Melatonin Enhances Sorafenib-Induced Cytotoxicity in FLT3-ITD Acute Myeloid Leukemia Cells by Redox Modification

Authors

Tian Tian
Jiajun Li
Yizhuo Li
Yun-Xin Lu
Yan-Lai Tang
Hua Wang
Fufu Zheng
Dingbo Shi
Qian Long
Miao Chen
Guillermo Garcia-Manero
Yumin Hu
Lijun Qin
Wuguo Deng

Publication Date

1-1-2019

Journal

Theranostics

DOI

10.7150/thno.34327

PMID

31281512

PMCID

PMC6587355

PubMedCentral® Posted Date

5-31-2019

PubMedCentral® Full Text Version

Post-print

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

Animals, Apoptosis, Cell Line, Tumor, Cell Proliferation, Female, Gene Duplication, Humans, Leukemia, Myeloid, Acute, Melatonin, Mice, Inbred BALB C, Models, Biological, Oxidation-Reduction, Reactive Oxygen Species, Sorafenib, Xenograft Model Antitumor Assays, fms-Like Tyrosine Kinase 3

Comments

This article has been corrected. See Theranostics. 2025 Jun 15;15(14):7176.

Published Open-Access

yes

Recommended Citation

Tian, Tian; Li, Jiajun; Li, Yizhuo; et al., "Melatonin Enhances Sorafenib-Induced Cytotoxicity in FLT3-ITD Acute Myeloid Leukemia Cells by Redox Modification" (2019). Faculty, Staff and Student Publications. 4420.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4420