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.
aInstitute of Chemical Biology
bThe Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng, China
Correspondence to Song-qiang Xie, Institute of Chemical Biology, Henan University, 475004 Kaifeng, China Tel: +86 378 2864665; fax: +86 378 3880680; e-mail: firstname.lastname@example.org and Correspondence to Chao-jie Wang, The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, China Tel/fax: +86 378 3880680; e-mail: email@example.com
Received April 11, 2012
Accepted August 24, 2012