Li Qiao-lu, Zhang Ping-ping, Wang Pei-qin, Yu Hao-bing, Sun Fan, Hu Wen-zheng, Wu Wen-hui, Zhang Xin, Chen Fei, Chu Zhi-yong, Zhang Jun-ping, Chen Shun-shen, Lin Hou-wen
Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 PuJian Road, Pudong District, Shanghai 200127, China.
Anticancer Agents Med Chem. 2015;15(3):291-7. doi: 10.2174/1871520614666141114201027.
Hepatocellular carcinoma (HCC) is the fifth most common form of cancer and the third most frequent cause of cancer-associated mortality worldwide. We isolated aaptamine from the marine sponge Aaptos, and synthesized derivatives of this compound. Aaptamine and synthetic derivatives displayed various biological activities. This represents the first account of studies on the effects of aaptamine and its derivatives in hepatocarcinogenesis. In this study, Cell Counting Kit (CCK8) was used to evaluate the anti-proliferative effect of aaptamine on HCC in vitro. Additionally, a subcutaneous xenograft model was used to determine if aaptamine could inhibit hepatocellular carcinoma in vivo. We also used RT-PCR and Western blot to analyze the mechanisms behind these effects. Our results showed that aaptamine has anti-proliferation effects on the cell lines LM3 and HepG2. Aaptamine also suppressed the colony-formation ability of HCC cells. We found that aaptamine treatment led to cell cycle arrest in HCC cells, reduced the expression of SOX9 and CDK2. Significant anti-tumor effects were observed in aaptamine-administered tumor-bearing mice as compared to controls. However, structural changes made to aaptamine yielded two derivatives for which all the effects listed above were considerably reduced as compared to the original compound aaptamine. In conclusion, aaptamine is demonstrated for the first time to inhibit liver cancer progression. The aaptamine-induced cell cycle arrest was associated with the increased binding of p21 to Cdk2-cyclin D/E complexes, inhibition of Cdk2 kinase activity in HCC cells. Furthermore, aaptamine appears to be a promising and efficient treatment of liver cancer HCC-LM3 in vivo. We have also uncovered structural changes that might affect the biological activity. The work provides a promising drug candidate for HCC treatment.
肝细胞癌（HCC）是全球第五大常见癌症形式，也是癌症相关死亡的第三大常见原因。我们从海洋海绵Aaptos中分离出了aaptamine，并合成了该化合物的衍生物。Aaptamine及其合成衍生物表现出多种生物活性。这是关于aaptamine及其衍生物在肝癌发生过程中作用的首次研究报道。在本研究中，使用细胞计数试剂盒（CCK8）评估aaptamine在体外对肝癌的抗增殖作用。此外，使用皮下异种移植模型来确定aaptamine在体内是否能抑制肝细胞癌。我们还使用逆转录-聚合酶链反应（RT-PCR）和蛋白质免疫印迹法（Western blot）分析这些作用背后的机制。我们的结果表明，aaptamine对LM3和HepG2细胞系具有抗增殖作用。Aaptamine还抑制了肝癌细胞的集落形成能力。我们发现aaptamine处理导致肝癌细胞的细胞周期停滞，降低了SOX9和CDK2的表达。与对照组相比，在给予aaptamine的荷瘤小鼠中观察到了显著的抗肿瘤作用。然而，对aaptamine进行结构改变后得到了两种衍生物，与原始化合物aaptamine相比，上述所有作用均显著降低。总之，首次证明aaptamine可抑制肝癌进展。aaptamine诱导的细胞周期停滞与p21与Cdk2-细胞周期蛋白D/E复合物结合增加、肝癌细胞中Cdk2激酶活性受到抑制有关。此外，aaptamine似乎是一种有前途且有效的体内治疗肝癌HCC-LM3的药物。我们还发现了可能影响生物活性的结构变化。这项工作为肝癌治疗提供了一个有前途的候选药物。
