The Function And Mechanism Of Platinum-containing Compound Platinum Pyrithione In Ovarian Tumor Therapy

Background and ObjectiveOvarian cancer mortality among the top of the gynecology malignant tumor and to improve the survival of patients with diffuse ovarian cancer.especially those with activated epithelial ovarian cancer(EOC),Therefore it is urgent to search for novel agents for the treatment of epithelial ovarian cancer(EOC),In recent years,with proteasome inhibitors Velcade used in diseases such as multiple myeloma and mantle cell lymphoma has achieved good results,Inhibition of proteasome-associated deubiquitinases(DUBs)is emerging as anovel strategy for cancer therapy.In the present study,platinum pyrithione(PtPT),a chemically well-characterized synthetic complex of platinum,inhibits proteasome function and thereby exhibits greater and more selective cytotoxicity to Lung cancer cells and leukemia cells than cisplatin,without showing discernible DNA damage both in vitro and in vivo.We found that PtPT induced growth inhibition and apoptosis of both A2780 and SKOV3 cell lines in vitro and in vivo,which is associated with proteasome malfunction.These findings provide significant pre-clinical evidence for potential usage PtPT,Therefore,PtPT is a possible potential candidate for the treatment of ovarian cancer.In the preliminary study of the study group,a transition metal complexes are synthesized with pyrithione and their abilities to inhibit proteasomal deubiquitinases and carcinoma of the lungs are investigated in vitro and in vivo.PtPT primarily deactivates 26 S proteasome-associated deubiquitinases USP14 and UCHL5.In most of the ovarian cancer tissues,UCHL5 expression has raised,and whether UCHL5 expression or not is an independent prognostic factor.It is hoped that alternative proteasome inhibitors with different selectivities for proteasome subunits,enhanced or prolonged potencies,or reduced side effects will generate more satisfying effects on ovarian cancer.Methods and resultsIn Cell viability assaywe found that the selectivity PtPT induced tumor cell death,which showed More sensitive than cisplatin tumor cell.By the cell cycle flow detection we found treatment of A2780 and SKOV3 cells with PtPT resulted in a significant increase in the proportion of cells at the G2/M phase.As for Western bloting testing,we found that PtPT endoplasmic reticulum stress can induce ovarian tumor cells,mitochondrial membrane potential decreased,the way such as casepase activation induced apoptosis,while most casepase pathway inhibitor Z-vad can reverse cell death induced by PtPT,suggests that the proteasome function is necessary to induce cell apoptosis.At the same time,the Western Blot results show PtPT can induce ovarian cancer cells of ubiquitin protein aggregation and occurred before the induction of apoptosis,These results show that the apoptosis induced by PtPT occurs after the proteasome inhibition.In A2780 and SKOV3 cells in nude mice transplantation tumor animal models of experiments,we found that PtPT can significantly inhibit the growth of tumor tissue,as well as the experimental animals had no effect on weight,western blot results showed that treatment with the PtPT increased the levels of Ub-prs,K48 and cleaved PARP Similarly to the western blot results,The immunostaining analysis was performed to detect the effect of PtPT on in vivo proteasome function.Ub-prs,K48,Bax and activated caspase-3 proteins were all significantly increased in the PtPT treated tumors.Together,these results demonstrate that PtPT selectively inhibits proteasome function and tumor growth in vitro and in vivo.Conclusions 1.PtPT induces ovarian cancer cell proliferation inhibition in vitro by inhibiting the proteasome-associated DUBs.2.PtPT inhibits the proteasome-associated DUBs andovarian tumor growth in vivo.