Biotransformation of arsenic trioxide by AS3MT favors eradication of acute promyelocytic leukemia: revealing the hidden facts

Abstract

Arsenic trioxide (ATO) is one of the most effective drugs for treatment of acute promyelocytic leukemia (APL). It could specifically target the PML/RARα fusion oncoprotein stability and induces APL cell differentiation as well as apoptosis. Although many studies have been conducted to document the anticancer effects and mechanism of ATO, there is little information about the association between biotransformation of ATO to active arsenic metabolites and APL therapy. Generally, ATO can be rapidly converted into trivalent methylated metabolites by arsenic (+3 oxidation state) methyltransferase (AS3MT) mostly in liver and redistributed to bloodstream of APL patients who receiving ATO treatment, thereby leading to a balance between cytotoxicity and differentiation, which is proposed to be the key event in successful treatment of APL. In this review, we comprehensively discussed possible roles of AS3MT and methylated arsenic metabolites in APL therapy, so as to reveal the association between individual differences of AS3MT expression and activity with the therapeutic efficacy of ATO in APL patients.

Keywords:

• Arsenic (+3 oxidation state) methyltransferase
• acute promyelocytic leukemia
• arsenic trioxide
• PML/RARα
• monomethylarsonous acid
• dimethylarsinous acid
• reactive oxygen species

Acknowledgements

The authors apologize that not all of publications related to the field could be discussed in this review due to space limitations.

Author contributions

M. Y. wrote the draft; N. H. and H. H. Z. edited the manuscript; M. Y. and Y. C. searched and collected related literatures. All authors read and approved the final manuscript.

Disclosure statement

The authors declare there is no competing interest.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [No. 81673521, 81603125, 81600139, 81872942], the National Science and Technology Major Project of the Ministry of Science and Technology of China [No. 2018ZX10302-206] and the Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents.