title: BND-12, a novel nonhaematotoxic naphthalimide derivative, inhibits tumour growth and metastasis of hepatocellular carcinoma.
abstract: OBJECTIVE
  Naphthalimides have shown potent antitumour activity against a variety of murine and human cancer cells. However, most of them have been abandoned because of a poor therapeutic index and haematotoxicity, such as amonafide. To overcome these disadvantages, many novel naphthalimide derivatives have been designed and synthesized as antitumour agents.
  
  
  METHODS
  The cytotoxicity of 6,6-(propane-1,3-diylbis(azanediyl)bis(2-(2-(dimethylamino)ethyl)-1H-benzo[de]isoquinoline-1-3(2H)-dione) (BND-12) was evaluated using multiparameter cytotoxicity 2 kit by High Content Screening (HCS). The antiproliferative ability of BND-12 was evaluated using MTT assay. BND-12-mediated cell apoptosis was evaluated using HCS. Antitumor effects and systemic toxicity of BND-12 were evaluated in vivo using Kunming male mice.
  
  
  RESULTS
  After screening, we found BND-12, a novel naphthalimide derivative, exerted favourable antitumour activity in vitro and in vivo. Our data demonstrated that the cytotoxicity of BND-12 was due to cell apoptosis via the mitochondrial pathway. Interestingly, we demonstrated that BND-12 exerted more potent antitumour activity in subcutaneous xenograft tumour growth, survival time and lung metastasis than amonafide in vivo. Encouragingly, preliminary toxicological evaluation demonstrated that BND-12 had no obvious systemic toxicity at the therapeutic dose, especially haematotoxicity.
  
  
  CONCLUSIONS
  BND-12 exerted potent effects against HCC in vivo and in vitro, importantly, it had no obvious systemic toxicity at the therapeutic dose.
authors.affiliation: Institute of Chemical Biology The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng, China.
authors.forename: Song-Qiang
authors.initials: SQ
authors.lastname: Xie
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Ya-Hong
authors.initials: YH
authors.lastname: Zhang
authors.forename: Zhan
authors.initials: Z
authors.lastname: Li
authors.forename: Jin
authors.initials: J
authors.lastname: Zhao
authors.forename: Chao-Jie
authors.initials: CJ
authors.lastname: Wang
mesh_terms: D000225:Adenine; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D053644:Naphthalimides / Q000494:pharmacology* / Q000633:toxicity; D009362:Neoplasm Metastasis; D063065:Organophosphonates; D015996:Survival Rate; D018675:Toxicity Tests; D023041:Xenograft Model Antitumor Assays
chemical_list: C577803:6,6-(propane-1,3-diylbis(azanediyl)bis(2-(2-(dimethylamino)ethyl))-1H-benzo(de)isoquinoline-1-3(2H)-dione); D000970:Antineoplastic Agents; D053644:Naphthalimides; D063065:Organophosphonates; C037020:amonafide; D000225:Adenine