The Study Of Berberine-cisplatin Conjugate Inhibiting Cancer Growth And Its Mechanism Of Action Preliminarily

The classic bivalent platinum(Pt(Ⅱ))drugs(cisplatin,carboplatin,oxaliplatin)as one of the most representative drugs in the field of tumor chemotherapy,has a milestone significance for the development of chemotherapy.However,the serious side effects and drug resistance limit the further application of Pt(Ⅱ)in clinic.Some studies have introduced bioactive molecules with different functions into the synthesis of tetravalent platinum complexes(Pt(Ⅳ))in axial position,which provides a new idea for improving the defects of Pt(Ⅱ)platinum drugs.In this paper,based on the previous research of our group,we found that berberine has good anticancer effect,safety and tumor selectivity.We introduced berberine into the axial position of Pt(Ⅳ)with cisplatin or oxaliplatin as the mother nucleus respectively,in order to obtain a new Pt(Ⅳ)prodrug with high efficiency,low toxicity,no cross resistance with cisplatin and potential application prospect.In vitro cytotoxicity test showed that berberine cisplatin conjugate(B-D)had significantly better anticancer activity than cisplatin on human colon cancer cells,lung cancer cells,ovarian cancer cells A2780 and cisplatin resistant ovarian cancer cells,which were about 8 times,7 times,6 times and 14 times of cisplatin,respectively.What’s more,the toxicity of normal intestinal epithelial cells is very small(IC50 is about 250 μM).Based on the drug design of new Pt(Ⅳ)prodrug,the anticancer activity of B-D was enhanced,and the biological selectivity of berberine was retained.The preliminary mechanism of action showed that B-D caused DNA damage,and apoptosis by inducing p53,cleaved-PARP and cleaved-caspase 3 up regulated.In addition,B-D also affects cell cycle.Further research shows that B-D can greatly improve the platinum accumulation in a variety of cancer cells.But the accumulation of Pt in normal intestinal epithelial cells was not significantly increased by B-D as that of cancer cells.We combined ATP enzyme inhibitor(Oligomycin A)with B-D,found that the accumulation of platinum in cancer cells decreased by about 80%,which proved that B-D mainly depends on energy to enter cancer cells.Interestingly,Oligomycin A has little effect on B-D entering normal intestinal epithelial cells.It indicates that B-D has different transport modes for normal cells and cancer cells.In the nude mice transplantation,B-D also showed stronger antitumor ability than cisplatin,and had no hepatorenal toxicity and good safety.