Expression of Concern: Conjugation of substituted naphthalimides to polyamines as cytotoxic agents targeting the Akt/mTOR signal pathway.

Expression of Concern for 'Conjugation of substituted naphthalimides to polyamines as cytotoxic agents targeting the Akt/mTOR signal pathway' by Zhi-Yong Tian et al., Org. Biomol. Chem., 2009, 7, 4651-4660, https://doi.org/10.1039/B912685F.

NPC-16, a novel naphthalimide-polyamine conjugate, induced apoptosis and autophagy in human hepatoma HepG2 cells and Bel-7402 cells.

The antitumor effects and molecular mechanism of NPC-16, a novel naphthalimide-polyamine conjugate, were evaluated in HepG2 cells and Bel-7402 cells. Apoptosis and necrosis were evaluated by Annexin V-FITC detection kit, and autophagy by acridine orange and Lyso-Tracker Red staining. The change of mitochondrial transmembrane potential was measured using rhodamine 123 staining. The protein expression of Beclin 1, LC3 II and mTOR, p70S6 K, 14-3-3, caspase, and Bcl-2 family members was detected by immunofluorescence assays and Western Blot. Here, we elucidated the nature of cellular response of HepG2 cells and Bel-7402 cells to NPC-16 at IC(50). NPC-16 induced caspase-dependent apoptosis via the mitochondrial pathway and death receptor pathway in Bel-7402 cells. Differently, NPC-16 triggered HepG2 cells both apoptosis and autophagy, further autophagy facilitated cellular apoptosis. Furthermore, mTOR signal pathway was involved in NPC-16-mediated autophagy in HepG2 cells. Thus, NPC-16 may be useful as a potential template for investigation the molecular mechanism of naphthalimide-polyamine conjugate against hepatocellular carcinoma.

Conjugation of substituted naphthalimides to polyamines as cytotoxic agents targeting the Akt/mTOR signal pathway.

Though several naphthalimide derivatives have exhibited antitumor activity in clinical trials, some issues such as toxicity prompted further structural modifications on the naphthalimide backbone. A series of naphthalimides conjugated with polyamines were synthesized to harness the polyamine transporter (PAT) for drug delivery, which was beneficial for the tumor cell selectivity. Bioevaluation in human hepatoma HepG2 cells treated with alpha-difluoromethylornithine (DFMO) or spermidine (Spd), human hepatoma Bel-7402 and normal QSG-7701 hepatocyte confirmed the PAT recognition and cell selectivity. In addition, the novel naphthalimide polyamine conjugate kills cells via apoptosis, and the Akt/mTOR signal pathway was first identified as the upstream cellular target through the apoptotic mechanism research. The presence of DFMO or Spd only either elevated or attenuated the cell apoptosis, but did not change the signal pathway. Collectively, the proper polyamine recognition element (i.e., homospermidine) mediated effective drug delivery via the PAT, and helped the proper cytotoxic goods (i.e., diverse naphthalimides) exert antitumor properties.

[Synthesis and in vitro cytotoxicity of naphthalimide polyamine conjugates as antitumor agents].

Six naphthalimide polyamine conjugates were synthesized and their structures were confirmed by elemental analysis, 1H NMR, 13C NMR and MS. Antitumor activities were evaluated in vitro using MTT assay on Leukemia cells (K562), human breast cancer cells (MB-231) and prostate cancer cells (Ln cap cell). The results showed that most of the six compounds were superior to the control (amonafide), 6d, 6e, and 6f exhibited nice selectivity in a screen of hepatoma cells (BEL-7402) and human normal hepatocytes (QSG-7701).