Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng, 475001, China.
Org Biomol Chem. 2009 Nov 21;7(22):4651-60. doi: 10.1039/b912685f. Epub 2009 Sep 3.
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.
尽管已有几种萘酰亚胺衍生物在临床试验中表现出抗肿瘤活性，但一些问题，如毒性，促使人们对萘酰亚胺骨架进行进一步的结构修饰。为了利用多胺转运体（PAT）进行药物递送，合成了一系列与多胺偶联的萘酰亚胺，这有利于肿瘤细胞的选择性。用α-二氟甲基鸟氨酸（DFMO）或精脒（Spd）处理人肝癌 HepG2 细胞、人肝癌 Bel-7402 和正常 QSG-7701 肝细胞进行生物评价，证实了 PAT 的识别和细胞选择性。此外，新型萘酰亚胺多胺缀合物通过细胞凋亡杀死细胞，并且首次通过凋亡机制研究鉴定 Akt/mTOR 信号通路作为上游细胞靶标。DFMO 或 Spd 的存在仅能增强或减弱细胞凋亡，但不会改变信号通路。总的来说，适当的多胺识别元件（即同精脒）通过 PAT 介导有效的药物递送，并有助于适当的细胞毒性物质（即不同的萘酰亚胺）发挥抗肿瘤特性。
