Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, Lanzhou 730000, China.
Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, Lanzhou 730000, China.
Bioorg Med Chem. 2019 Oct 15;27(20):115071. doi: 10.1016/j.bmc.2019.115071. Epub 2019 Aug 23.
Based on our previous research, a series of targeting hepatocellular carcinoma complexes, [R-Glycyrrhetinic acid-CHCH-[Co(CO)] (R = H, 1; R = NSAIDs-COOH, 2-4; R = Aromatic acid, 5-7; R = Amino acid, 8-10), were synthesized. The test showed they are slow CO releasers. Using HeLa, A549, HT-29, SMMC7721 and HepG2 cells as models, their activities against tumor cell proliferation were firstly evaluated. The resulting data show all the complexes displayed a good anti-proliferation activity against the HepG2 and SMMC-7721 liver cancer cells, and their IC values were in the range of 10.07-66.06 µM; compared with cis-platin (DDP), their activities were comparable or even better under the same condition. Among them, complexes 3, 4, 6 and 9 exhibited higher anti-proliferation activities against HepG2 and SMMC-7721 cell lines than the other cell lines. To confirm further these complexes have selectivity to the liver cells, the uptakes of complexes 3, 4, 6 and 9 by HepG2, HT-29, A549 and SMMC7721 cell lines were studied. The results show the cell uptake rates of the complexes by HepG2 cells and SMMC7721 cells were much greater than by other cells under the same condition. In following tests, the tested complexes displayed higher activities in inhibiting NF-kB, COX-2 and iNOS; and they induced HepG2 cells apoptosis by mitochondrial pathway, which assessed by staining with different fluorescent reagent DAPI, PI, Mito-Tracker Green and DCFH-DA. Meanwhile, the tested complexes up-regulated the expression levels of caspase-3 and Bax, down-regulated the Bcl-2 expression. In addition, they had no effect on zebrafish embryo survival, embryo hatching, embryonic movement, zebrafish malformation and zebrafish movement at below 0.5 µM. This suggests the complexes are potential candidates to be used in clinic for liver cancers.
基于我们之前的研究，我们合成了一系列靶向肝癌的复合物，[R-甘草次酸-CHCH-[Co(CO)]（R=H，1；R=NSAIDs-COOH，2-4；R=芳香酸，5-7；R=氨基酸，8-10）]。实验表明它们是一种缓慢的 CO 释放剂。我们以 HeLa、A549、HT-29、SMMC7721 和 HepG2 细胞为模型，首先评估了它们对肿瘤细胞增殖的抑制活性。结果表明，所有复合物均对 HepG2 和 SMMC-7721 肝癌细胞表现出良好的抗增殖活性，其 IC 值在 10.07-66.06µM 范围内；与顺铂（DDP）相比，在相同条件下，它们的活性相当或更好。其中，复合物 3、4、6 和 9 对 HepG2 和 SMMC-7721 细胞系的增殖抑制活性高于其他细胞系。为了进一步证实这些复合物对肝癌细胞具有选择性，我们研究了复合物 3、4、6 和 9 在 HepG2、HT-29、A549 和 SMMC7721 细胞系中的摄取情况。结果表明，在相同条件下，复合物被 HepG2 细胞和 SMMC7721 细胞摄取的速率明显高于其他细胞。在后续实验中，我们发现这些复合物在抑制 NF-kB、COX-2 和 iNOS 方面表现出更高的活性；通过使用不同的荧光试剂 DAPI、PI、Mito-Tracker Green 和 DCFH-DA 对 HepG2 细胞进行染色，发现复合物可通过线粒体途径诱导 HepG2 细胞凋亡。同时，这些复合物上调了 caspase-3 和 Bax 的表达水平，下调了 Bcl-2 的表达水平。此外，在低于 0.5µM 浓度下，复合物对斑马鱼胚胎的存活率、孵化率、胚胎运动、斑马鱼畸形和运动没有影响。这表明这些复合物有潜力成为用于肝癌临床治疗的候选药物。
