Celastrol induce apoptosis of human multiple myeloma cells involving inhibition of proteasome activity.
Celastrol exhibits anticancer activity and has a number of potential molecular targets. Among them, the proteasome has attracted particular attention. Although celastrol inhibits multiple myeloma (MM) cell proliferation, the induction of proteasome-inhibitory activity by celastrol in MM cells at the cellular level and in tumors of mice bearing xenografts has not been confirmed. In the present study, we found that celastrol inhibited the caspase-like (β1), trypsin-like (β2) and chymotrypsin-like (β5) proteasome activities of purified human 20S proteasomes, with half-maximal inhibitory concentration (IC50) values of 7.1, 6.3, and 9.3 μmol/L, respectively. Celastrol also inhibited human MM cellular β1, β2, and β5 proteasome activities, with IC50 values of 2.3, 2.1, and 0.9 μmol/L, respectively. After MM cells were treated with celastrol, a population of apoptotic cells and a population of cells in G0/G1 were observed. Celastrol also inhibited proteasome activity and induced apoptosis in tumor tissue. Treatment of MM.1S and RPMI 8226 tumor-bearing severe combined immunodeficiency (SCID) mice with celastrol reduced the tumor volume. In conclusion, our results reveal the effects of celastrol on proteasome activity in MM cells and shed light on the underlying mechanisms of its anticancer activity, providing a basis for developing celastrol as a potential therapeutic agent for MM.
['Zhong|Yue-Ling|YL|', 'Xu|Gao-Jie|GJ|', 'Huang|Sheng|S|', 'Zhao|Li|L|', 'Zeng|Yan|Y|', 'Xiao|Xiao-Fan|XF|', 'An|Jing-Lin|JL|', 'Liu|Jin|J|', 'Yang|Tai|T|']
D000818:Animals D017209:Apoptosis D045744:Cell Line, Tumor D049109:Cell Proliferation D005260:Female D059585:G1 Phase Cell Cycle Checkpoints D006801:Humans D051379:Mice D009101:Multiple Myeloma D053978:Pentacyclic Triterpenes D046988:Proteasome Endopeptidase Complex D061988:Proteasome Inhibitors D016192:Resting Phase, Cell Cycle D014315:Triterpenes D023041:Xenograft Model Antitumor Assays
Celastrol Apoptosis Multiple myeloma Proteasome