title: UP12, a novel ursolic acid derivative with potential for targeting multiple signaling pathways in hepatocellular carcinoma.
abstract: Targeting cancer cell glucose metabolism is a promising strategy for cancer therapy. In past approaches to cancer drug discovery, ursolic acid (UA) has been chemically modified to improve its antitumor activities and bioavailability. Here, a novel ursolic acid (UA) derivative UP12 was developed via computer-aided drug design to explore potent anti-cancer agents and to examine possible mechanisms. The structural docking analyses suggested that UP12 could bind to the active sites of glucokinase (GK), glucose transporter 1 (GLUT1) and ATPase, which are the main enzymes involved in cancer glucose metabolism. We further investigated the synergistic effect between UP12 and glycolysis inhibitor 2-deoxy-d-glucose (2-DG) in inhibiting glucose metabolism of cancer cells. The pharmacological results showed that the combination enhanced depletion of intracellular ATP and decrease in lactate production, and pushed more cancer cells arrested in the S and G2/M cycle phases. The combination selectively down-regulated the expression of Bcl-2 and HKII proteins, up-regulated the expression of Bax and p53, and collectively resulted in enhanced apoptosis related to caspase-3, -8, and -9 activities, in addition to inhibition on the cell mitochondrial membrane potential. The animal studies further demonstrated that the combination exhibited significant antitumor activity without obvious toxicity. In summary, UP12 can interfere cancer cell metabolism pathway and further enhance the therapeutic effects of 2-DG likely through synergistic suppression of cancer cell glucose metabolism, making UP12 a likely new candidate for anti-cancer drug development.
authors.affiliation: Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, Fuzhou 350002, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Dong
authors.affiliation: Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, Fuzhou 350002, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Yang
authors.affiliation: Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, Fuzhou 350002, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Xie
authors.affiliation: Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, Fuzhou 350002, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Xiang
authors.affiliation: Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, Fuzhou 350002, China.
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, Fuzhou 350002, China.
authors.forename: Minrui
authors.initials: M
authors.lastname: Ou
authors.affiliation: Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, Fuzhou 350002, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Chi
authors.affiliation: Department of Medical Oncology, Fujian Provincial Hospital, Fuzhou 350001, China.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, Fuzhou 350002, China.
authors.forename: Suhong
authors.initials: S
authors.lastname: Yu
authors.affiliation: Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, Fuzhou 350002, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Gao
authors.affiliation: School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350001, China.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Chen
authors.affiliation: Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, Fuzhou 350002, China; Biopharmaceutical Photocatalysis, State Key Laboratory of Photocatalysis on Energy and Environment, Fuzhou University, Fuzhou 350002, China. Electronic address: shaojingwei@fzu.edu.cn.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Shao
authors.affiliation: Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, Fuzhou 350002, China; Biopharmaceutical Photocatalysis, State Key Laboratory of Photocatalysis on Energy and Environment, Fuzhou University, Fuzhou 350002, China. Electronic address: pharmlink@gmail.com.
authors.forename: Lee
authors.initials: L
authors.lastname: Jia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D017433:Protein Structure, Secondary; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014315:Triterpenes / Q000008:administration & dosage* / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000097245:Ursolic Acid
chemical_list: D000970:Antineoplastic Agents; D014315:Triterpenes; D000097245:Ursolic Acid
keywords: 2-Deoxy-d-glucose (2-DG); 2-Deoxy-d-glucose (Pubchem CID: 439268); 2-Methylpiperazine (Pubchem CID: 66057); 3-BrPA (Pubchem CID: 70684); Anti-cancer drug; Dichloromethane (Pubchem CID: 6433); Glucose metabolism; Piperazine (Pubchem CID: 4837); Pyridine (Pubchem CID: 1049); Synergistic effect; Tert-butyl dimethyl chlorosilane (Pubchem CID: 28928); Tetrahydrofuran (Pubchem CID: 8028); Ursolic acid (Pubchem CID: 64945); Ursolic acid derivative