Academic Journal
Micheliolide exerts effects in myeloproliferative neoplasms through inhibiting STAT3/5 phosphorylation via covalent binding to STAT3/5 proteins
| العنوان: | Micheliolide exerts effects in myeloproliferative neoplasms through inhibiting STAT3/5 phosphorylation via covalent binding to STAT3/5 proteins |
|---|---|
| المؤلفون: | Huang, Huijun, Liu, Jinqin, Yang, Lin, Yan, Yiru, Chen, Meng, Li, Bing, Xu, Zefeng, Qin, Tiejun, Qu, Shiqiang, Wang, Liang, Huang, Gang, Chen, Yue, Xiao, Zhijian |
| المصدر: | Blood Science ; ISSN 2543-6368 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health) |
| سنة النشر: | 2023 |
| الوصف: | Ruxolitinib is a cornerstone of management for some subsets of myeloproliferative neoplasms (MPNs); however, a considerable number of patients respond suboptimally. Here, we evaluated the efficacy of micheliolide (MCL), a natural guaianolide sesquiterpene lactone, alone or in combination with ruxolitinib in samples from patients with MPNs, JAK2 V617F-mutated MPN cell lines, and a Jak2 V617F knock-in mouse model. MCL effectively suppressed colony formation of hematopoietic progenitors in samples from patients with MPNs and inhibited cell growth and survival of MPN cell lines in vitro. Co-treatment with MCL and ruxolitinib resulted in greater inhibitory effects compared with treatment with ruxolitinib alone. Moreover, dimethylaminomicheliolide (DMAMCL), an orally available derivative of MCL, significantly increased the efficacy of ruxolitinib in reducing splenomegaly and cytokine production in Jak2 V617F knock-in mice without evident effects on normal hematopoiesis. Importantly, MCL could target the Jak2 V617F clone and reduce mutant allele burden in vivo. Mechanistically, MCL can form a stable covalent bond with cysteine residues of STAT3/5 to suppress their phosphorylation, thus inhibiting JAK/STAT signaling. Overall, these findings suggest that MCL is a promising drug in combination with ruxolitinib in the setting of suboptimal response to ruxolitinib. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1097/bs9.0000000000000168 |
| DOI: | 10.1097/BS9.0000000000000168 |
| الاتاحة: | http://dx.doi.org/10.1097/bs9.0000000000000168 https://journals.lww.com/10.1097/BS9.0000000000000168 |
| Rights: | http://creativecommons.org/licenses/by/4.0/ |
| رقم الانضمام: | edsbas.60EDC88F |
| قاعدة البيانات: | BASE |
| DOI: | 10.1097/bs9.0000000000000168 |
|---|