2. Academic Validation
  3. Tumor killing by a dietary curcumin mono-carbonyl analog that works as a selective ROS generator via TrxR inhibition

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

  • Eur J Med Chem. 2023 Mar 15;250:115191. doi: 10.1016/j.ejmech.2023.115191.
Xuefeng Liu 1,  Hongmei Cui 2,  Mi Li 3,  Zuohu Chai 4,  Haibo Wang 4,  Xiaojie Jin 3,  Fang Dai 5,  Yongqi Liu 6,  Bo Zhou 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu, 730000, China; School of Pharmacy, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu, 730000, China; College of Pharmacy, Gansu University of Chinese Medicine, 35 Dingxi East Road, Lanzhou, Gansu, 730000, China.
  • 2 School of Public Health, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu, 730000, China.
  • 3 College of Pharmacy, Gansu University of Chinese Medicine, 35 Dingxi East Road, Lanzhou, Gansu, 730000, China; Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, 35 Dingxi East Road, Lanzhou, Gansu, 730000, China.
  • 4 State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu, 730000, China.
  • 5 State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu, 730000, China. Electronic address: daifang@lzu.edu.cn.
  • 6 Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, 35 Dingxi East Road, Lanzhou, Gansu, 730000, China. Electronic address: liuyongqi73@163.com.
  • 7 State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu, 730000, China. Electronic address: bozhou@lzu.edu.cn.
PMID: 36758308 DOI: 10.1016/j.ejmech.2023.115191
Abstract

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 introduction 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 μM) 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.

Keywords

Anticancer; Apoptosis; Curcumin; Ferroptosis; Reactive oxygen species; Thioredoxin reductase.

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