The reversal effect of magnetic Fe3O4 nanoparticles loaded with cisplatin on SKOV3/DDP ovarian carcinoma cells

Abstract

Zhi Jiang1,6, Bao-An Chen1,6, Guo-Hua Xia1, Qiang Wu2, Yu Zhang1, Tie-Yan Hong1, Wei Zhang1, Jian Cheng1, Feng Gao1, Li-Jie Liu3, Xiao-Mao Li4, Xue-Mei Wang51Department of Hematology, the Affiliated Zhongda Hospital of Southeast University, Nanjing, China; 2The Jiangsu Province Cancer Hospital, Nanjing, China; 3Institutions of Physiology, Southeast University, Nanjing, China; 4Department of Physics, University of Saarland, Saarbruechen, Germany; 5National Key Lab of Bioelectronics (Chien-Shiung Wu Laboratory), Southeast University, Nanjing, China; 6These authors have contributed equally to this workAbstract: To explore whether the magnetic nanoparticles of Fe3O4 (MNPs-Fe3O4) loaded with cisplatin can reverse the diaminedichloro platinum (DDP) resistance to multidrug resistance of ovarian carcinoma cells and to investigate its mechanisms. The SKOV3/DDP cells were divided into DDP treatment (DDP group), MNPs-Fe3O4 treatment (MNPs-Fe3O4 group), DDP + MNPs-Fe3O4 treatment (DDP + MNPs-Fe3O4 group), and control group. After incubation with those conjugates for 48 h, the cytotoxic effects were measured by MTT assay. Apoptosis and the intracellular DDP concentration were investigated by flow cytometry and inductively coupled plasma atomic emission spectroscopy, respectively. The expression of apoptosis associated gene Bcl-2 mRNA was detected by reverse transcription polymerase chain reaction and the expressions of MDR1, lung resistance-related protein (LRP), and P-glycoprotein (P-gp) genes were studied by Western blot. Our results indicated that the 50% inhibition concentration (IC50) of the MNPs-Fe3O4 loaded with DDP was 17.4 µmol/ l, while the IC50 was 39.31 µmol/l in DDP groups (p < 0.05); Apoptosis rates of SKOV3/DDP cells increased more than those of DDP groups. Accumulation of intracellular cisplatin in DDP + MNPs-Fe3O4 groups was higher than those in DDP groups (p < 0.05). Moreover, the expression of Bcl-2 mRNA and the protein expressions of MDR1, LRP, and P-gp were decreased when compared with those of DDP groups, respectively. Our results suggest that MNPs-Fe3O4 can reverse the DDP resistance to the ovarian carcinoma cell. The effects may be associated with over-expression of MDR1, LRP, P-gp, and Bcl-2, which can increase the intracellular platinum accumulation and induce the cell apoptosis.Keywords: magnetic nanoparticles of Fe3O4 , multidrug resistance reversal, SKOV3/DDP, MDR1, LRP, P-gp, Bcl-2