6-Dithio-2'-deoxyguanosine analogs induce reactive oxygen species-mediated tumor cell apoptosis via bi-targeting thioredoxin 1 and telomerase.

Abstract

Thioredoxin 1 (Trx1) and telomerase play key roles in the development and progression process of most tumors, and they both are promising drug therapy targets. We have, for the first time, discovered that Trx1 and telomerase had a dual-target synergistic effect. Based on that results, we designed a series of 6-dithio-2'-deoxyguanosine analogs (named as YLS00X) and verified whether they can inhibit Trx1 and telomerase simultaneously. TrxR1/Trx1 system activity and telomerase expression were significantly inhibited by 6-dithio-2'-deoxyguanosine analogs, especially YLS004. YLS004 can also cause ROS accumulation, and induce tumor cell apoptosis. The vitro antitumor activity of 6-dithio-2'-deoxyguanosine analogs using MTT assay on 11 different human cancer cells and found that human colon cancer cells(HCT116) and melanoma cells (A375) were the most sensitive cells to 6-dithio-2'-deoxyguanosine analogs treatment and vivo xenografts models also confirmed that. The serum biochemical parameters and multiple organs HE staining results of subacute experiments indicated that YLS004 might be mildly toxic to immune organs, including the thymus, spleen, and hematopoietic system. Besides, YLS004 was rapidly metabolized in the rats' blood. Our study revealed that YLS004, a Trx1 and telomerase inhibitor, has strong anti-tumor effects to colon cancer and melanoma cells and is a promising new candidate drug.

• Authors: Yang Zhang, Jiabei Zhou, Qin Ye, Kui Zeng, Jie Pan, Lu Chen, Yingying Wang, Bo Yang, Qiaojun He, Jianqing Gao, Su Zeng, Lushan Yu
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 401 Pg. 115079 (08 15 2020) ISSN: 1096-0333 [Electronic] United States
• PMID: 32497534 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Reactive Oxygen Species
• Thioredoxins
• Telomerase
• Deoxyguanosine

Topics

• A549 Cells
• Animals
• Antineoplastic Agents (administration & dosage, chemistry)
• Apoptosis (drug effects, physiology)
• Cell Line, Tumor
• Cell Survival (drug effects, physiology)
• Deoxyguanosine (administration & dosage, analogs & derivatives)
• Dose-Response Relationship, Drug
• Drug Delivery Systems (methods)
• HCT116 Cells
• HT29 Cells
• Hep G2 Cells
• Humans
• K562 Cells
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Rats
• Reactive Oxygen Species (agonists, metabolism)
• Telomerase (antagonists & inhibitors, metabolism)
• Thioredoxins (antagonists & inhibitors, metabolism)