Anovel Gstm Inhibitor Rescue The Sensitivity Of Human Ovary Cancer Cells To Ddp And The Underlying Mechnism Study

Ovarian cancer has the highest death rate in gynecology oncology, themain strategy of ovarian cancer therapy after operation is chemotherapy,for example, cisplatin(DDP) and adriamycin(ADM) are common drugs forchemotherapy, the first leading cause of chemotherapy failure isdrug-resistance of cancers in the process of treatment. Many researchesdemonstrate that GST isozyme family has responsibility to drug-resistance,in most solid cancers, GST isozyme (GSTP) is abundant while isozyme(GSTA) and (GSTM) are just detectable.EAD and BPD are monovalent pro-inhibitors of GSTM which weresynthesized in our laboratory, the product of EAD has strong potency andhigh isozyme-selectivity while product of BPD has low isozyme-selectivity.In this study, we tested whether EAD/BPD can effectively overcomeresistance to cisplatin of ovarian cancer SKOV3or COC1and theirpossible mechanism.By comparing the expression of GSTM and GSTA in SKOV3、SKOV3/DDP，COC1、COC1/DDP、LO2and HEK293cell lines, we found that expression of GSTM and GSTA in SKOV3/DDP and COC1/DDP arehigher than other cell lines, hence, over-expression of GSTM and GSTA isclosely related to resistance of SKOV3and COC1to DDP. Further more,SKOV3/DDP and COC1/DDP became sensitive to DDP after GSTM wasknocked out by siRNA.Cells were treated with DDP and EAD/BPD in different concentrationfor72h respectively, then the growth inhibiting effects were detected byCCK-8assay and IC50was determined for the sake of figure up the reverserate. The result illustrates that EAD/BPD could let drug-resistance cell besensitive to DDP as same as normal cells. And death rate was tested withFCM, it also indicate inhibitor can overcome resistance to DDP ofSKOV3/DDP and COC1/DDP. Activation of apoptosis signal triggered byinhibitors plus DDP in SKOV3/DDP and COC1/DDP were detected byWestern-Blot and the pro-apoptotic proteins like caspase-3、bak、bax areup-regulated while anti-apoptotic proteins like bcl-2、bcl-xl have reducedtheir expression obviously.In conclusion, over-expression of GSTM and GSTA is closely relatedto resistance of SKOV3and COC1to DDP, GST inhibitors may provideassistance for further study on tumor drug sensitization agent.