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

Huang, Ming-Jer; Cheng, Yuan-chih; Liu, Chien-Ru; Lin, Shufan; Liu, H. Eugene

doi:10.1016/j.exphem.2006.06.019

« Previous Next »Experimental Hematology
Volume 34, Issue 11 , Pages 1480-1489, November 2006

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

Ming-Jer Huang
- Department of Medicine, MacKay Memorial Hospital, Taipei, Taiwan
Yuan-chih Cheng
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
Chien-Ru Liu
- Department of Radiation Oncology, Taipei Municipal Hospital, Ren-Ai Branch, Taipei, Taiwan
Shufan Lin
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
H. Eugene Liu
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Internal Medicine, Wanfang Hospital, Taipei Medical University, Taipei, Taiwan
- Offprint requests to: H. Eugene Liu, M.D., Ph.D., Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 2F, 30-1, Jinhua St, Zhongchen District, Taipei, Taiwan, 100

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 that10058-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.