Abstract
Celastrol is an active compound extracted from the root bark of the traditional Chinese medicine Tripterygium wilfordii Hook F. To investigate the effect of celastrol on human multiple myeloma cell cycle arrest and apoptosis and explore its molecular mechanism of action. The activity of celastrol on LP-1 cell proliferation was detected by WST-8 assay. The celastrol-induced cell cycle arrest was analyzed by flow cytometry after propidium iodide staining. Nuclear translocation of the nuclear factor kappa B (NF-κB) was observed by fluorescence microscope. Celastrol inhibited cell proliferation of LP-1 myeloma cell in a dose-dependent manner with IC50 values of 0.8817 µM, which was mediated through G1 cell cycle arrest and p27 induction. Celastrol induced apoptosis in LP-1 and RPMI 8226 myeloma cells in a time and dose dependent manner, and it involved Caspase-3 activation and NF-κB pathway. Celastrol down-modulated antiapoptotic proteins including Bcl-2 and survivin expression. The expression of NF-κB and IKKa were decreased after celastrol treatment. Celastrol effectively blocked the nuclear translocation of the p65 subunit and induced human multiple myeloma cell cycle arrest and apoptosis by p27 upregulation and NF-kB modulation. It has been demonstrated that the effect of celastrol on NF-kB was HO-1-independent by using zinc protoporphyrin-9 (ZnPPIX), a selective heme oxygenase inhibitor. From the results, it could be inferred that celastrol may be used as a NF-kB inhibitor to inhibit myeloma cell proliferation.
Highlights
Multiple myeloma (MM) is still an incurable hematological malignancy with a median survival of 4 years despite the use of various treatment options including thalidomide, lenalidomide, bortezomib, and hematopoietic stem cell transplantation [1,2]
The findings in molecular mechanisms that lead to MM and its progression have lead to the clarification of molecular targets of this disease and may contribute to the development of new biological targeted therapies for MM [3]
The effects of celastrol was examined with triterpenoid quinone methide structure (Figure 1) on the cellular proliferation of human MM cell line LP-1
Summary
Multiple myeloma (MM) is still an incurable hematological malignancy with a median survival of 4 years despite the use of various treatment options including thalidomide, lenalidomide, bortezomib, and hematopoietic stem cell transplantation [1,2]. The findings in molecular mechanisms that lead to MM and its progression have lead to the clarification of molecular targets of this disease and may contribute to the development of new biological targeted therapies for MM [3]. For the past 30 years, many natural products derived from plants and marine have provided leading structures for developing new agents with enhanced biological properties and less toxicity than chemotherapeutic agents [7,8]. Many natural products induced apoptosis of human cancer cells through the basic molecular mechanisms that take place in cancer [9,10]. It is our hypothesis that the novel therapeutic agents with anti-inflammatory activity may prolong MM progression and overcome drug resistance
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