Reprogrammed metabolisms are critical in the energy supply and material resourcing of cancer cells during their survival, proliferation, and metastasis. Cancer cells tend to have higher glucose uptake to satisfy their abnormal metabolic needs by glycolysis. Hexokinase (HK), as a rate-limiting enzyme, catalyzes the conversion of glucose to glucose-6-phosphate in the glycolysis pathway. Among the subtypes of the HK enzyme family, HK2 is overexpressed in malignant tumors, including glioblastoma, up to sevenfold higher than in normal cells. The previous studies suggest that abnormal HK2 gene expression can be activated by p53 mutation, hypoxia-inducible factor 1α, or other signaling molecules (e.g., insulin). Consequently, it can assist tumor cells to harness the shortcuts of adenosine triphosphate (ATP) generation by aerobic glycolysis (notoriously as the Warburg effect) and change the metabolic profiles required by tumor proliferation and construction of tumor microenvironment. HK2 has been proposed as a pivotal target of the reprogrammed metabolisms for the development of anticancer drugs. Clinical trials have been initiated by using 2-deoxyglucose (2-DG) as a mimic of glucose to compete with the binding site of HK2. Occasional case in hospitals has been reported to treat liver cancers with 3-bromopyruvate (3-BP) as a potent HK2 inhibitor. However, concerns on the side effects of these two drugs have been raised by clinical research, including uncontrolled inactivation, off-target interactions, promoted drug resistance, and other undesired physiochemical parameters (e.g., unable to cross the blood-brain barrier). There is an urgent need to screen new anticancer drug molecules to target HK2 with high inhibition efficiency and low side effect.
Recently, Professor Jian Liu and Professor Zhenhui Kang of our institute, together with Professor Tingjun Hou of Zhejiang University, reported finding a glycolytic inhibitor targeting glioblastoma with graphite dots–assisted laser desorption/ionization mass spectrometry as an integrated drug screening and pharmacokinetic platform (GLMSD). As a brand-new HK2 inhibitor screened out by our platform, Compd 27 has been tested to treat glioblastoma in vitro and in vivo. Their experiments have revealed the mechanisms of Compd 27 in normalizing the reprogrammed glycolysis pathways of glioblastoma cells. This team has demonstrated effective glioblastoma suppression by synergizing the HK2 inhibitor (Compd 27) and temozolomide (TMZ) in a subcutaneous tumor mouse model and an orthotopic mouse brain tumor model. The GLMSD features the following merits: (i) label-free and no limitation of “blind-zones”; (ii) high-sensitivity, high-salinity tolerance leading to simplified sample pretreatment; (iii) high throughput performance and minimal sample volume (≤10μL per test), which may revolutionize the pharmacokinetic research, and significantly reduce the animal sacrifice required by the conventional techniques. The glycolytic inhibitor discovery in this work can inspire personalized medicine targeting reprogrammed metabolisms of malignant tumors. GLMSD enables large, high-quality data for next-generation artificial intelligence–aided drug development.
The first author Dr. Rui Shi is from FUNSOM, Soochow University.
Title:High-throughput screening technology based on MALDI mass spectrometry facilitates glycolytic inhibitor discovery against tumors
Authors:Rui Shi†, Peichen Pan†, Rui Lv†, Chongqing Ma, Enhui Wu, Ruochen Guo, Zhihao Zhao, Hexing Song, Joe Zhou, Yang Liu, Guoqiang Xu, Tingjun Hou*, Zhenhui Kang*, Jian Liu*
Link to Paper:https://www.science.org/doi/10.1126/sciadv.abl4923
Link to Prof. Liu’s group:http://web.suda.edu.cn/jliu/index.html
Link to Prof. Kang’s group:http://nano.suda.edu.cn/kanggroup/
Acknowledgment:
This work is supported by the National Key Research and Development Program of China (2017YFE0131700, 2020YFA0406104, and 2020YFA0406101), the National Natural Science Foundation of China (21874096, 51725204, 21771132, 51972216, and 52041202), National MCF Energy R&D Program of China (2018YFE0306105), Innovative Research Group Project of the National Natural Science Foundation of China (51821002), Natural Science Foundation of Jiangsu Province (BK20190041), Key-Area Research and Development Program of GuangDong Province (2019B010933001), a project supported by Collaborative Innovation Center of Suzhou Nano Science and Technology, the 111 Project, Joint International Research Laboratory of Carbon-Based Functional Materials and Devices, Jiangsu Key Laboratory of Neuropsychiatric Diseases (BM2013003), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the Suzhou Key Laboratory of Nanotechnology and Biomedicine, Suzhou Key Laboratory of Functional Nano & Soft Materials.
Editor: Guo Jia