Bi-targeting of thioredoxin 1 and telomerase by thiotert promotes cell death of myelodysplastic syndromes and lymphoma
Abstract Thioredoxin1 (TRX1) and telomerase are both attractive oncology targets that are tightly implicated in tumor initiation and development. Here, we reported that the 6-dithio-2-deoxyguanosine analog thiotert exhibits an effective cytotoxic effect on myelodysplastic syndromes (MDS) cell SKM-1...
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2025-01-01
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| Online Access: | https://doi.org/10.1186/s13062-025-00594-2 |
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| author | Qiangan Jing Yunyi Wu Yanchun Li Chaoting Zhou Junyu Zhang Jun Xia Keyi Li Yuhuan Shen Hongfeng Yao Xiangmin Tong Jing Du Lushan Yu Ying Wang |
| author_facet | Qiangan Jing Yunyi Wu Yanchun Li Chaoting Zhou Junyu Zhang Jun Xia Keyi Li Yuhuan Shen Hongfeng Yao Xiangmin Tong Jing Du Lushan Yu Ying Wang |
| author_sort | Qiangan Jing |
| collection | DOAJ |
| description | Abstract Thioredoxin1 (TRX1) and telomerase are both attractive oncology targets that are tightly implicated in tumor initiation and development. Here, we reported that the 6-dithio-2-deoxyguanosine analog thiotert exhibits an effective cytotoxic effect on myelodysplastic syndromes (MDS) cell SKM-1 and lymphoma cell U-937. Further studies confirmed that thiotert effectively disrupts cellular redox homeostasis, as evidenced by elevated intracellular reactive oxygen species (ROS) levels, increased MnSOD, accelerated DNA impairment, and activated apoptosis signal. Mechanistically, our present study revealed that thiotert treatment effectively inhibited the function of the TRX1/TRXR1 system and telomerase reverse transcriptase (TERT), rendering oxidative damage and impairment of telomeres. Meanwhile, pharmacological administration of glutathione (GSH), N-acetylcysteine (NAC), and mitoquinone (MitoQ), or genetic overexpression of TRX1 or TERT in MDS and cells could dampen the toxicity caused by thiotert. Remarkably, the in vivo mouse model of MDS demonstrated that thiotert administration exhibited greater efficacy in tumor reduction compared to the conventional chemotherapy drug cytarabine. Collectively, these results provide experimental insights into the mechanism of thiotert-induced MDS and lymphoma cell death and unveil that thiotert may be an effective and promising new drug for future MDS and lymphoma treatment. Graphical Abstract |
| format | Article |
| id | doaj-art-f98555e74ffb4807bef30d2f331817b2 |
| institution | Kabale University |
| issn | 1745-6150 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Biology Direct |
| spelling | doaj-art-f98555e74ffb4807bef30d2f331817b22025-01-19T12:13:24ZengBMCBiology Direct1745-61502025-01-0120111710.1186/s13062-025-00594-2Bi-targeting of thioredoxin 1 and telomerase by thiotert promotes cell death of myelodysplastic syndromes and lymphomaQiangan Jing0Yunyi Wu1Yanchun Li2Chaoting Zhou3Junyu Zhang4Jun Xia5Keyi Li6Yuhuan Shen7Hongfeng Yao8Xiangmin Tong9Jing Du10Lushan Yu11Ying Wang12Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital(Affiliated People’s Hospital), Hangzhou Medical CollegeLaboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital(Affiliated People’s Hospital), Hangzhou Medical CollegeDepartment of Clinical Laboratory, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake UniversityLaboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital(Affiliated People’s Hospital), Hangzhou Medical CollegeDepartment of Hematology, Lishui Central HospitalLaboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital(Affiliated People’s Hospital), Hangzhou Medical CollegeLaboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital(Affiliated People’s Hospital), Hangzhou Medical CollegeLaboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital(Affiliated People’s Hospital), Hangzhou Medical CollegeDepartment of Clinical Laboratory, Zhuji People’s Hospital of Zhejiang ProvinceDepartment of Clinical Laboratory, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake UniversityLaboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital(Affiliated People’s Hospital), Hangzhou Medical CollegeInstitute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang UniversityDepartment of Clinical Laboratory, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake UniversityAbstract Thioredoxin1 (TRX1) and telomerase are both attractive oncology targets that are tightly implicated in tumor initiation and development. Here, we reported that the 6-dithio-2-deoxyguanosine analog thiotert exhibits an effective cytotoxic effect on myelodysplastic syndromes (MDS) cell SKM-1 and lymphoma cell U-937. Further studies confirmed that thiotert effectively disrupts cellular redox homeostasis, as evidenced by elevated intracellular reactive oxygen species (ROS) levels, increased MnSOD, accelerated DNA impairment, and activated apoptosis signal. Mechanistically, our present study revealed that thiotert treatment effectively inhibited the function of the TRX1/TRXR1 system and telomerase reverse transcriptase (TERT), rendering oxidative damage and impairment of telomeres. Meanwhile, pharmacological administration of glutathione (GSH), N-acetylcysteine (NAC), and mitoquinone (MitoQ), or genetic overexpression of TRX1 or TERT in MDS and cells could dampen the toxicity caused by thiotert. Remarkably, the in vivo mouse model of MDS demonstrated that thiotert administration exhibited greater efficacy in tumor reduction compared to the conventional chemotherapy drug cytarabine. Collectively, these results provide experimental insights into the mechanism of thiotert-induced MDS and lymphoma cell death and unveil that thiotert may be an effective and promising new drug for future MDS and lymphoma treatment. Graphical Abstracthttps://doi.org/10.1186/s13062-025-00594-2Myelodysplastic syndromesLymphomaTRX1ThiotertTERTApoptosis |
| spellingShingle | Qiangan Jing Yunyi Wu Yanchun Li Chaoting Zhou Junyu Zhang Jun Xia Keyi Li Yuhuan Shen Hongfeng Yao Xiangmin Tong Jing Du Lushan Yu Ying Wang Bi-targeting of thioredoxin 1 and telomerase by thiotert promotes cell death of myelodysplastic syndromes and lymphoma Biology Direct Myelodysplastic syndromes Lymphoma TRX1 Thiotert TERT Apoptosis |
| title | Bi-targeting of thioredoxin 1 and telomerase by thiotert promotes cell death of myelodysplastic syndromes and lymphoma |
| title_full | Bi-targeting of thioredoxin 1 and telomerase by thiotert promotes cell death of myelodysplastic syndromes and lymphoma |
| title_fullStr | Bi-targeting of thioredoxin 1 and telomerase by thiotert promotes cell death of myelodysplastic syndromes and lymphoma |
| title_full_unstemmed | Bi-targeting of thioredoxin 1 and telomerase by thiotert promotes cell death of myelodysplastic syndromes and lymphoma |
| title_short | Bi-targeting of thioredoxin 1 and telomerase by thiotert promotes cell death of myelodysplastic syndromes and lymphoma |
| title_sort | bi targeting of thioredoxin 1 and telomerase by thiotert promotes cell death of myelodysplastic syndromes and lymphoma |
| topic | Myelodysplastic syndromes Lymphoma TRX1 Thiotert TERT Apoptosis |
| url | https://doi.org/10.1186/s13062-025-00594-2 |
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