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Arsenic trioxide, a therapeutic agent for APL

Abstract

Acute promyelocytic leukemia (APL) is an interesting model in cancer research, because it can respond to the differentiation/apoptosis induction therapy using all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3). Over the past 5 years, it has been well demonstrated that As2O3 induces a high complete remission (CR) rate in both primary and relapsed APL patients (around 8590%). The side effects are mild to moderate in relapsed patients, while severe hepatic lesions have been found in some primary cases. After CR obtained in relapsed patients, chemotherapy in combination with As2O3 as post-remission therapy has given better survival than those treated with As2O3 alone. The effect of As2O3 has been shown to be related to the expression of APL-specific PML–RARα oncoprotein, and there is a synergistic effect between As2O3 and ATRA in an APL mouse model. Cell biology studies have revealed that As2O3 exerts dose-dependent dual effects on APL cells. Apoptosis is evident when cells are treated with 0.52.0 μM of As2O3 while partial differentiation is observed using low concentrations (0.10.5 μM) of the drug. The apoptosis-inducing effect is associated with the collapse of mitochondrial transmembrane potentials in a thiol-dependent manner, whereas the mechanisms underlying APL cell differentiation induced by low dose arsenic remain to be explored. Interestingly, As2O3 over a wide range of concentration (0.12.0 μM) induces degradation of a key leukemogenic protein, PML–RARα, as well as the wild-type PML, thus setting up a good example of targeting therapy for human cancers.

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Acknowledgements

This work is supported in part by the Chinese National Key Project for Basic Research (973), Chinese National High Tech Program (863), National Natural Science Foundation of China, Samuel Waxman Cancer Research Foundation and Clyde Wu Foundation of Shanghai Institute of Hematology.

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Correspondence to Zhu Chen.

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Zhang, TD., Chen, GQ., Wang, ZG. et al. Arsenic trioxide, a therapeutic agent for APL. Oncogene 20, 7146–7153 (2001). https://doi.org/10.1038/sj.onc.1204762

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  • DOI: https://doi.org/10.1038/sj.onc.1204762

Keywords

  • arsenic trioxide (AS2O3)
  • acute promyelocytic leukemia (APL)
  • apoptosis
  • differentiation
  • PML-RARα

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