Screening Anticancer Of Dihydroartemisinin Derivatives And Study Its Underlying Mechanism

Objective To investigated cell growth inhibition and study its underlying mechanism of a series of dihydroartemisinin derivatives.Methods The antiproliferative effects against human breast cancer MCF-7 cell line, adriamycin resistant cell line MCF-7/Adr and MDA-MB-231 cell line of all 20 artemisinin derivatives were determined by MTT assay. We selected one representative candidate compound. Flow Cytometry and Western Blotting method to determine its underlying anti-human breast cancer MCF-7, MCF-7/Adr cell line mechanism. Embarked DHX01 to conduct antitumor activity in vivo towards MDA-MB-231 xenograft model.Results For MCF-7cells line, IC50 values ranged from0.192 ?M to 0.571 ?M. The antiproliferative effects were more potent than the lead compound DHA but weaker than positive control doxorubicin(Adr). DHX01 and DHX03 presented to be the most potent arteminsin ethers with IC50 values of 0.213±0.55 ?M and 0.192±0.03 ?M;20 dihydroartemisinin derivatives showed preferable activity and selectivity than DHA and Adr against MCF-7/Adr cells, with IC50 values ranging from 0.017 ?M to 0.41 ?M and the selective ratios(SR) 3.5~20, Among them, DHX01, DHX05, DYX01 showed significant antiproliferative effects against MCF-7/Adr cells with IC50 values about 20 nM. The IC50 values of 20 compounds ranged from 0.2 ?M to 1.4 ?M against MDA-MB-231 cells. DHX01 and DHX02 showed significant antiproliferative effects. The concentrations of 0.1 ?M, 0.5 ?M, 1 ?M and 0.01 ?M, 0.05 ?M, 0.1 ?M DHX01 in MCF-7 and MCF-7/Adr caused G0/G1 phase arrestin in a time and dose-dependent manner. The concentrations of 0.25 ?M, 0.5 ?M in a time and dose-dependent manner decreased the expression cyclin D1 and in a time-dependent decreased the expression cyclin B1 while increased p27. The level of cyclin D1 and cyclin B1 could be downregulated, increased p27 by DHX01 at the concentrations of 0.025 ?M, 0.05 ?M in MCF-7/Adr cells. DHX01 treatment finally caused G0/G1 phase arrest without altering P-gp. DHX01 exhibited inhibiton ratios of 33.3%, 44.86% and 73.25% respectively, and T/C% in high dose group reached 38.22%.Conclusions Dihydroartemisinin derivatives exhibited growth inhibitory effect towards human breast cancer MCF-7 cell line, adriamycin resistant cell line MCF-7/Adr and MDA-MB-231 cell line and showed significant antiproliferative effects against MCF-7/Adr cells, which could be selected for further study about MDR cells; DHX01 decreased the expression of both cyclin D1 and cyclin B1, while increased p27 to cause G0/G1 phase arrest and consequent growth inhibition in MCF-7/Adr and MCF-7 cell line. DHX01 treatment finally caused G0/G1 phase arrest without altering P-gp; DHX01 exhibited inhibiton ratios of 33.3%, 44.86% and 73.25% respectively, and T/C% in high dose group reached 38.22%, which was close to the cancer therapeutically effective standard and worth further study.