Dihydrocelastrol inhibits multiple myeloma cell proliferation and promotes apoptosis through ERK1/2 and IL-6/STAT3 pathways in vitro and in vivo

• Published in: Acta biochimica et biophysica Sinica 2017-05, Vol.49 (5), p.420-427
• Main Authors: Hu, Liangning, Wu, Huiqun, Li, Bo, Song, Dongliang, Yang, Guang, Chen, Gege, Xie, Bingqian, Xu, Zhijian, Zhang, Yong, Yu, Dandan, Hou, Jun, Xiao, Wenqin, Sun, Xi, Chang, Gaomei, Zhang, Yiwen, Gao, Lu, Dai, Bojie, Tao, Yi, Shi, Jumei, Zhu, Weiliang
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Interleukin-6 - metabolism; Male; MAP Kinase Signaling System - drug effects; Mice; Mice, Nude; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; STAT3 Transcription Factor - metabolism; Treatment Outcome; Triterpenes - administration & dosage
• ISSN: 1672-9145; 1745-7270
• DOI: 10.1093/abbs/gmx021

Multiple myeloma （MM） is the second most frequent malignant hematological disease. Dihydrocelastrol （DHCE） is synthesized by hydrogenated celastrol, a treterpene isolated from Chinese medicinal plant Tripterygium regeliL In this study, we first reported the anti-tumor activity of DHCE on MM cells. We found that DHCE could inhibit cell proliferation and promote apoptosis through caspase-dependent way in vitro. In addition, DHCE could inactivate the expression of interleukin （IL）-6 and downregulate the phosphorylation of extracellular regulated protein kinases （ERK1/2） and the signal transducer and activator of transcription 3 （STAT3） in MM. It also retained its activity against MM cell lines in the presence of IL-6. Furthermore, treatment of MM cells with DHCE resulted in an accumulation of cells in G0/G1 phase of the cell cycle. Notably, DHCE reduced the expression of cyclin D1 and cyclin-dependent kinases 4 and 6 in MM cell lines. Additionally, its efficacy toward the MM cell lines could be enhanced in combination with the histone deacetylase inhibitor panobinostat （LBH589）, which implied the possibility of the combination treatment of DHCE and LBH589 as a potential therapeutic strategy in MM. In addition, treatment of NCI-H929 tumor-bearing nude mice with DHCE （10 mg/kg/d, i.p., 1-14 days） resulted in 73% inhibition of the tumor growth in vivo. Taken together, the results of our present study indicated that DHCE could inhibit cellular proliferation and induce cell apoptosis in myeloma cells mediated through different mechanisms, possibly through inhibiting the IL-6/STAT3 and ERK1/2 pathways. And it may pro- vide a new therapeutic option for MM patients.