Combinatorial Approach to Therapeutic Application of Energy Metabolic Regulators

Combinatorial Approach to Therapeutic Application of Energy Metabolic Regulators | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Combinatorial Approach to Therapeutic Application of Energy Metabolic Regulators Wei-ping Zeng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8409406/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Low intracellular pH (pHi) is a cell intrinsic trigger of apoptosis, and cells highly active in proliferation and energy production are particularly sensitive to the low pHi-induced apoptosis. Therefore, cancer cells and activated inflammatory cells can be selectively depleted over normal tissue structure-functional cells by lowering pHi. In this study, we designed a combinatorial composition comprising low doses of the energy metabolic regulators that inhibit glutaminolysis and aerobic glycolysis and activate the influx of carbons derived from pyruvate and fatty acids to the TCA cycle. We demonstrated that this combinatorial composition effectively lowered pHi while the individual components alone showed little effect. Treatment of B cell lymphoma cells with the combinatorial composition depleted the cancer cells. Using animal models, we also demonstrated excellent therapeutic potentials of the combinatorial composition for the treatment of lupus, multiple sclerosis, inflammatory arthritis and obesity. Moreover, the combinatorial composition is expected to have low toxicity because normal tissue structure-functional cells are relatively tolerant to low pHi and the composition is unlikely to cause severe energy deficit in the cells. Thus, the combinatorial composition could be a promising medication with broad therapeutic index. Cellular Metabolism Cancer Inflammatory Glutaminolysis Aerobic glycolysis Intracellular pH TCA cycle Apoptosis Energy Metabolism Mitochondrial Full Text Additional Declarations The authors declare potential competing interests as follows: The author has ownership of Therazwimm a private company. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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