Oroxylin A Induce Differentiation and G0/G1 Phase Arrest of Acute Myeloid Leukemia (AML)Cells Via Effects on PPARγ/RXRα Heterodimers,

It has been shown that oroxylin A, a monoflavonoid extracted from the root of the Chinese herb medicine Scutellaria baicalensis, could effectively inhibit the proliferation of several cancer cell lines. However, little is known about the effect of oroxylin A on leukemic cells. In the current study the effects of oroxylin A were analized on growth, differentiation and cell cycle of myeloid leukemic cell lines.

This study used AML cell lines including NB4, U937 and HL60. Expression and distribution of the proteins were analyzed by flow cytometry, western blots and Immunofluoresence assay. The growth inhibition effect of the drug was evaluated by MTT and cell cycle assay. The differentiation of cells was estimated by Giemsa stain and NBT reduction assay.

The growth of U937, HL60 and NB4 cells incubated with oroxylin A was inhibited in a time- and concentration-dependent manner but no apoptosis effect could be observed. Moreover, oroxylin A induced monocytic differentiation and G0/G1 phase arrest in U937 and HL60 cells, meanwhile, the expresstion of PPARγ, a nuclear receptor correlated with monocytic differentiation, was enhanced specificly and a nuclear accumulation of PPARγ was induced. Effects of differentiation and the upregulation of p21 could be attenuated by GW9662, a specific inhibitor of PPARγ. Oroxylin A dramatically displayed synergistic effect with ATRA or VD3 on growth and differentiation of NB4 or U937 cells respectively. We investigated the phosphorylation of RXRα, a nuclear receptor which assists RARα, PPARγ and VDR to exert differentiation effects through heterodimerize with them, was inhibited especially in nuclear of NB4, U937 and HL60 cells treated with oroxylin A. Activition of MAPK/ERK pathway, which is responsible for phosphorylation of RXRα, was also inhibited by oroxylin A.

The results showed here demonstrated that oroxylin A could induce growth inhibition, G0/G1 phase arrest and differentiation of U937 and HL60 and show synergistic effects in combination with ATRA in NB4 and with VD3 in U937 cells via potential inhibition effect on phosphorylation of RXRα.

No relevant conflicts of interest to declare.