Synergism of ursolic acid derivative US597 with 2-deoxy-D-glucose to preferentially induce tumor cell death by dual-targeting of apoptosis and glycolysis

• Published in: Scientific reports 2014-05, Vol.4 (1), p.5006, Article 5006
• Main Authors: Wang, Jichuang, Jiang, Zhou, Xiang, Liping, Li, Yuanfang, Ou, Minrui, Yang, Xiang, Shao, Jingwei, Lu, Yusheng, Lin, Lifeng, Chen, Jianzhong, Dai, Yun, Jia, Lee
• Format: Article
• Language: English
• Subjects: 13/2; 13/31; 14/34; 14/63; 140/131; 140/58; 631/154; 631/67/1059; 631/80/82; 631/92/95; 64/60; Adenosine Triphosphate - biosynthesis; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Apoptosis - drug effects; Cancer; Carcinoma, Hepatocellular - drug therapy; Caspase; Cell cycle; Cell death; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Deoxyglucose - pharmacology; Depolarization; Drug Synergism; Female; G1 phase; G1 Phase Cell Cycle Checkpoints - drug effects; Glucokinase; Glucokinase - antagonists & inhibitors; Glucose; Glycolysis; Glycolysis - drug effects; HeLa Cells; Hep G2 Cells; Hepatoma; Hexokinase; Hexokinase - antagonists & inhibitors; Humanities and Social Sciences; Humans; Lactic acid; Lactic Acid - biosynthesis; Liver Neoplasms - drug therapy; Membrane potential; Membrane Potential, Mitochondrial - drug effects; Mice; Mitochondria; multidisciplinary; Neoplasm Transplantation; Science; Synergism; Triterpenes - chemistry; Triterpenes - pharmacology; Tumor cell lines; Ursolic Acid
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep05006

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.