Arsenic trioxide and all-trans-retinoic acid selectively exert synergistic cytotoxicity against FLT3-ITD AML cells via co-inhibition of FLT3 signaling pathways

Abstract

FLT3-ITD mutations occur in approximately 30% of acute myeloid leukemia (AML) and are associated with a poor outcome. Currently available FLT3 inhibitors have in vitro but limited clinical activity in FLT3-ITD AML. Reports have shown that an arsenic trioxide (ATO)/all-trans-retinoic acid (ATRA) combination improves prognosis in acute promyelocytic leukemia, especially with FLT3-ITD, and ATO or ATRA alone enhances apoptosis in FLT3-ITD AML cells treated with FLT3 inhibitors, providing a rationale to investigate the role of ATO/ATRA in FLT3-ITD AML. Here, we demonstrate that an ATO/ATRA combination selectively exerts synergistic cytotoxicity against FLT3-ITD AML cell lines (MV4;11/MOLM-13). The signaling pathways affected by ATO/ATRA include FLT3/STAT5/MYC, FLT3/STAT5/E2F1, FLT3/ERK/ATF5 and FLT3/AKT/ATF5.ATF5 may function as an oncogene in FLT3-ITD AML. Our findings provide experimental evidence that supports further exploration of ATO/ATRA in FLT3-ITD AML in vivo and warrants a clinical evaluation of regimens comprising an ATO/ATRA combination.

Keywords:

• Acute myeloid leukemia
• FLT3-ITD
• arsenictrioxide
• all-trans-retinoic acid
• ATF5

Acknowledgments

Thank you to the following investigators: Prof. Yue-Qin Chen at the Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, for providing critical help with experiments; Dr. Pan JX at Zhongshan School of Medicine, Sun Yat-sen University, for providing MV4;11 cell line; and Dr. Ma J at the Institute of Hematology and Oncology, the First Hospital of Harbin for providing purified ATO powder.

This study was supported by grants from the Science and Technology Planning Project of Guangdong Province, China [Grant No. 2016A020215045 and 2014A020221008], the Medical Scientific Research Foundation of Guangdong Province, China [Grant No. A2016175], and the Science and Technology Planning Project of Guangzhou, China [Grant No. 201604020128].

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at http://dx.doi.org/10.1080/10428194.2017.1289522.