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S1PR3-G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation
Masayasu Toyomoto1, Asuka Inoue2, Kei Iida3
1Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; Department of Drug Discovery for Lung Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Abstract:
Metabolic activities are altered in cancer cells compared with those in normal cells, and the cancer-specific pathway becomes a potential therapeutic target. Higher cellular glucose consumption, which leads to lower glucose levels, is a hallmark of cancer cells. In an objective screening for chemicals that induce cell death under low-glucose conditions, we discovered a compound, denoted as ALESIA (Anticancer Ligand Enhancing Starvation-induced Apoptosis). By our shedding assay of transforming growth factor α in HEK293A cells, ALESIA was determined to act as a sphingosine-1-phosphate receptor 3-G12-biased agonist that promotes nitric oxide production and oxidative stress. The oxidative stress triggered by ALESIA resulted in the exhaustion of glucose, cellular NADPH deficiency, and then cancer cell death. Intraperitoneal administration of ALESIA improved the survival of mice with peritoneally disseminated rhabdomyosarcoma, indicating its potential as a new type of anticancer drug for glucose starvation therapy.
Insights
Researchers discovered ALESIA, a compound that targets cancer cells by inducing glucose starvation and oxidative stress, leading to cancer cell death. This novel approach shows promise as an anticancer therapy, improving survival in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cancer cells exhibit altered metabolic activities, with high glucose consumption being a key characteristic.
- Targeting cancer-specific metabolic pathways offers a promising therapeutic strategy.
Purpose of the Study:
- To identify novel compounds that induce cancer cell death under low-glucose conditions.
- To investigate the mechanism of action of a newly discovered compound, ALESIA.
Main Methods:
- Objective screening for chemicals inducing cell death in low-glucose conditions.
- HEK293A cell shedding assay to determine ALESIA's mechanism of action.
- In vivo studies using mice with peritoneally disseminated rhabdomyosarcoma.
Main Results:
- ALESIA was identified as a sphingosine-1-phosphate receptor 3-G12-biased agonist.
- ALESIA promotes nitric oxide production and oxidative stress, leading to glucose exhaustion and NADPH deficiency.
- ALESIA administration improved survival in a mouse model of rhabdomyosarcoma.
Conclusions:
- ALESIA induces cancer cell death through glucose starvation and oxidative stress.
- ALESIA demonstrates potential as a novel anticancer therapeutic agent for glucose starvation therapy.
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