overcome the drug resistance of BTZ, and that, alone or in combination with BTZ, lycorine is a potential therapeutic strategy for MM treatments.

Multiple Myeloma Inhibitory Activity of Plant Natural Products

“…Therefore, the chemical structure of lycorine was used as natural lead for further drug development. Wang et al investigated the effect of lycorine on myeloma cell lines ARP1, KMS11, ANBL6, and ANBL6 and found that the compound inhibited proliferation by decreasing ALDH1 + cells, which are supposed to be cancer stem cells [ 28 ]. Furthermore, lycorine was found to act via the Wnt/β-catenin pathway by lowering β-catenin protein levels and to exhibit synergistic effects when combined with bortezomib.…”

Identification and Characterization of Multiple Myeloma Stem Cell-Like Cells

“…ALDH1A1 is the dominant isoform in MM; when the expression of ALDH1A1 in ARP1 and OPM1 cells was driven by a lentivirus vector, the cells showed resistance to bortezomib and adriamycin [ 41 ]. In BTZ-resistant (ANBL6-BR) cells, ALDH1 + cells constitute a larger proportion of the population than in wild-type (ANBL6) cells, and ALDH1A1 is highly expressed in BTZ-resistant cells [ 42 ]. ALDH-activity detection has been used to reflect the stemness of MM cells in the study of drug killing-effect detection, surface markers, and characteristic proteins identification in the MM stem cell-like population [ 18 , 43 , 44 , 45 ]…”

“…Additionally, wee1 kinase inhibitor MK1775 can significantly decrease the rate of ALDH1 + cells. Surprisingly, proteasome inhibitor BTZ can enhance the percent of ALDH1 + cells in glioblastoma, synovial sarcoma, pancreatic adenocarcinoma, and MM cells [ 42 , 50 ]. Furthermore, lycorine or wee1 kinase inhibitor MK1775 can decrease the rate of ALDH1 + cells in combination with BTZ [ 35 , 42 ].…”

“…Surprisingly, proteasome inhibitor BTZ can enhance the percent of ALDH1 + cells in glioblastoma, synovial sarcoma, pancreatic adenocarcinoma, and MM cells [ 42 , 50 ]. Furthermore, lycorine or wee1 kinase inhibitor MK1775 can decrease the rate of ALDH1 + cells in combination with BTZ [ 35 , 42 ]. However, the role of immunomodulators, other proteasome inhibitors, and other MM clinical drugs in ALDH has not yet been reported.…”

“…Drugs targeting the Wnt signal pathway have been developed frequently. Interestingly, Wnt3a can enhance the ratio of ALDH1+ cells by enhancing the expression of the β-catenin protein, but lycorine can inhibit ALDH1 + cells through Wnt/β-catenin pathway inhibition [ 42 ]. There are similar inhibitors, such as GSK126 [ 28 ], resveratrol [ 86 ] and BC2059 [ 87 ].…”