School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China; School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China.
School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China; Department of Pharmacy, Jingzhou Central Hospital, Jingzhou 434020, PR China.
Life Sci. 2022 Dec 15;311(Pt A):121105. doi: 10.1016/j.lfs.2022.121105. Epub 2022 Oct 19.
In this study, we synthesized a 10-fluorine-substitution derivative of CPT (Camptothecin) YCJ100 and evaluated its antitumor activity and systemic toxicity.
Determination of in vitro antitumor activity and mechanism of YCJ100 by the MTT assay, Molecular docking, EdU staining, Cell cycle and apoptosis determination, Western blot analysis and Topoisomerase I activity assay. The antitumor effects of YCJ100 were evaluated in primary HCC (hepatocellular carcinoma), ICC (intrahepatic cholangiocarcinoma) mouse models, and pancreatic cancer xenograft models.
YCJ100 showed superior cytotoxic activity compared to Topotecan in SW480, SW1990, Hep3B, HepG2, A549, A2780, HeLa, and QBC cells. YCJ100 blocked the cell cycle in the G2/M phase, inhibited cell proliferation and induced apoptosis in HepG2 and SW1990 cells. Mechanistically, YCJ100 inhibited topoisomerase I activity in both a cell-free system and a cellular system, similar to the mechanism of Topotecan. YCJ100 showed significant antitumor activity and was more potent than Topotecan in primary HCC and ICC mouse models, as well as a xenograft mouse model. Additionally, YCJ100 showed only minor toxicity to the mouse hematopoietic system, liver, and kidney. These findings indicate that YCJ100 has high antitumor activity and low systemic toxicity.
Our findings demonstrate that YCJ100, as a Topoisomerase I inhibitor, has in vitro and in vitro antitumor activity. This study provides a new lead compound worthy of further preclinical evaluation and potential clinical development.
本研究合成了喜树碱（CPT）YCJ100 的 10-氟取代衍生物，并评价了其抗肿瘤活性和全身毒性。
通过 MTT 检测、分子对接、EdU 染色、细胞周期和凋亡检测、Western blot 分析和拓扑异构酶 I 活性检测，确定 YCJ100 的体外抗肿瘤活性和机制。在原发性肝癌（肝细胞癌）、ICC（肝内胆管癌）小鼠模型和胰腺癌异种移植模型中评估 YCJ100 的抗肿瘤作用。
YCJ100 在 SW480、SW1990、Hep3B、HepG2、A549、A2780、Hela 和 QBC 细胞中的细胞毒性活性均优于拓扑替康。YCJ100 阻滞细胞周期于 G2/M 期，抑制 HepG2 和 SW1990 细胞的增殖并诱导凋亡。机制上，YCJ100 抑制游离体系和细胞体系中的拓扑异构酶 I 活性，与拓扑替康的机制相似。YCJ100 在原发性 HCC 和 ICC 小鼠模型以及异种移植小鼠模型中表现出显著的抗肿瘤活性，且比拓扑替康更有效。此外，YCJ100 对小鼠造血系统、肝脏和肾脏的毒性较小。这些发现表明 YCJ100 具有高抗肿瘤活性和低全身毒性。
我们的研究结果表明，YCJ100 作为拓扑异构酶 I 抑制剂，具有体外和体内抗肿瘤活性。本研究提供了一个有前途的先导化合物，值得进一步的临床前评估和潜在的临床开发。
