title: NSCA-1-a novel N-substituted coumalamide derivative-increases Adriamycin sensitivity in HepG2/adriamycin cells through modulating Akt/GSK-3β signaling and p53-dependant apoptotic pathway.
abstract: Coumalamide derivatives are one of 2-pyrones derivatives, exerting multifunctional bioactivity. An array of coumalamide derivatives have been developed and presented good antiproliferative properties on cancer cells. However, the synthesis of 5-substituted coumalamide derivatives has not yet been published. Resistance to chemotherapeutic drugs is a major obstacle in hepatocellular carcinoma therapy. Recent evidence suggests that overexpression of constitutively active Akt confers on cancer cells resistance to chemotherapy. In this study, we report the synthesis and biological evaluation of a novel N-substituted coumalamide derivative (NSCA-1). The results indicated that NSCA-1 exerts synergistic cytotoxicity with Adriamycin in HepG2/ADR (HepG2/adriamycin) cells. Furthermore, both of the Akt kinase activity and phosphorylated Akt (Ser473) were found to be inhibited by NSCA-1 and subsequently resulting in decreased phosphorylation of GSK-3β. The intracellular accumulation of Adriamycin was also boosted by NSCA-1 via reducing the expression of p-gp. In addition, we found that combined treatment with NSCA-1 enhance cell apoptosis induced by Adriamycin via p53-dependant apoptotic pathway.
authors.affiliation: School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China; Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang 110840, China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, School of Pharmaceutical Engineering, Shenyang 110016, China.
authors.forename: Jianyu
authors.initials: J
authors.lastname: Liu
authors.affiliation: School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China; Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang 110840, China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, School of Pharmaceutical Engineering, Shenyang 110016, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, School of Pharmaceutical Engineering, Shenyang 110016, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang 110840, China. Electronic address: zhaoqingchun1967@163.com.
authors.forename: Qingchun
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China; Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, School of Pharmaceutical Engineering, Shenyang 110016, China. Electronic address: ynxu@syphu.edu.cn.
authors.forename: Yongnan
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000577:Amides; D000813:Anilides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000577:Amides; D000813:Anilides; D000970:Antineoplastic Agents; C494826:BAX protein, human; C000614271:N-(3-((3 4-dimethoxybenzyl)oxy)phenyl)-2-oxo-2H-pyran-5-carboxamide; D019253:Proto-Oncogene Proteins c-bcl-2; D011753:Pyrones; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D004317:Doxorubicin; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D053453:Caspase 9
keywords: Adriamycin resistance; Akt; Apoptosis; HepG2/ADR cells; N-Substituted coumalamide derivative; p53