Meisoindigo is a promising agent with in vitro and in vivo activity against human acute myeloid leukemia.

Meisoindigo, a derivative of Indigo naturalis, has been used in China for chronic myeloid leukemia. In vitro cell line studies have shown that this agent might induce apoptosis and myeloid differentiation of acute myeloid leukemia (AML). In this study, we explored its mechanisms and potential in AML. NB4, HL-60, and U937 cells and primary AML cells were used to examine its effects and the NOD/SCID animal model was used to evaluate its in vivo activity. Meisoindigo inhibited the growth of leukemic cells by inducing marked apoptosis and moderate cell-cycle arrest at the G(0)/G(1) phase. It down-regulated anti-apoptotic Bcl-2, and up-regulated pro-apoptotic Bak and Bax and cell-cycle related proteins, p21and p27. Furthermore, it induced myeloid differentiation, as demonstrated by morphologic changes, up-regulation of CD11b, and increased nitroblue tetrazolium reduction activity in all cell lines tested. In addition, meisoindigo down-regulated the expression of human telomerase reverse transcriptase and enhanced the cytotoxicity of conventional chemotherapeutic agents, cytarabine and idarubicin. As with the results from cell lines, meisoindigo also induced apoptosis, up-regulated p21 and p27, and down-regulated Bcl-2 in primary AML cells. The in vivo anti-leukemic activity of meisoindigo was also demonstrated by decreased spleen size in a dose-dependent manner. Taking these results together, meisoindigo is a potential agent for AML.

A small-molecule c-Myc inhibitor, 10058-F4, induces cell-cycle arrest, apoptosis, and myeloid differentiation of human acute myeloid leukemia.

OBJECTIVE: The protooncogene c-Myc plays an important role in the control of cell proliferation, apoptosis, and differentiation, and its aberrant expression is frequently seen in multiple human cancers, including acute myeloid leukemia (AML). As c-Myc heterodimerizes with Max to transactivate downstream target genes in leukemogenesis. Inhibition of the c-Myc/Max heterodimerization by the recently identified small-molecule compound, 10058-F4, might be a novel antileukemic strategy. MATERIALS AND METHODS: HL-60, U937, and NB4 cells and primary AML cells were used to examine the effects of 10058-F4 on apoptosis and myeloid differentiation. RESULTS: We showed that 10058-F4 arrested AML cells at G0/G1 phase, downregulated c-Myc expression and upregulated CDK inhibitors, p21 and p27. Meanwhile, 10058-F4 induced apoptosis through activation of mitochondrial pathway shown by downregulation of Bcl-2, upregulation of Bax, release of cytoplasmic cytochrome C, and cleavage of caspase 3, 7, and 9. Furthermore, 10058-F4 also induced myeloid differentiation, possibly through activation of multiple transcription factors. Similarly, 10058-F4-induced apoptosis and differentiation could also be observed in primary AML cells. CONCLUSION: Our study has shown that inhibition of c-Myc/Max dimerization with small-molecule inhibitors affects multiple cellular activities in AML cells and represents a potential antileukemic approach.