ObjectiveTo investigate whether low-dose fractionated radiation (LDFRT) could enhance cisplatin sensitivity in drug-resistant human ovarian cancer cells SKOV3/DDP, and to further explore the underlying mechanism.MethodsSKOV3/DDP ovarian cancer cells were divided into three groups as follows: control, LDFRT, and conventional-dose radiation groups. Cells from all three groups were treated with different concentrations of cisplatin (0, 1.25, 2.5, 5, 10, and 20 µg/mL) for 48 h. The proliferation inhibition rate was investigated using the cell counting kit 8 (CCK8). The rate of apoptosis was determined by flow cytometry (FCM). Protein levels of AKT, P-AKT, GSK-3β, P-GSK-3β, P21, cyclin D1, and P27 were examined by Western blotting.ResultsAs expected, LDFRT significantly reduced the half-maximal inhibitory concentration (IC50) of cisplatin and promoted apoptosis in SKOV3/DDP cells. Moreover, in the LDFRT group, protein levels of P-AKT, P-GSK-3β, and cyclin D1 were markedly decreased, those of P21 and P27 were greatly increased, and total AKT and GSK-3β levels showed no significant difference compared to those in both the control and conventional-dose radiation groups.ConclusionLDFRT sensitizes resistant SKOV3/DDP ovarian cancer cells to cisplatin through inactivation of PI3K/AKT/GSK-3β signaling.