title: Synergism of ursolic acid derivative US597 with 2-deoxy-D-glucose to preferentially induce tumor cell death by dual-targeting of apoptosis and glycolysis.
abstract: Ursolic acid (UA) is a naturally bioactive product that exhibits potential anticancer effects. The relatively safe and effective molecule intrigued us to explore a way to further improve its anti-cancer activity and tumor-targeting specificity. In the present study, a series of structural modifications of UA was achieved, which resulted in significant increase in growth inhibition on various cancer cell lines with minimal effects on normal cells. The leading molecule US597 (UA-4) caused depolarization of mitochondrial membrane potential, cell arrest in G0/G1 phase and apoptosis/necrosis in a dose-dependent manner. Structural docking suggested that the carbon chains of the modified UA derivatives compete strongly with glucose for binding to glucokinase, the key glycolysis enzyme presumably active in cancer cells. The combination of 2-deoxy-D-glucose (2-DG) and UA-4 induced cell cycle arrest in G2/M phase, promoted caspase-dependent cell death, reduced hexokinase activity, aggravated depletion of intracellular ATP, decreased lactate production and synergistically inhibited cancer cell growth in vitro (HepG2) and in vivo (H22). Collectively, our findings suggest that the structural modification enhances efficacy and selectivity of UA, and the combination of UA-4 with 2-DG produces synergistic inhibition on hepatoma cell proliferation by dual targeting of apoptosis and glycolysis.
authors.affiliation: 1] Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, 523 Industry Road, Science Building, 3FL., Fuzhou, Fujian 350002, China [2].
authors.forename: Jichuang
authors.initials: J
authors.lastname: Wang
authors.affiliation: 1] Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, 523 Industry Road, Science Building, 3FL., Fuzhou, Fujian 350002, China [2].
authors.forename: Zhou
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, 523 Industry Road, Science Building, 3FL., Fuzhou, Fujian 350002, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Xiang
authors.affiliation: Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, 523 Industry Road, Science Building, 3FL., Fuzhou, Fujian 350002, China.
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, 523 Industry Road, Science Building, 3FL., Fuzhou, Fujian 350002, China.
authors.forename: Minrui
authors.initials: M
authors.lastname: Ou
authors.affiliation: Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, 523 Industry Road, Science Building, 3FL., Fuzhou, Fujian 350002, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Yang
authors.affiliation: Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, 523 Industry Road, Science Building, 3FL., Fuzhou, Fujian 350002, China.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Shao
authors.affiliation: Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, 523 Industry Road, Science Building, 3FL., Fuzhou, Fujian 350002, China.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, 523 Industry Road, Science Building, 3FL., Fuzhou, Fujian 350002, China.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Lin
authors.affiliation: School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350108, China.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Chen
authors.affiliation: Virginia Commonwealth University and the Massey Cancer Center, Room 234 Goodwin Research Building, 401 College Street, Richmond VA 23298, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, 523 Industry Road, Science Building, 3FL., Fuzhou, Fujian 350002, China.
authors.forename: Lee
authors.initials: L
authors.lastname: Jia
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005941:Glucokinase / Q000037:antagonists & inhibitors; D006019:Glycolysis / Q000187:drug effects*; D006367:HeLa Cells; D056945:Hep G2 Cells; D006593:Hexokinase / Q000037:antagonists & inhibitors; D006801:Humans; D019344:Lactic Acid / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000188:drug therapy; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D009368:Neoplasm Transplantation; D014315:Triterpenes / Q000737:chemistry* / Q000494:pharmacology*; D000097245:Ursolic Acid
chemical_list: D000255:Adenosine Triphosphate; D000972:Antineoplastic Agents, Phytogenic; D003847:Deoxyglucose; D005941:Glucokinase; D006593:Hexokinase; D019344:Lactic Acid; D014315:Triterpenes; D000097245:Ursolic Acid; C000603751:3-acetoxyurs-12-en-28-oic acid hexamethylenediamine
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