title: Antitumor effects and preliminary systemic toxicity of ANISpm in vivo and in vitro.
abstract: Polyamines as a vector to ferry toxic agents have attracted attention, and naphthalimide-polyamine conjugates show potent activity and tumor cell selectivity. The present study was carried out to evaluate the antitumor effects and preliminary systemic toxicity of ANISpm, a novel 3-amino-naphthalimide-spermine conjugate. The polyamine transport system recognition of ANISpm, supported by α-difluoromethylornithine (DFMO)/spermidine (Spd) experiments, is in accordance with its potent cell selectivity between human hepatoma HepG2 cells and normal QSG7701 hepatocyte. The antiproliferative effect is because of ANISpm-induced cell apoptosis, a common characteristic of both naphthalimide and polyamine analogs. Various apoptotic assessment assays have shown that ANISpm can induce apoptosis through the PI3K/Akt signal pathway. The apoptotic signaling cascade involves Akt inactivation, which results in a series of cellular events. The downstream pathway includes Bad dephosphorylation, dissociation of 14-3-3 and Bad, and binding to Bcl-xL, which triggers the disruption of the mitochondrial membrane, release of cytochrome c, and caspases' cascade activation. Furthermore, the Akt/mTOR signal pathway is also involved in ANISpm-mediated cell-cycle arrest. Additive DFMO or Spd, which only enhances or attenuates ANISpm-mediated cell apoptosis, respectively, does not alter the signal pathway. In addition, preliminary toxicology evaluation showed that ANISpm had no obvious system toxicity at a dose of 2.5 mg/kg, which exerted potent antitumor activity in vivo, especially hematotoxicity. Thus, ANISpm merits further investigation as a potential chemotherapeutic agent against hepatocellular carcinoma.
authors.affiliation: Institute of Chemical Biology, Henan University, Kaifeng, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Ya-Hong
authors.initials: YH
authors.lastname: Zhang
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Tian
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Ma
authors.forename: Jin
authors.initials: J
authors.lastname: Zhao
authors.forename: Song-Qiang
authors.initials: SQ
authors.lastname: Xie
authors.forename: Chao-Jie
authors.initials: CJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016466:CHO Cells; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D053644:Naphthalimides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013096:Spermine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D018675:Toxicity Tests; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: C580956:ANISpm compound; D053644:Naphthalimides; D051025:bcl-Associated Death Protein; D013096:Spermine; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases