The Anti-tumor Activity Of CypA Inhibitor And Proposed Binding Model For CypA-Activator Complex

Cyclophilin A (CypA), which has the activity of peptidylprolyl cis-trans isomerase, is a cytosolic binding protein of the immunosuppressive drug CsA. CypA plays an important role in protein folding, transportation, assemble, immune modulation and cell signaling, and the over expression of CypA involves in many diseases including immune disease, viral infection, cancer and so on.In this paper, we studied the anti-tumor activity of CypA inhibitors in six cancer cells. We found several compounds that displayed good inhibition on CypA in vitro, showed antiproliferative activity on cancer cells. From the above compounds, we investigated the anti-tumor mechanism of compound 1 and found it could block the H446 cell at S phase in cell cycle. The results of proteomic analysis, western blot and RNAi analysis showed that compound 1 could down-regulation the expression of CypA, which consequently down-regulated Protein 1 and inhibited proliferation of the H446 cell, but a further investigated is still needed to understand the exactly mechanism.Besides CypA inhibitors, we found an activator of cyclophilin A - compound la luckily. We constructed a possible binding model of CypA-activator complex by site mutation and computer simulation, and hoped it could be used for the development of CypA activators. The result of western blot showed that the inhibition of ERK phosphorylation which caused by CsA could be relieved by compound la in dose dependent in H446 cell. The above results suggested that compound la may be used to relieve the CsA hypermedication.