Study On The Mechanism And Mechanism Of Tumor Multidrug Resistance Reversing Small Molecule H6 And Mogrol

Multiple drug resistance (multidrug resistance;MDR) is a phenomenon that human tumours that acquire resistance to one type of drug are often found to be cross-resistant to a whole range of drugs never exposed to and with quite different structure and mode of action. The development of MDR to chemotherapy remains a major challenge in the treatment of cancer. To overcome MDR characteristics of tumor cells to chemotherapeutic agents, researchers have been looking for effective inhibitors of MDR, which are also known as MDR modulators, reversal agents or chemotherapy sensitizer. In recent years, a variety of natural products were found to reverse the MDR of cancer cells. Screening high efficiency and low toxicity MDR reversal agents from natural products is becoming more and more important in the medical profession for their low cytotoxity and good safety.In our study, we selected a library of nature products and characterized the reversal activity of H6%Mogrol、Z88and H5in human oral carcinoma and breast cancer multi-drug resistance cell line KB/VCR and MCF-7/ADR in vitro. In this thesis, we focused on the role of Gypenoside H6and Siraitia grosvenorii Swingle sponin Mogrol in the reversal of MDR and their internal mechanism.H6was prepared from gypenoside XLIX by alkaloid hydrolysis. As the our results showed, H6could reverse the MDR of the resistant cancer cell line、increase the sensitivity of KB/VCR and MCF-7/ADR cells to chemotherapy drugs and promote ADR and VCR induced G2/M arrest and apoptosis. Colony formation assay indicated that H6enhanced proliferation inhibition of ADR and VCR to KB/VCR and MCF-7/ADR cells. MDR related proteins P-gp, MRP1and ABCG2were overexpressed in KB/VCR and MCF-7/ADR cells, suggested that H6could reverse the MDR via modulating their function and expression. Therefore, we detected the affection of H6on the accumulation of their specific substrates Rho123, CFDA and Mitoxantone in further study. The results investigated that, H6increased the accumulation of P-gp substrates Rho123in MDR cells by inhibiting the transport function of P-gp. H6could also inhibit the transport function of MRP1and increase its specific substrate CFDA accumulation. H6also reduced the expression level of MRP1by inhibiting the phosphorylation of STAT3. H6had no effect on the activity of ABCG2and the expression of P-gp and ABCG2.Mogrol is an aglycone of sponins from Siraitia grosvenorii Swingle, such as IA1、 ⅠE1、ⅡE、Ⅲ、Ⅳ、ⅣE and Ⅴ. Our study found the reversal activity of Mogrol on multidrug resistance. Mogrol could increase the sensitivity of KB/VCR and MCF-7/ADR cells to chemotherapy drugs, promote ADR induced G2/M arrest in MCF-7/ADR cells and enhance the apoptosis of KB/VCR cells induced by VCR. The research on the mechanism of Mogrol reversal activity revealed that Mogrol increased the accumulation of Rho123in KB/VCR and MCF-7/ADR cells via modulating the ATPase activity of P-gp. Mogrol had no significant effect on the activity of MRP1and ABCG2protein. Mogrol reduced the expression level of both P-gp and MRP1but no effect on ABCG2expression.In conclusion, our research found the reversal activity of H6and Mogrol on multidrug resistant cell line KB/VCR and MCF-7/ADR. These new findings provide new candidate compounds for MDR inhibitors. The research on the mechanism of the MDR reversal activity of H6and Mogrol provide a theoretical basis for the further development and utilization of both compounds. Our results developed a new field of application for traditional Chinese medicine, Gynostemma Pentaphyllum and Siraitia grosvenorii Swingle, improved their medicinal value and economic value.