Tetra-O-Methyl Nordihydroguaiaretic Acid Inhibits Growth and Induces Death of Leukemia Cells Independent of Cdc2 and Survivin.

Abstract

Tetra-O-methyl nordihydroguaiaretic acid (M4N) was shown to induce G2 arrest in mammalian cells and suppress the growth of human xenograft tumors by inhibiting Cdc2 and survivin expression. We have previously shown that inhibition of survivin expression by antisense oligonucleotide induced G2 block and subsequent cell death in HL-60 cells. In this study, we examined the effect of M4N on leukemic cells and found that M4N inhibited growth and induced apoptosis in various leukemic cell lines and blasts from AML patients at concentrations from 5μM to 40μM. However, Cdc2 and survivin levels were not significantly affected. In agreement with these results, no G2 arrest was observed. Cell death and cell growth inhibition induced by M4N in leukemia cells were dependent neither on XIAP, Bcl-2, or Bcl-XL levels nor on caspase-8. Although M4N induced the loss of mitochondrial membrane potential in HL-60 cells, overexpression of Bcl-2 or Bcl-XL did not attenuate cell growth inhibition and cell death induced by M4N. M4N did not promote cell differentiation in HL-60 cells. Interestingly, significant inhibition of AKT and to a lesser degree of ERK phosphorylation was observed at 24 hours in OCI-AML3 cells treated with M4N. Collectively, our data showed that M4N inhibited cell growth and induced cell death in both leukemic cell lines and AML patient sample through a mechanism not mediated by Cdc2 and survivin inhibition and independent of death receptor and mitochondrial apoptotic pathways.