Hypoxia-simulating agents and selective stimulation of arsenic trioxide-induced growth arrest and cell differentiation in acute promyelocytic leukemic cells.

Abstract

BACKGROUND AND OBJECTIVES:

We recently reported that hypoxia-mimetic agents cobalt chloride (CoCl2 CoCl2 ) and desferrioxamine (DFO) could induce differentiation of acute myeloid leukemic (AML) cells. Here, we investigate whether these two agents influence the in vitro differentiation-inducing effect of arsenic trioxide (As2O3) on AML cells, an effective drug for the treatment of acute promyelocytic leukemia (APL) that is a unique subtype of AML with a specific fusion protein, PML-RARalpha.

DESIGN AND METHODS:

The APL cell line NB4 and non-APL promonocytic leukemic cell line U937 were treated with As2O3 (0.5 microM) combined with CoCl2 (50 microM) or DFO (10 microM). The U937/PR9 subclone, whose expression of PML-RARalpha protein can be induced by Zn2+, was also investigated. Cellular differentiation was evaluated by morphological criteria and myeloid differentiation-related antigens and marker gene expression. The hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA and protein were detected, respectively, by semi-quantitative/real-time quantitative reverse transcription polymerase chain reaction and immunoblots. PML-RARalpha protein was also analyzed.

RESULTS:

CoCl2 and DFO potentiated the growth-inhibiting and differentiation-inducing effects of low-dose As2O3, the latter enhancing CoCl2 and DFO-induced accumulation of HIF-1alpha protein in NB4 cells but not in U937 cells. These two hypoxia-mimetic agents also accelerated As2O3-induced modulation and degradation of PML-RARalpha protein in NB4 cells. Furthermore, inducible expression of the fusion gene restored the co-operative effects of As2O3 and CoCl2/DFO on U937/PR9 cells in terms of growth arrest, differentiation induction and HIF-1alpha protein accumulation.

INTERPRETATION AND CONCLUSIONS:

Mimicked hypoxia enhanced As2O3-induced differentiation, in which HIF-1alpha and PML/RARalpha proteins played an important role. These data provide new insights into the understanding of the mechanisms of the action of As2O3 in the treatment of patients with APL.

• Authors: Hua Yan, Zhen-Gang Peng, Ying-Li Wu, Yi Jiang, Yun Yu, Ying Huang, Yuan-Shan Zhu, Qian Zhao, Guo-Qiang Chen
• Journal: Haematologica (Haematologica) Vol. 90 Issue 12 Pg. 1607-16 (Dec 2005) ISSN: 1592-8721 [Electronic] Italy
• PMID: 16330433 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Arsenicals
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Neoplasm Proteins
• Oncogene Proteins, Fusion
• Oxides
• promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
• Cobalt
• Tretinoin
• cobaltous chloride
• Deferoxamine
• Arsenic Trioxide
• Oxygen

Topics

• Antineoplastic Agents (pharmacology)
• Arsenic Trioxide
• Arsenicals (pharmacology)
• Bone Marrow (metabolism, pathology)
• Cell Differentiation (drug effects)
• Cell Division (drug effects)
• Cell Hypoxia (drug effects)
• Cell Line, Tumor (cytology, drug effects)
• Cobalt (pharmacology)
• Deferoxamine (pharmacology)
• Drug Synergism
• Gene Expression Regulation, Leukemic (drug effects)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (biosynthesis, genetics)
• Leukemia, Promyelocytic, Acute (drug therapy, genetics, pathology)
• Neoplasm Proteins (biosynthesis, genetics)
• Oncogene Proteins, Fusion (biosynthesis, genetics)
• Oxides (pharmacology)
• Oxygen (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Tretinoin (pharmacology)
• U937 Cells (cytology, drug effects)