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

Abstract

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 regelii. 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 provide a new therapeutic option for MM patients.

The Role of Signal Transducer and Activator of Transcription 3 (STAT3) and Its Targeted Inhibition in Hematological Malignancies

“…Also, Jung et al showed that phosphotyrosine-STAT3 expression is correlated with poor prognosis and survival in MM patients [ 67 ]. Recent studies have implied that inhibition of STAT3 signalling can inhibit tumor growth, re-sensitize them to therapy, and induce apoptosis under both in vitro [ 68 , 69 ] and in vivo [ 70 ] conditions.…”

Dihydrocelastrol exerts potent antitumor activity in mantle cell lymphoma cells via dual inhibition of mTORC1 and mTORC2

“…At the end of treatment, mice were sacrificed by cervical dislocation following intraperitoneal injection of 1% pentobarbital sodium (50 mg/kg). Hematoxylin-eosin (26) and TUNEL staining of the tumor tissue sections were then performed.…”

Celastrol and its Potential Health Benefits

“…35 Bir başka çalışmada ise dihidrocelastrolün insan multipl miyeloma hücrelerinde hücre proliferasyonunu inhibe ettiği, ERK1/2 ve IL-6/STAT3 yolağı inhibisyonu üzerinden apoptozu uyardığı bildirilmiştir. 36…”