Biomedicine & Pharmacotherapy (Jul 2023)
TLR8 agonist Motolimod-induced inflammatory death for treatment of acute myeloid leukemia
- Wei Yang,
- Xiongfei Sun,
- Shuai Liu,
- Ying Xu,
- Yunlei Li,
- Xiaoru Huang,
- Kaiqing Liu,
- Longyi Mao,
- Shasha Min,
- Linjiang Liu,
- Shi Li,
- Yuqi Zhu,
- Yu Zhang,
- Xina Xie,
- Kui Xu,
- Changqing Sun,
- Jie Yan,
- Zesong Li
Affiliations
- Wei Yang
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine). Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging. School of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen 518060, China; Corresponding authors.
- Xiongfei Sun
- Department of hematopathology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, PR China; Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, PR China
- Shuai Liu
- Department of Laboratory, Shenzhen Samii International Medical Center (Shenzhen Fourth People’s Hospital), Shenzhen 518118, PR China
- Ying Xu
- Department of hematopathology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, PR China
- Yunlei Li
- Department of Clinical Laboratory, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, PR China
- Xiaoru Huang
- Institute of Biomedical Engineering, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, PR China
- Kaiqing Liu
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine). Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging. School of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen 518060, China
- Longyi Mao
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine). Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging. School of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen 518060, China
- Shasha Min
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine). Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging. School of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen 518060, China
- Linjiang Liu
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine). Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging. School of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen 518060, China
- Shi Li
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine). Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging. School of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen 518060, China
- Yuqi Zhu
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine). Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging. School of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen 518060, China
- Yu Zhang
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine). Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging. School of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen 518060, China
- Xina Xie
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine). Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging. School of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen 518060, China
- Kui Xu
- Institute of Biomedical Engineering, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, PR China
- Changqing Sun
- Department of Clinical Laboratory, Shenzhen Baoan Pure Traditional Chinese Medicine Hospital, Shenzhen 518126, PR China
- Jie Yan
- The Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, Guangzhou, PR China
- Zesong Li
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine). Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging. School of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen 518060, China; Corresponding authors.
- Journal volume & issue
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Vol. 163
p. 114759
Abstract
The clinical treatment of AML is dominated by ''7 + 3'' therapy, but it often shows great toxicity and limited therapeutic efficacy in application. Therefore, it is urgent to develop novel therapeutic strategies to achieve safe and efficient treatment of AML. Small-molecule inhibitors have the characteristics of high specificity, low off-target toxicity and remarkable therapeutic effect, and are receiving more and more attention in tumor therapy. In this study, we screened a library of 1972 FDA-approved small molecular compounds for those that induced the inflammatory death of AML cells, among which the TLR8 agonist Motolimod (MTL) showed stronger anti-AML activity in the animal model but slight affection on normal lymphocytes in control mice. In terms of mechanism, cellular experiments in AML cell lines proved that TLR8 and LKB1/AMPK are the key distinct mechanisms for MTL triggered caspase-3-dependent cell death and the expression of a large number of inflammatory factors. In conclusion, our findings identified the immunoactivator MTL as a single agent exerting significant anti-AML activity in vitro and in vivo, with strong potential for clinical translation.
