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ORIGINAL ARTICLE
Year : 2020  |  Volume : 6  |  Issue : 3  |  Page : 353-361

The antitumor activity and mechanism of MCL3 in G422 glioblastoma


1 Department of Pharmacology, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
2 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Correspondence Address:
Prof. Xian-Dao Pan
Institute of Materia Medica, Chinese Academy of Medical Sciencesand Peking Union Medical College, 1 Xian Nong Tan Street, Beijing
China
Prof. Yan Li
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/wjtcm.wjtcm_46_20

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Objective: Parthenolide (PTL) induces anti-tumor effects via the nuclear factor kappa B (NF-κB) signaling pathway. MCL3, a PTL derivative, is a sesquiterpene lactone synthesized by the rearrangement and subsequent oxidation of PTL. The aim of this study was to elucidate the antitumor activity and mechanism of action of MCL3 in glioblastoma (GBM). Materials and Methods: The effects of MCL3 on G422 cell proliferation, apoptosis, invasion, and angiogenesis in vitro were measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, the cell invasion, and tube formation assays. The subcutaneously transplanted G422 xenograft model was used to detect the effect of MCL3 on tumor growth in vivo. Pathological changes were analyzed by immunohistochemical staining. The effects of MCL3 on NF-κB and Stat3 transcriptional activities were examined using a dual-luciferase reporter assay. Protein levels related to the NF-κB/ interleukin (IL)-6/Stat3 signaling pathway were determined using western blot analysis. Results: MCL3 inhibited GBM cell proliferation, invasion, and angiogenesis in a concentration-dependent manner. Moreover, MCL3 decreased the transcriptional activities of NF-κB and Stat3. MCL3 suppressed tumor growth in the subcutaneously transplanted G422 xenograft model, while the inhibition rate was 79% in tumor weight at 40.0 mg/kg. MCL3 blocked the NF-κB/IL-6/Stat3 signaling pathway in G422 cells and tumor tissues, resulting in the downregulation of Stat3 target genes related to apoptosis, invasion, etc., Conclusion: The results show that MCL3 might inhibit G422 GBM growth partly due to the inhibition of the NF-κB/IL-6/Stat3 signaling pathway.


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