%0 Journal Article
%T HSP90 inhibitor, celastrol, arrests human monocytic leukemia cell U937 at G0/G1 in thiol-containing agents reversible way
%A Bin Peng
%A Limin Xu
%A Fanfan Cao
%A Tingxuan Wei
%A Chunxin Yang
%A Georges Uzan
%A Denghai Zhang
%J Molecular Cancer
%D 2010
%I BioMed Central
%R 10.1186/1476-4598-9-79
%X Celastrol affected the proliferation of U937 in a dose-dependent way, arresting the cell cycle at G0/G1 with 400 nM doses and triggering cell death with doses above 1000 nM. Cell cycle arrest was accompanied by inhibition of HSP90 ATPase activity and elevation in HSP70 levels (a biochemical hallmark of HSP90 inhibition), a reduction in Cyclin D1, Cdk4 and Cdk6 levels, and a disruption of the HSP90/Cdc37/Cdk4 complex. The observed effects of celastrol on the U937 cell cycle were thiol-related, firstly because the effects could be countered by pre-loading thiol-containing agents and secondly because celastrol and thiol-containing agents could react with each other to form new compounds.Our results disclose a novel action of celastrol-- causing cell cycle arrest at G0/G1 phase based upon thiol-related HSP90 inhibition. Our work suggests celastrol's potential in tumor and monocyte-related disease management.Cancer therapy targeting HSP90 has shown great promise [1,2]. A wide range of oncogenic client proteins crucial for oncogenesis are stabilized, matured by, and thus dependent on HSP90. The harsh environmental conditions found in tumors, such as hypoxia and low pH, as well as outside factors, such as poor nutrition, tend to destabilize proteins and further their dependence on HSP90. This hypothesis is supported by the higher HSP90 levels found in tumor cells, which can comprise as much as 4-6% of cellular proteins in contrast to the 1-2% seen in normal cells [3,4]. When used as a single agent or in combination with chemotherapy, HSP90 inhibitors have shown anti-tumor effects in cellular studies, animal model studies, and clinical evaluations [5-7]. However, it is too early for many of these inhibitors or their derivatives to have received Food and Drug Administration approval. In this sense, research on novel HSP90 inhibitors is attractive.Natural substances are often key components of HSP90 inhibitors [8]. After geldanamycin, a natural product isolated from the bacte
%U http://www.molecular-cancer.com/content/9/1/79