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

Abstract

Arsenic trioxide (ATO) synergistically promotes all trans retinoic acid (ATRA)-induced differentiation of PML-RARalpha negative HL-60 myeloblastic leukemia cells. In PML-RARalpha positive myeloid leukemia cells, ATO is known to cause degradation of PML-RARalpha with subsequent induced myeloid differentiation. We found that ATO by itself does not cause differentiation of the PML-RARalpha 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-RARalpha negative leukemias.

• Authors: Satyaprakash Nayak, Miaoqing Shen, Rodica P Bunaciu, Stephen E Bloom, Jeffrey D Varner, Andrew Yen
• Journal: Leukemia & lymphoma (Leuk Lymphoma) Vol. 51 Issue 9 Pg. 1734-47 (Sep 2010) ISSN: 1029-2403 [Electronic] United States
• PMID: 20615082 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Arsenicals
• Oncogene Proteins, Fusion
• Oxides
• promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
• Tretinoin
• Mitogen-Activated Protein Kinases
• Arsenic Trioxide

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis (drug effects)
• Arsenic Trioxide
• Arsenicals (administration & dosage)
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Differentiation (drug effects)
• Cell Proliferation (drug effects)
• Drug Synergism
• Flow Cytometry
• Humans
• Leukemia, Promyelocytic, Acute (drug therapy, metabolism, pathology)
• Mitogen-Activated Protein Kinases (metabolism)
• Oncogene Proteins, Fusion (metabolism)
• Oxides (administration & dosage)
• Tretinoin (administration & dosage)
• Tumor Cells, Cultured