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micheliolide exerts effects in myeloproliferative neoplasms through inhibiting STAT3/5 phosphorylation via covalent binding to STAT3/5 proteins

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Blood Science 2023年第4期5卷 258-268页

作者： Huijun Huang Jinqin Liu Lin Yang Yiru Yan Meng Chen Bing Li Zefeng Xu Tiejun Qin Shiqiang Qu Liang Wang Gang Huang Yue Chen Zhijian Xiao State Key Laboratory of Experimental Hematology National Clinical Research Center for Blood DiseasesHaihe Laboratory of Cell EcosystemInstitute of Hematology&Blood Diseases HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300020China MDS and MPN Centre Institute of Hematology and Blood Diseases HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjinChina State Key Laboratory of Medicinal Chemical Biology College of ChemistryNankai University94 Weijin RoadTianjinChina Department of Cell System&Anatomy the University of Texas Health Science Center at San AntonioSan AntonioTX 78229USA Mays Cancer Center Joe R.&Teresa Lozano Long School of Medicinethe University of Texas Health Science Center at San AntonioSan AntonioTX 78229USA Hematologic Pathology Center Institute of Hematology and Blood Diseases HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjinChina.

Ruxolitinib is a cornerstone of management for some subsets of myeloproliferative neoplasms(MPNs);however,a considerable number of patients respond ***,we evaluated the efficacy of micheliolide(MCL),a natural guaianolide sesquiterpene lactone,alone or in combination with ruxolitinib in samples from patients with MPNs,JAK2V617F-mutated MPN cell lines,and a Jak2V617F knock-in mouse *** effectively suppressed colony formation of hematopoietic progenitors in samples from patients with MPNs and inhibited cell growth and survival of MPN cell lines in ***-treatment with MCL and ruxolitinib resulted in greater inhibitory effects compared with treatment with ruxolitinib ***,dimethylaminomicheliolide(DMAMCL),an orally available derivative of MCL,significantly increased the efficacy of ruxolitinib in reducing splenomegaly and cytokine production in Jak2V617F knock-in mice without evident effects on normal ***,MCL could target the Jak2V617F clone and reduce mutant allele burden in ***,MCL can form a stable covalent bond with cysteine residues of STAT3/5 to suppress their phosphorylation,thus inhibiting JAK/STAT ***,these findings suggest that MCL is a promising drug in combination with ruxolitinib in the setting of suboptimal response to ruxolitinib.

关键词： micheliolide Myeloproliferative neoplasms Ruxolitinib STAT3/5 Suboptimal response

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Autophagy induced by micheliolide alleviates acute irradiation-induced intestinal injury via inhibition of the NLRP3 inflammasome

Autophagy induced by micheliolide alleviates acute irradiati...

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2021年中国肿瘤标志物学术大会暨第十五届肿瘤标志物青年科学家论坛

作者： Jin Li The First Affiliated Hospital of Chengdu Medical College 成都医学院

Radiation-induced enteropathy(RIE) is one of the most common and fatal complications of abdominal radiotherapy, with no effective interventions available. Pyroptosis, a form of proinflammatory regulated cell death, was recently found to play a vital role in radiation-induced inflammation and may represent a novel therapeutic target for RIE. To address this, we screened a high throughput pyroptosis drug library with 441 compounds and found that MCL exerted anti-radiation effects in vitro. Therefore,we postulated that MCL may play a promising role in the treatment of RIE and investigated the therapeutic effects of MCL in RIE and evaluated the possible mechanisms by which it may be therapeutic. We developed a mouse model of RIE by exposing C57 BL/6 J mice to abdominal irradiation. MCL treatment significantly ameliorated radiation-induced intestinal tissue damage,inflammatory cell infiltration, and pro-inflammatory cytokine release. Moreover, MCL markedly inhibited radiation-induced activation of the nucleotide binding domain leucine-rich repeat-containing receptor-pyrin domain containing 3(NLRP3) and suppressed pyroptosis in vivo and in ***, we observed that MCL treatment induced autophagy, which inhibited activation of the NLRP3 inflammasome and prevented caspase-1-dependent interleukin(IL)-1β and IL-18 secretion. In agreement with these observations, the beneficial effects of MCL treatment in RIE were abolished in Becn1+/-mice. Furthermore, super-resolution microscopy revealed a close association between NLRP3 and lysosome-associated membrane protein/light chain 3-positive vesicles following MCL treatment, suggesting that MCL facilitates phagocytosis of the NLRP3 inflammasome. These data support the notion that MCL-mediated induction of autophagy can ameliorate RIE by NLRP3 inflammasome degradation and identify MCL as a novel therapy for RIE.

关键词： Autophagy micheliolide NLRP3 inflammasome Radiation-induced enteropathy

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Discovery of anti-cancer stem cells drug:synthesis and biological evaluation of a library of natural products and their analogues

Discovery of anti-cancer stem cells drug:synthesis and biolo...

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第一届《药学学报》药学前沿论坛暨2015年中国药学会中药与天然药物专业委员会会议

作者： SANG Feng YANG Zhan-tao DING Ya-hui ZHAI Jia-dai LU Ya-xin YANG Guang ZHANG Quan 陈悦 State Key Laboratory of Medicinal Chemical Biology College of PharmacyCollaborative Innovation Center of Chemical Science and Engineering(Tianjin)

It is widely reported that cancer stem cells play a key role in carcinogenesis,cancer disease progression,relapse,and drug ***,compounds that selectively inhibit CSC growth are rarely *** designed and synthesized several series of natural products and their *** biological assay revealed that some compounds can selectively eradicate cancer stem or progenitor *** them,one compound was able to reduce the proportion of cancer stem cells and colony-forming units,and maintained high activity against multiple drug resistant ***,it was submitted to SFDA as an investigational new drug.

关键词： targeting cancer stem cell natural product micheliolide rakicidin A

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