Arsenic trioxide cooperates with all trans retinoic acid to enhance mitogen-activated protein kinase activation and differentiation in PML–RARα negative human myeloblastic leukemia cells

Abstract

Arsenic trioxide (ATO) synergistically promotes all trans retinoic acid (ATRA)-induced differentiation of PML–RARα negative HL-60 myeloblastic leukemia cells. In PML–RARα positive myeloid leukemia cells, ATO is known to cause degradation of PML–RARα with subsequent induced myeloid differentiation. We found that ATO by itself does not cause differentiation of the PML–RARα negative HL-60 cells, but enhances ATRA's capability to cause differentiation. ATO augmented ATRA-induced RAF/MEK/ERK axis signaling, expression of CD11b and p47^PHOX, and inducible oxidative metabolism. ATO enhanced ATRA-induced population growth retardation without evidence of apoptosis or enhanced G1/G0 growth arrest. Compared to ATRA-treated cells, the ATRA plus ATO-treated cells progressed more slowly through the cell cycle as detected by a slower rate of accumulation in G2/M following nocodazole treatment. Hoechst/PI staining showed that low-dose ATO did not induce apoptosis. In summary, our results indicate that ATO in conjunction with ATRA is of potential chemotherapeutic use in PML–RARα negative leukemias.

Keywords:

• HL-60
• all trans retinoic acid
• arsenic trioxide
• MAPK
• differentiation

Acknowledgements

The authors would like to thank Dr. Deanna Schaefer for her kind help in Wright's staining of slides. Additionally, we acknowledge the careful review of the manuscript by Ryan Tasseff of Prof. Jeffrey Varner's research group.

Declaration of interest: This work was supported in part by grants from NIH (USPS) (CA 033505), NYSTEM, NY Department of Health, and NSF CAREER #CBET-0846876.