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

Yang，Wei1; Sun，Xiongfei2,3; Liu，Shuai4; Xu，Ying2; Li，Yunlei5; Huang，Xiaoru6; Liu，Kaiqing1; Mao，Longyi1; Min，Shasha1; Liu，Linjiang1; Li，Shi1; Zhu，Yuqi1; Zhang，Yu1; Xie，Xina1; Xu，Kui6; Sun，Changqing7; Yan，Jie8; Li，Zesong1

2023-07-01

10.1016/j.biopha.2023.114759

Biomedicine and Pharmacotherapy   影响因子和分区

0753-3322

1950-6007

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.

Acute myeloid leukemia AMPK LKB1 Motolimod TLR8

SCI

英语

其他

Natural Science Foundation of Guangdong Province[2022A1515012606];National Natural Science Foundation of China[81972366];National Natural Science Foundation of China[82200192];

Research & Experimental Medicine ; Pharmacology & Pharmacy

Medicine, Research & Experimental ; Pharmacology & Pharmacy

WOS:000988690800001

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER

2-s2.0-85153271479

Scopus

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
2.Department of hematopathology,Shenzhen People's Hospital (The Second Clinical Medical College,Jinan University,Southern University of Science and Technology),Shenzhen,Guangdong,518020,China
3.Shenzhen Clinical Research Centre for Geriatrics,Shenzhen People's Hospital (The Second Clinical Medical College,Jinan University,Southern University of Science and Technology),Shenzhen,Guangdong,518020,China
4.Department of Laboratory,Shenzhen Samii International Medical Center (Shenzhen Fourth People's Hospital),Shenzhen,518118,China
5.Department of Clinical Laboratory,Shenzhen Traditional Chinese Medicine Hospital,The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine,Shenzhen,518033,China
6.Institute of Biomedical Engineering,Shenzhen People's Hospital (The Second Clinical Medical College,Jinan University,Southern University of Science and Technology),Shenzhen,Guangdong,518020,China
7.Department of Clinical Laboratory,Shenzhen Baoan Pure Traditional Chinese Medicine Hospital,Shenzhen,518126,China
8.The Second Affiliated Hospital,The State Key Laboratory of Respiratory Disease,Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology,Guangzhou Medical University,Guangzhou,China

Yang，Wei,Sun，Xiongfei,Liu，Shuai,et al. TLR8 agonist Motolimod-induced inflammatory death for treatment of acute myeloid leukemia[J]. Biomedicine and Pharmacotherapy,2023,163.

Yang，Wei.,Sun，Xiongfei.,Liu，Shuai.,Xu，Ying.,Li，Yunlei.,...&Li，Zesong.(2023).TLR8 agonist Motolimod-induced inflammatory death for treatment of acute myeloid leukemia.Biomedicine and Pharmacotherapy,163.

Yang，Wei,et al."TLR8 agonist Motolimod-induced inflammatory death for treatment of acute myeloid leukemia".Biomedicine and Pharmacotherapy 163(2023).