文献类型：期刊文献

英文题名：Tumor killing by a dietary curcumin mono-carbonyl analog that works as a selective ROS generator via TrxR inhibition

作者：Liu, Xuefeng[1,2];Cui, Hongmei[3];Li, Mi[4,5,6];Chai, Zuohu[1];Wang, Haibo[1];Jin, Xiaojie[4,5,6];Dai, Fang[1];Liu, Yongqi[5,6];Zhou, Bo[1]

第一作者：Liu, Xuefeng

通信作者：Dai, F[1];Zhou, B[1];Liu, YQ[2];Liu, YQ[3]

机构：[1]Lanzhou Univ, State Key Lab Appl Organ Chem, 222 Tianshui St S, Lanzhou 730000, Gansu, Peoples R China;[2]Lanzhou Univ, Sch Pharm, 222 Tianshui St S, Lanzhou 730000, Gansu, Peoples R China;[3]Lanzhou Univ, Sch Publ Hlth, 222 Tianshui St S, Lanzhou 730000, Gansu, Peoples R China;[4]Gansu Univ Chinese Med, Coll Pharm, 35 Dingxi East Rd, Lanzhou 730000, Gansu, Peoples R China;[5]Gansu Univ Chinese Med, Gansu Univ Key Lab Mol Med, 35 Dingxi East Rd, Lanzhou 730000, Gansu, Peoples R China;[6]Gansu Univ Chinese Med, Chinese Med Prevent & Treatment Major Dis, 35 Dingxi East Rd, Lanzhou 730000, Gansu, Peoples R China

第一机构：Lanzhou Univ, State Key Lab Appl Organ Chem, 222 Tianshui St S, Lanzhou 730000, Gansu, Peoples R China

通信机构：[1]corresponding author), Lanzhou Univ, State Key Lab Appl Organ Chem, 222 Tianshui St S, Lanzhou 730000, Gansu, Peoples R China;[2]corresponding author), Gansu Univ Chinese Med, Gansu Univ Key Lab Mol Med, 35 Dingxi East Rd, Lanzhou 730000, Gansu, Peoples R China;[3]corresponding author), Gansu Univ Chinese Med, Chinese Med Prevent & Treatment Major Dis, 35 Dingxi East Rd, Lanzhou 730000, Gansu, Peoples R China.|[10735]甘肃中医药大学;

年份：2023

卷号：250

外文期刊名：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000931859600001)】；

基金：This work was supported by the National Natural Science Foundation of China (Grant Nos. 22177045 and 21672091) .

语种：英文

外文关键词：Anticancer; Curcumin; Thioredoxin reductase; Reactive oxygen species; Apoptosis; Ferroptosis

摘要：In comparison with normal cells, cancer cells feature intrinsic oxidative stress, thereby being more vulnerable to further production of reactive oxygen species (ROS) by pro-oxidative anticancer agents (PAAs). However, PAAs also inevitably generate ROS in normal cells, resulting in their narrow therapeutic window and toxic side effects that greatly limit their clinical application. To develop PAAs that generate ROS selectively in cancer cells over in normal cells, we rationally designed three series of 21 dietary curcumin 5-carbon mono-carbonyl analogs differentiated by either placement of the cyclohexanone, piperidone, and methylpiperidone linkers, or intro-duction of electron-withdrawing trifluoromethyl and electron-donating methoxyl groups on its two aromatic rings in the ortho, meta, or para position to the linkers. From the designed molecules, 2c, characterized of the presence of the meta-CF3-substituted mode and the piperidone linker, was identified as a potent selective ROS-generating agent, allowing its ability to kill selectively human non-small cell lung cancer NCI-H460 (IC50 = 0.44 mu M) over human normal lung MRC-5 cells with a selectivity index of 32.0. Additionally, it was more potent and selective than the conventional chemotherapeutic agents (5-fluorouracil and camptothecin) did. Mechanistical investigation reveals that by means of its Michael acceptor unit and structure characteristics as described above, 2c could covalently modify the Sec-498 residue of intracellular thioredoxin reductase (TrxR) to generate ROS selectively, resulting in ROS-dependent apoptosis and ferroptosis of NCI-H460 cells. Noticeably, 2c inhibited significantly the growth of NCI-H460 cell xenograft tumor in nude mice without obvious toxicity to liver and kidney. Together, this work highlights a practical strategy of targeting TrxR overexpressed in cancer cells to develop PAAs capable of generating ROS selectively, as evidenced by the example of 2c.