Involvement of C/EBPβ in monocytic differentiation of acute myeloid leukemia cells induced by LW-218, a new synthesized flavonoid

Abstract

Our previous study investigated the effects of differentiation inducted by flavonoids derived from a Chinese herb. In this study, we found that LW-218, a new synthesized flavonoid, inhibited proliferation and induced differentiation of acute myeloid leukemia cells. The IC50s of LW-218 in HL-60, U937, K562, and NB4 cell lines were all less than 5 μM, suggesting greater capacity than compounds we have reported. LW-218 induced differentiation effects including morphologic changes, NBT reduction, and both of CD11b and CD14 expression. Results of western blots and siRNA transfection revealed that LW-218 increased the LAP/LIP ratio of C/EBPβ which regulated monocytic differentiation of leukemia cells. Meanwhile, these differentiation effects could be attenuated by silencing PLSCR1 via siRNA transfection. In addition, regulation on LAP/LIP ratio, of C/EBPβ was properly mediated by PLSCR1 which was up-regulated by LW-218. All these results suggested that C/EBPβ was involved in regulation of PKCδ/PLSCR1 pathway during flavonoids-induced differentiation. LW-218 was a prospective differentiation inductor of AML cells and was requisite to proceed further investigation.

C/EBPβIsoforms Expression in the Rat Brain during the Estrous Cycle

“…In different cell models, the isoforms ratio is important to determine cell fate and variations in the LAP/LIP ratio can significantly activate or inhibit expression of target genes [ 51 , 52 ]. The LAP/LIP ratio is therefore an important indicator of C/EBP β transcriptional activity [ 53 ].…”

Established Human Cell Lines as Models to Study Anti-leukemic Effects of Flavonoids

“…Accordingly, many clinically used anticancer drugs are either natural products or obtained by derivatization of naturally occurring lead compounds [ 62 , 96 - 98 ]. Indeed, as a matter of fact, up to 70% of chemotherapeutic drugs approved by the US Federal Drug Administration are derived from natural sources [ 15 , 12 , 24 , 27 , 28 , 89 , 99 - 102 ]. Examples of such agents include Vinca alkaloids vincristine and vinblastine, taxanes (Paclitaxel and Docetaxel), podophyllotoxin derivatives (etoposide and teniposide), and camptothecins like topotecan [ 11 , 24 , 28 , 37 , 95 , 103 - 106 ].…”

“…As tumor cells are typically characterized by different mutations in cell cycle regulating genes, the same flavonoid can cause cell cycle arrest in different phases depending on the certain cellular model [ 118 , 159 , 176 ]. Plant flavonoids can also induce or enhance the differentiation of cancer cells [ 12 , 18 , 77 , 94 , 96 , 109 , 138 , 180 ], inhibit angiogenesis [ 8 , 96 , 98 , 109 , 143 ], or block the processes related to invasion and metastasis, as depicted in (Fig. 2 ), and reviewed elsewhere [ 8 , 96 ].…”

“…Using the agents that force immature leukemia cells to undergo terminal differentiation or so-called differentiation therapy, is potentially a less toxic alternative to treat hematopoietic neoplasms [ 13 , 17 - 19 , 40 , 53 , 54 , 68 - 70 ]. Indeed, granulocytic differentiation induced by ATRA is proven to be clinically effective for treatment of acute promyelocytic leukemia (APL) leading to a breakthrough in cure of this AML subtype [ 12 , 16 , 20 , 38 , 71 - 75 ]. However, application of differentiation therapy can be effective only in certain forms of leukemia and the treatment might be accompanied by severe side effects as well as development of resistance [ 20 , 73 - 77 ].…”