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

doi:10.1016/j.biopha.2023.114759

TLR8 agonist Motolimod-induced inflammatory death for treatment of acute myeloid leukemia

Biomed Pharmacother. 2023 Jul:163:114759. doi: 10.1016/j.biopha.2023.114759. Epub 2023 Apr 25.

Authors

Wei Yang¹, Xiongfei Sun², Shuai Liu³, Ying Xu⁴, Yunlei Li⁵, Xiaoru Huang⁶, Kaiqing Liu⁷, Longyi Mao⁷, Shasha Min⁷, Linjiang Liu⁷, Shi Li⁷, Yuqi Zhu⁷, Yu Zhang⁷, Xina Xie⁷, Kui Xu⁶, Changqing Sun⁸, Jie Yan⁹, Zesong Li¹⁰

Affiliations

¹ 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. Electronic address: yangw6@mail2.sysu.edu.cn.
² 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.
³ Department of Laboratory, Shenzhen Samii International Medical Center (Shenzhen Fourth People's Hospital), Shenzhen 518118, PR China.
⁴ 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.
⁵ Department of Clinical Laboratory, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, PR China.
⁶ 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.
⁷ 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.
⁸ Department of Clinical Laboratory, Shenzhen Baoan Pure Traditional Chinese Medicine Hospital, Shenzhen 518126, PR China.
⁹ 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.
¹⁰ 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. Electronic address: lzssc@email.szu.edu.cn.

PMID: 37105077
DOI: 10.1016/j.biopha.2023.114759

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.

Keywords: AMPK; Acute myeloid leukemia; LKB1; Motolimod; TLR8.

MeSH terms

Adjuvants, Immunologic / therapeutic use
Animals
Benzazepines / pharmacology
Cell Line, Tumor
Leukemia, Myeloid, Acute* / metabolism
Mice
Toll-Like Receptor 8*

Substances

VTX-2337
Toll-Like Receptor 8
Benzazepines
Adjuvants, Immunologic