Theranostics 2019; 9(13):3768-3779. doi:10.7150/thno.34327

Research Paper

Melatonin enhances sorafenib-induced cytotoxicity in FLT3-ITD acute myeloid leukemia cells by redox modification

Tian Tian1*, Jiajun Li1*, Yizhuo Li1*, Yun-Xin Lu1*, Yan-Lai Tang3, Hua Wang1, Fufu Zheng3, Dingbo Shi1, Qian Long1, Miao Chen1, Guillermo Garcia-Manero4, Yumin Hu1✉, Lijun Qin2✉, Wuguo Deng1✉

1. Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
2. Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510000, China.
3. The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
4. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
*These authors contributed equally to this article.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Tian T, Li J, Li Y, Lu YX, Tang YL, Wang H, Zheng F, Shi D, Long Q, Chen M, Garcia-Manero G, Hu Y, Qin L, Deng W. Melatonin enhances sorafenib-induced cytotoxicity in FLT3-ITD acute myeloid leukemia cells by redox modification. Theranostics 2019; 9(13):3768-3779. doi:10.7150/thno.34327. Available from http://www.thno.org/v09p3768.htm

File import instruction

Abstract

Acute myeloid leukemia (AML) with an internal tandem duplication in Fms-related tyrosine kinase 3 (FLT3-ITD) is identified as a subgroup with poor outcome and intrinsic resistance to chemotherapy and therefore urgent need for development of novel therapeutic strategies.

Methods: The antitumor effects of melatonin alone or combined with sorafenib were evaluated via flow cytometry and immunoblotting assays in FLT-ITD AML cells. Also, the ex vivo and in vivo models were used to test the synergistic effects of melatonin and sorafenib against leukemia with FLT3/ITD mutation.

Results: Our study shows for the first time that melatonin inhibits proliferation and induces apoptosis in FLT3/ITD-positive leukemia cells. Mechanistically, melatonin preferentially causes overproduction of reactive oxygen species (ROS) and ultimately massive cell death in FLT3-ITD AML cells. Moreover, melatonin significantly enhances the cytotoxicity induced by the FLT3 tyrosine kinase inhibitor sorafenib in AML cells with FLT3/ITD through redox modification. Importantly, combination of melatonin and sorafenib exhibited highly synergistic therapeutic activity in MV4-11 xenografts and a murine model bearing FLT3/ITD leukemia.

Conclusion: This study indicates that melatonin, alone or in combination with sorafenib, has potential to improve the therapeutic outcome of AML patients with FLT3-ITD mutation that merits further investigation.

Keywords: Melatonin, Sorafenib, FLT3-ITD, Leukemia, Redox modification