The Antitumor Effect Of A Hybrid Platinum Drug DCA-Pt(Ⅱ)

The platinum anticancer drugs represented by cisplatin is applied in clinic widely.In the standardize cancer treatment protocols,the proportion of the directly or indirectly application of platinum has been 50%.While the serious toxicity and resistance of cisplatin cause unnecessary restriction on its further usage.Therefore,the platinum anticancer drug discovery has been focus on the formation of diverse cisplatin ligands coordination,the intracellular signaling pathways,cell cycle control,cell apoptosis,the interaction between cancer cells and extracellular matrix components,to reduce the side effects and overcome drug resistance.Most tumors have a unique glycolytic metabolism,known as the Warburg effect,which is associated with resistance to apoptosis that enables cancer cells to survive.Dichoroacetate(DCA)has been proved to reverse the Warburg effect by inhibiting a key enzyme in cancer cells,pyruvate dehydrogenase kinase(PDK),that is required for the process.In view of the characteristics of cisplatin and DCA,DCA-Pt(Ⅱ)was synthesised.It is a new kind of platinum molecules,which contains the main structure groups of cisplatin and DCA.We hope that the DCA-Pt(Ⅱ)can be able to own the both functions of cisplatin and DCA,which is targeted to the DNA and mitochondria separately.By means of this way,DCA-Pt(Ⅱ)is expected to have a batter inhibition of tumor and to overcome cisplatin resistance.In this study,A2780 and A2780/DDP was the main study objects.From two aspects of the toxicity and resistance,we studied the effect of DCA-Pt(Ⅱ)on cell proliferation,apoptosis,cell cycle and mitochondria function.The study not only provided a new platinum molecule based on cisplatin and DCA,but also plugged the gap of this type of platinum’s toxicity and resistance on A2780 and A2780/DDP cells.In this study,we adopted a serious of strictly designed experiments,analysis techniques,data statistics and comparative analysis,and obtained the following results:DCA-Pt(Ⅱ)exhibited remarkably cytotoxicity against both cisplatin-sensitive(A2780)and cisplatin-resistant(A2780/DDP)ovarian cancer cells.Platinum and Pt-DNA adducts contents test showed that less platinum cellular uptake and fewer Pt-DNA adducts present after DCA-Pt(Ⅱ)treatment compared with cisplatin,carboplatin and some other drugs.In the end,the effects of DCA-Pt(Ⅱ)on cell cycle and apoptosis were investigated,which showed that DCA-Pt(Ⅱ)induced S phase arrest,and mitochondrial-mediated apoptosis in both sensitive and resistant cells lines.Interestingly,DCA-Pt(Ⅱ)produced much greater effects on mitochondria in A2780/DDP cell lines than A2780 cell lines.