Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells

Guo Qiang Chen, Xue Geng Shi, Wei Tang, Shu Min Xiong, Jun Zhu, Xun Cai, Ze Guang Man, Jian Hua Ni, Gui Ying Shi, Pei Ming Jia, Meng Min Liu, Kai Li He, Chao Niu, Jun Ma, Peng Zhang, Ting Dong Zhang, Pascale Paul, Tomoki Naoe, Kunio Kitamura, Wilson MillerSamuel Waxman, Zhen Yi Wang, Hugues De The, Sai Juan Chen, Zhu Chen

Research output: Contribution to journalArticlepeer-review

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Abstract

Recent clinical studies in China showed that As2O3 is an effective and relatively safe drug in the treatment of acute promyelocytic leukemia (APL). We found previously that As2O3 can trigger apoptosis of AFL cell line NB4 cells, which is associated with downregulation of bcl-2 gene expression and modulation of PML-RARα chimeric protein. To further understand the mechanisms of this alternative therapy for APL, we investigated in this report the effects of a wide range of concentrations of As2O3 on cultured primary APL cells, all-trans retinoic acid (ATRA)-susceptible (NB4 cells) and ATRA-resistant (MR2 subclone) APL cell lines. The results indicated that As2O3 had dose-dependent dual effects on APL cells: inducing preferentially apoptosis at relatively high concentrations (0.5 to 2 μmol/L) and inducing partial differentiation at low concentrations (0.1 to 0.5μmol/L). The rapid modulation and degradation of PML-RARα proteins, which was induced by As2O3 at 0.1 to 2μmol/L, could contribute to these two effects. Bone marrow and peripheral blood examination showed that myelocyte-like cells, probably as a result of partial in vivo differentiation, and degenerative cells increased after 2 to 3 weeks of continuous in vivo As2O3 treatment when leukemic promyelocytes decreased. In conclusion, combination of induction of apoptosis and partial differention could be the main cellular mechanisms of AS2O3 in the treatment of APL, and PML-RARα could play an important role in determining the specific effects of As2O3 on APL cells.

Original languageEnglish
Pages (from-to)3345-3353
Number of pages9
JournalBlood
Volume89
Issue number9
StatePublished - 1 May 1997
Externally publishedYes

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