| To investigate the anticancer effect of dihydroartemisinin through the inhibition of the phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt) pathway in multiple myeloma(MM) cells.Methods:U266 and RPMI8226 cells were cultured in vitro and randomly divided into the following groups according to the random number table method:control group,dihydroartemisinin(40 μmol/L) group,dihydroartemisinin(40 μmol/L)+N-acetyl-L-cysteine(NAC)(ROS scavenger,5 mmol/L) group,and dihydroartemisinin(40 μmol/L)+insulin-like growth factor 1(IGF-1)(PI3K/Akt activator,100 μg/L) group.After treatment with dihydroartemisinin,NAC,and IGF-1,cell proliferation inhibition rates and apoptosis rates were determined by CCK-8 assay and flow cytometry.The levels of reactive oxygen species(ROS),superoxide dismutase(SOD),and catalase(CAT) were measured.Western blot was used to detect the expression of proliferation cell nuclear antigen(PCNA),Bcl2-associated X protein(Bax),caspase-9,cleaved caspase-9,caspase-3,cleaved caspase-3,and proteins related to the PI3K/Akt pathway.U266 and RPMI8226 cell xenograft models were established in nude mice,and tumor volume and weight were measured.Results:Compared with the control group,the dihydroartemisinin group showed significantly decreased levels of SOD(11.13±1.22 vs.2.08±0.36,11.33±1.41 vs.2.08±0.36)U/mg and CAT(7.98±0.86 vs.1.29±0.13,7.74±0.85 vs.1.13±0.19)U/mg,reduced PCNA expression(1.31±0.23 vs.0.41±0.06,1.14±0.20 vs.0.33±0.04),and declining levels of p-PI3K/PI3K(0.77±0.10 vs.0.13±0.03,0.84±0.12 vs.0.17±0.04),p-Akt/Akt(0.83±0.13 vs.0.18±0.04,0.91±0.16 vs.0.19±0.03),tumor volume(1 479.73±50.18 vs.460.54±37.62,1,397.86±48.21 vs.359.71±39.40)mm3,and tumor weight(0.76±0.12 vs.0.22±0.07,0.69±0.10 vs.0.16±0.05)g(P<0.05).The cell proliferation inhibition rate(0.00±0.00 vs.51.15±9.93,0.00±0.00 vs.48.16±10.12)%,apoptosis rate(1.60±0.39 vs.55.18±9.74,1.49±0.36 vs.53.10±9.45)%,ROS levels(1.00±0.00 vs.12.90±1.64,1.00±0.00 vs.13.12±2.69),and expression of Bax(0.55±0.10 vs.1.28±0.19,0.43±0.11 vs.1.19±0.13),caspase-9(0.33±0.05 vs.1.24±0.17,0.30±0.05 vs.1.16±0.18),cleaved caspase-9(0.22±0.06 vs.0.89±0.11,0.20±0.05 vs.0.86±0.10),caspase-3(0.18±0.05 vs.0.78±0.09,0.17±0.04 vs.0.74±0.08),and cleaved caspase-3(0.11±0.03 vs.0.70±0.08,0.10±0.02 vs.0.67±0.07) were significantly increased(P<0.05).Both IGF-1 and NAC reduced the effect of dihydroartemisinin on MM cells.Conclusion:Dihydroartemisinin exerts anticancer effect by inhibiting the PI3K/Akt signaling pathway to promote ROS production,decrease antioxidant enzyme activity,and inhibit MM cell proliferation and tumor growth in nude mice,thereby inducing ROS-dependent cell apoptosis. |
