title: LRD-22, a novel dual dithiocarbamatic acid ester, inhibits Aurora-A kinase and induces apoptosis and cell cycle arrest in HepG2 cells.
abstract: In this study we investigated the antitumor activity of the novel dual dithiocarbamatic acid ester LRD-22 in vitro and in vivo. Several cancer cell lines were employed to determine the effect of LRD-22 on cell growth, and the MTT assay showed there was a significant decrease in viable tumor cell numbers in the presence of LRD-22, especially in the HepG2 cell line. Colony formation assay also showed LRD-22 strongly inhibits HepG2 cell growth. Evaluation of the mechanism involved showed that inhibitory effects of LRD-22 on cell growth are due to induction of apoptosis and G2/M arrest. LRD-22 inhibited Aurora-A phosphorylation at Thr288 and subsequently impaired p53 phosphorylation at Ser315 which was associated with the proteasome degradation pathway. Tumor suppressor protein p53 is stabilized by this mechanism and accumulates through inhibition of Aurora-A kinase activity via treatment with LRD-22. In vivo study of HepG2 xenograft in nude mice also shows LRD-22 suppresses tumor growth at a concentration of 5 mg/kg without animals suffering loss of body weight. In conclusion, our results demonstrate LRD-22 acts as an Aurora-A kinase inhibitor to induce apoptosis and inhibit proliferation in HepG2 cells, and should be considered as a promising targeting agent for HCC therapy.
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, PR China.
authors: Huiling
authors: H
authors: Wang
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, PR China.
authors: Ridong
authors: R
authors: Li
authors: Department of Cell Biology, School of Basic Medical Sciences, Peking University, Beijing, PR China.
authors: Li
authors: L
authors: Li
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, PR China.
authors: Zemei
authors: Z
authors: Ge
authors: Department of Cell Biology, School of Basic Medical Sciences, Peking University, Beijing, PR China. Electronic address: rlzhou@bjmu.edu.cn.
authors: Rouli
authors: R
authors: Zhou
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, PR China. Electronic address: lirt@bjmu.edu.cn.
authors: Runtao
authors: R
authors: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052117:Benzodioxoles / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013859:Thiocarbamates / Q000737:chemistry / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C000597480:2-(3-((d)(1,3)dioxol-5-yl)acryloyl)propane-1,3-diyl bis(dimethylcarbamodithioate); D000970:Antineoplastic Agents; D052117:Benzodioxoles; D047428:Protein Kinase Inhibitors; C495901:TP53 protein, human; D013859:Thiocarbamates; D016159:Tumor Suppressor Protein p53; D064096:Aurora Kinase A
keywords: Apoptosis; Aurora-A; Cell cycle; Dual dithocarbamatic acid ester; HepG2 cell; p53