Zhang Lei, Wang Jing, Liu Lai, Zheng Chengyue, Wang Yang
School of Pharmacy, Zunyi Medical University, 201 Dalian Road, Zunyi 563003, Guizhou, China.
Molecules. 2017 Apr 17;22(4):628. doi: 10.3390/molecules22040628.
With the purpose of creating a multifunctional drug for gastric cancer treatment, a novel -retinoic acid () conjugate with podophyllotoxin () was designed and synthesized, and its in vitro antiproliferative activity was evaluated against human gastric cancer cell lines using CCK-8 assay. The conjugate, , exhibited significant anticancer activity against MKN-45 and BGC-823 cells with IC values of 0.419 ± 0.032 and 0.202 ± 0.055 μM, respectively. Moreover, efficiently triggered cell cycle arrest and induced apoptosis in MKN-45 and BGC-823 cells due to modulation of cell cycle arrest- (CDK1, CDK2, CyclinA and CyclinB1) and apoptosis- (cleaved caspase-3, -8 and -9) related proteins, respectively. Further mechanism studies revealed that could increase the expression levels of RARα and RARβ, and decrease the level of RARγ in MKN-45 and BGC-823 cells. Finally, inhibited the ERK1/2 and AKT signaling in the above two cancer cell lines. More importantly, the underlying mechanisms of were similar to those of precursor but different with the other precursor . Together, the conjugate was a promising candidate for the potential treatment of human gastric cancer.
为了研发一种用于治疗胃癌的多功能药物，设计并合成了一种新型的视黄酸（）与鬼臼毒素（）的共轭物，并使用CCK-8法评估了其对人胃癌细胞系的体外抗增殖活性。该共轭物，对MKN-45和BGC-823细胞表现出显著的抗癌活性，IC值分别为0.419±0.032和0.202±0.055μM。此外，由于分别调节了细胞周期阻滞相关蛋白（CDK1、CDK2、细胞周期蛋白A和细胞周期蛋白B1）和凋亡相关蛋白（裂解的半胱天冬酶-3、-8和-9），有效地引发了MKN-45和BGC-823细胞的细胞周期阻滞并诱导了凋亡。进一步的机制研究表明，可增加MKN-45和BGC-823细胞中RARα和RARβ的表达水平，并降低RARγ的水平。最后，抑制了上述两种癌细胞系中的ERK1/2和AKT信号传导。更重要的是，的潜在机制与前体相似，但与另一种前体不同。总之，共轭物是治疗人类胃癌的一个有前景的候选药物。
